Chemistry and Properties of Indolocarbazoles - Chemical Reviews

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Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

Chemistry and Properties of Indolocarbazoles Tomasz Janosik,*,† Agneta Rannug,‡ Ulf Rannug,§ Niklas Wahlström,∥ Johnny Slätt,⊥ and Jan Bergman*,@ †

Research Institutes of Sweden, Bioscience and Materials, RISE Surface, Process and Formulation, SE-151 36 Södertälje, Sweden Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden § Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden ∥ MagleChemoswed, Celciusgatan 35, SE-212 14 Malmö, Sweden ⊥ Department of Chemistry, Applied Physical Chemistry, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden @ Karolinska Institutet, Department of Biosciences and Nutrition, SE-141 83 Huddinge, Sweden

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‡

ABSTRACT: The indolocarbazoles are an important class of nitrogen heterocycles which has evolved significantly in recent years, with numerous studies focusing on their diverse biological effects, or targeting new materials with potential applications in organic electronics. This review aims at providing a broad survey of the chemistry and properties of indolocarbazoles from an interdisciplinary point of view, with particular emphasis on practical synthetic aspects, as well as certain topics which have not been previously accounted for in detail, such as the occurrence, formation, biological activities, and metabolism of indolo[3,2-b]carbazoles. The literature of the past decade forms the basis of the text, which is further supplemented with older key references.

CONTENTS 1. Introduction 1.1. Background 1.2. Historical Perspective 1.3. Scope 2. Indolo[2,3-a]carbazoles 2.1. Synthesis and Reactions 2.2. Indolo[2,3-a]carbazole Natural Products: Occurrence and Biosynthesis 2.2.1. Biosynthesis and Isolation of Indolo[2,3a]carbazole Natural Products 2.2.2. Indolo[2,3-a]carbazoles by Combinatorial Biosynthesis 2.3. Selected Synthetic Bioactive Indolo[2,3-a]carbazoles 2.4. Indolo[2,3-a]carbazole Based Materials for Anion Complexation 2.4.1. Anion Binding Studies Featuring Indolo[2,3-a]carbazole-Containing Host Molecules 2.4.2. Rotaxanes, Pseudorotaxanes, and Catenanes 2.4.3. Foldamers 2.5. Miscellaneous Studies Involving Indolo[2,3a]carbazoles 3. Indolo[3,2-a]carbazoles 3.1. Synthesis and Reactions 3.2. Indolo[3,2-a]carbazole Natural Products 3.3. Applications of Indolo[3,2-a]carbazoles as Functional Materials 4. Indolo[2,3-b]carbazoles © XXXX American Chemical Society

4.1. Synthesis and Reactions 4.2. Bioactive Indolo[2,3-b]carbazoles 4.3. Miscellaneous Applications and Studies 5. Indolo[3,2-b]carbazoles 5.1. Synthesis and Reactions 5.2. Naturally Occurring and Bioactive Indolo[3,2-b]carbazoles: Biosynthesis and Metabolism 5.2.1. Introduction and Background 5.2.2. Indolo[3,2-b]carbazole (ICZ) 5.2.3. 6-Formylindolo[3,2-b]carbazole (FICZ) 5.2.4. Indolo[3,2-b]carbazoles as Natural Aryl Hydrocarbon Receptor (AHR) Ligands 5.3. Indolo[3,2-b]carbazoles in Materials Science and Related Applications 5.4. Indolo[3,2-b]carbazole Polymers 6. Indolo[2,3-c]carbazoles 6.1. Synthesis and Reactions 6.2. Applications and Miscellaneous Studies 7. Overall Conclusions and Perspectives Author Information Corresponding Authors ORCID Notes Biographies References

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Received: March 23, 2018

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DOI: 10.1021/acs.chemrev.8b00186 Chem. Rev. XXXX, XXX, XXX−XXX

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Figure 1. Five indolocarbazole isomers, with atom numbering indicated.

1. INTRODUCTION 1.1. Background

There are five generally recognized indolocarbazole isomers, distinguished by the position and orientation of the fusion between the indole (at the C-2−C-3 bond) with one of the benzene rings of the carbazole unit, named according to the IUPAC nomenclature rules as 11,12-dihydroindolo[2,3-a]carbazole (1), 5,12-dihydroindolo[3,2-a]carbazole (2), 5,7dihydroindolo[2,3-b]carbazole (3), 5,11-dihydroindolo[3,2-b]carbazole (4), and 5,8-dihydroindolo[2,3-c]carbazole (5) (Figure 1). Although there are also other possible arrangements involving an indole and a carbazole core to form a fused pentacyclic system, these are rather rare and are usually not embodied in the “classical” indolocarbazole concept. The indolocarbazoles have been previously subject to a general and comprehensive review, covering the literature of the 20th century,1 which was followed by an update featuring new developments until the year 2007.2

Figure 2. Structures of K-252a (6) and rebeccamycin (7).

well as 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (8)25,26 (commonly referred to in the literature as 6formylindolo[3,2-b]carbazole (Figure 3), or FICZ, particularly

1.2. Historical Perspective

Most of the early developments in the field of indolocarbazoles were devoted to fundamental synthetic aspects. Despite a few prominent pioneering achievements from that period, such as the first practical protocol for preparation of 5,11dihydroindolo[3,2-b]carbazole (4) by Robinson from 1963,3 the overall progress at that time was rather slow, with fragmentary studies scattered over several decades, and an obvious lack of systematic and general approaches.1 However, this changed radically in the nineties, following reports from the late eighties that several naturally occurring members belonging to the indolo[2,3-a]carbazole family had been isolated and demonstrated to display interesting biological effects.4 The alkaloid K-252a (6), a potent inhibitor of protein kinase C5,6 isolated from culture broths of Actinomadura sp. SF23707 and Nocardiopsis sp. K-252,8 also early recognized as a challenging synthetic target,9,10 serves as an illustrative example (Figure 2). The same is true for the antitumor natural product rebeccamycin (7),11−13 which is one of the most influential indolo[2,3a]pyrrolo[3,4-c]carbazole derivatives with tremendous impact on subsequent research activities, which rapidly established the indolo[2,3-a]carbazole as the most intensely studied isomer. The indolo[2,3-a]pyrrolo[3,4-c]carbazoles have been reviewed thoroughly over the years, focusing not only on general aspects4,14−18 but also on more specialized topics such as biosynthesis19−21 and development of rebeccamycin analogues as anticancer agents.22,23 As a result of extensive studies of the aryl hydrocarbon receptor (AHR), it was discovered that the parent system 4,24 as

Figure 3. Structure of 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (8, FICZ).

in biologically oriented publications), are both powerful ligands for the AHR. Numerous subsequent biological and synthetic studies ensued,1,2 and the indolo[3,2-b]carbazole core may now be considered as a new emerging scaffold for drug development due to the diverse biological effects displayed by this compound class. In addition, the indolo[3,2-b]carbazoles have also been identified as a new class of functional materials,27 driving the frontiers of this field even further. The remaining three isomers, namely ring systems 2, 3, and 5, have received only very limited attention prior to the turn of the century, when the development of the first practical synthetic routes to simple derivatives of 5,12-dihydroindolo[3,2-a]carbazole (2),28 and 5,8-dihydroindolo[2,3-c]carbazole (5)29 set the stage for succeeding approaches. However, the chemistry and properties of these isomers are still rather unexploited. Although plausible reports on derivatives of the perhaps least studied isomer 5,7-dihydroindolo[2,3-b]carbazole (3) appeared in the literature already in the sixties,1 for a long time, there was relatively little significant progress with the exception of two concise syntheses of the parent ring system.30,31 However, the discovery of SR13668 (9) (Figure 4) as a cancer chemopreventive agent,32 and the quest for new functional materials B


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2. INDOLO[2,3-A]CARBAZOLES 2.1. Synthesis and Reactions

Coverage of the early progress in the synthesis of indolo[2,3a]carbazoles has been included in several previous accounts.1,2,4,15 Many of the synthetic approaches from that time are still widely used, and the discussion in this section will therefore focus on highlighting selected methods for ring synthesis and functionalization, with the aim to illustrate the most general synthetic routes, particularly the most recent advances. The famous Fischer indole synthesis was used for the preparation of 11,12-dihydroindolo[2,3-a]carbazole (1) itself already in the late fifties38 and has also been later used successfully for construction of, for instance, indolo[2,3a]pyrrolo[3,4-c]carbazoles.39 As is evident from the examples discussed below, the Fischer indolization starting from cyclohexane-1,2-dione or suitable 2,3,4,9-tetrahydrocarbazole-1-one derivatives as the carbonyl synthons may lead to mixed results. Yields are sometimes low, and an additional dehydrogenation step is required occasionally. Moreover, regioselectivity issues may be encountered in applications involving m-substituted phenylhydrazines. Despite these obvious drawbacks, these approaches are still useful due to their brevity, operational simplicity, and the easy access to the required building blocks. Cyclization of the hydrazone derived from cyclohexane-1,2dione and two equivalents of phenylhydrazine in a mixture of acetic acid and trifluoroacetic acid (10:1 w/w) provides convenient access to the parent system 1 (41.8% yield, 28 g scale).40 In a study toward a method for quantifying host−guest binding affinities for anion receptors, 2-fold Fischer indole syntheses involving cyclohexane-1,2-dione (10) and the phenylhydrazine derivatives 11a−b provided the products 12a (60% yield, with concomitant formation of the dechlorinated side product 1-chloro-11,12-dihydroindolo[2,3-a]carbazole in 18% yield; not depicted) and 12b (28% yield) (Scheme 1).41 Further

Figure 4. Structure of SR13668.

based on structurally novel fused nitrogen heterocycles, gave new promise for further efforts toward this isomer, a development which is now starting to materialize. Obviously, the current direction is increasingly turning toward applications of indolocarbazoles in materials science, and continued efforts in drug development, with major focus on the well-studied isomers, as well as certain extended fused indolocarbazole systems. In addition, there is also a notable increase in research activities dedicated to the previously rather scantily studied isomers. As might easily be imagined, this is in turn acting as a catalyst for many new studies focusing on modern and efficient preparative routes for construction of these ring systems and new methods for their selective functionalization. The field is clearly taking advantage of the numerous advances in general synthetic organic chemistry and new refined analytical techniques that have evolved over time. Accordingly, there is currently a continuous output of new significant publications featuring indolocarbazoles, with very promising prospects for further fruitful evolution of the field. 1.3. Scope

The scope of this survey is to provide a broad critical coverage of the developments with particular emphasis on the synthetic aspects disclosed since our latest account,2 with older key references and reports of historical importance included when considered appropriate. As the indolo[2,3-a]pyrrolo[3,4-c]carbazoles bearing carbohydrate moieties have been accounted for in detail on numerous occasions elsewhere (see section 1.2 for references), only selected publications will be cited from that particular field in order to highlight some of the key developments. A special section about the aryl hydrocarbon receptor (AHR) is included in connection with the discussion of biologically active indolo[3,2-b]carbazoles, as the discussion of the biological effects of FICZ (8) and related compounds relies on a fundamental understanding of the function of the AHR. This particular topic will also receive a more detailed treatment compared to some other themes, as it has never been reviewed before in a comprehensive manner. Readers interested in a broader perspective may also want to consult the outstanding reviews on carbazoles by Knölker,33,34 which also contain sections dedicated to indolocarbazoles. Material published in journals will form the basis for our text. Coverage of the extensive patent literature relevant to this field is beyond the scope of this survey. The chemistry and properties of extended heteroaromatic systems featuring for instance indolocarbazole cores have been discussed in depth in an excellent account35 and will therefore only be treated briefly in appropriate sections of the text when considered appropriate. Finally, the triazatruxenes will not be discussed, as these systems have been reviewed recently.36,37

Scheme 1. Stepwise Synthesis of Indolo[2,3-a]carbazoles via Hydrazone Formation and Fischer Indolization Involving ortho-Substituted Phenylhydrazines

application of the double Fischer indolization of cyclohexane1,2-dione (10) and suitable phenylhydrazine derivatives provided for example 11,12-dihydroindolo[2,3-a]carbazole1,10-dicarboxylic acid (20% yield), 1,10-dibromo-11,12dihydroindolo[2,3-a]carbazole (32% yield),42 dibutyl 11,12dihydroindolo[2,3-a]carbazole-3,8-dicarboxylate (68% yield over two steps including a dehydrogenation with Pd/C in refluxing DMF), and 11,12-dihydro-3,8-dimethoxyindolo[2,3a]carbazole (18% yield).43 Compound 13 underwent conversion to a mixture of 11,12dihydro-2-nitroindolo[2,3-a]carbazole (11% yield) and its 4nitro-isomer (12% yield) (14a and 15a, Scheme 2), as well as the corresponding methoxy-derivatives 14b and 15b in yields of 38% and 9%, respectively, upon cyclization with the phenylhydrazine derivatives 16a−b; the latter synthesis requiring a dehydrogenation step with p-chloranil in refluxing toluene.41 C


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Scheme 2. Synthesis of Unsymmetrical Indolo[2,3-a]carbazoles by Fischer Indolization Involving meta-Substituted Phenylhydrazines

Scheme 3. Ether Cleavage and Carbonate Formation Leading to the Product 17

Scheme 4. Sequential Application of Two Different Phenylhydrazine Derivatives in a Fischer Indolization Approach Rendering an Unsymmetrically Substituted Indolo[2,3-a]carbazole

Scheme 5. Double Cadogan Cyclization Route to the Indolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazole System and Some Examples of Its Reactions

Application of 2-(trifluoromethyl)phenylhydrazine hydrochloride and 2,3,4,9-tetrahydro-1H-carbazol-1-one (13) as the reaction partners in a Fischer indole synthesis mediated by sulfuric acid in refluxing n-butanol, followed by dehydrogenation with p-chloranil in refluxing toluene gave 11,12-dihydro-1(trifluoromethyl)indolo[2,3-a]carbazole in 52% yield.44 A more recent study on the same theme resulted in preparation of a substantial set of symmetrical as well as unsymmetrical indolo[2,3-a]carbazoles in good yields, including 3-chloro11,12-dihydro- and 3,8-dichloro-11,12-dihydroindolo[2,3-a]carbazole (tjipanazoles I and D, in yields of 75% and 72%, respectively),45 which are natural products originally isolated from the blue-green alga Tolypothrix tjipanasensis.46 Both these compounds have also been efficiently synthesized previously.47

An illustration of the synthetic utility of 11,12-dihydro-2methoxyindolo[2,3-a]carbazole (14b) prepared as outlined above was demonstrated by its conversion to the corresponding hydroxy-derivative, and further to the carbonate 17, which was included in a screening of potential receptor molecules for carboxylate anion recognition (Scheme 3).48 In yet another example involving the intermediacy of a 2,3,4,9tetrahydrocarbazol-1-one derivative featuring two sequential Fischer indole syntheses, cyclohexane-1,2-dione (10) was first allowed to react with 4-hydrazinobenzoic acid (18) in n-butanol in the presence of sulfuric acid, followed by a cyclization with ptolylhydrazine. Subsequent dehydrogenation with Pd/C in hot DMF, followed by saponification of an intermediate butyl ester, provided the system 19 in good overall yield en route to a D


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Scheme 6. Alternative Approach to Indolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazoles Based on Twofold Stille Coupling and Cadogan Reactions

Scheme 7. Synthesis of Staurosporine Aglycon (K-252c) Featuring a Cadogan Cyclization for Construction of the indolo[2,3a]pyrrolo[3,4-c]carbazole Core

polystyrene bead tethered indolo[2,3-a]carbazole (Scheme 4).49 Several approaches relying on the double Cadogan cyclization have appeared during the reporting period of this account. Suzuki coupling of 4,7-dibromo-2,1,3-benzothiadiazole (20) with 2-nitrophenylboronic acid gave the precursor 21, which was cyclized in refluxing triethyl phosphite to 12,13dihydroindolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazole (22) in moderate yield. Subsequent alkylation provided compounds 23a−c (Scheme 5),50 illustrating a commonly used strategy for achieving better solubility for indolocarbazoles. An adaptation of this route has also been used for the synthesis of the corresponding 2,10-dichloro-derivative of 22.51 In a later study, annulation of the intermediate 21 was accomplished in 92% yield by heating with triphenylphosphine in 1,2dichlorobenzene. Subsequent alkylation with 1-bromooctane, followed by halogenation using bromine in chloroform, gave the system 24 (Scheme 5), which eventually served as a monomer for preparation of copolymers.52 It is noteworthy that a completely different regioselectivity has been reported in previous studies during halogenation of closely related derivatives of 22 bearing longer or branched alkyl chains, as treatment thereof with NBS in the presence of silica using methylene chloride as the solvent has been claimed to provide products having the bromine substituents at C-2 and C-10 of the indolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazole core.53,54 Bromination reactions of indolo[2,3-a]carbazoles consistently give products functionalized at the carbon atoms para to the nitrogen atoms,52,55,56 which is also in line with the typical reactivity of indoles in this type of chemistry. Consequently, the deviant outcome in the reported bromination of the indolo[2,3a][1,2,5]thiadiazolo[3,4-c]carbazole system or its likes at C-2/ C-10 leaves reason for doubt.

A slightly different approach featuring annulation of the intermediate 25a (prepared via Stille coupling of the 2,1,3benzothiadiazole 26), having nitro groups at alternative locations compared to the precursor 21, has been used for the synthesis of the indolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazole derivative 27 in decent yield.51 In a sequent publication, higher yields were reported for the same sequence, including efficient syntheses of the new compound 28 and the unsubstituted ring system 22 by Cadogan cyclization of compounds 25a−c (Scheme 6).57 Extended indolo[2,3-a][1,2,5]thiadiazolo[3,4c]carbazoles featuring additional fused benzene rings have been realized efficiently in yet another application of the Stille/ Cadogan strategy.58 Additional variations of the 2-fold Cadogan cyclization have been used for construction of the benzo[c]indolo[2,3-a]carbazole system59 and synthesis of 5-fluoro11,12-dihydroindolo[2,3-a]carbazole during work toward pyrazole analogues of K-252c (see below).60 Likewise, several other recent routes to indolo[2,3-a]pyrrolo[3,4-c]carbazoles rely on cyclization of (o-nitrophenyl)carbazole derivatives under Cadogan conditions. In a total synthesis of staurosporine aglycon (K-252c, 29), 2-methylindole participated in a FeCl 3 -catalyzed condensation with methyl acetoacetate, providing the intermediate 30. Protection of the indole nitrogen atom followed by an allylic bromination and a Michaelis−Arbuzov reaction provided the indole derivative 31 in good overall yield. A Horner−Wittig−Emmons reaction with 2-nitrobenzaldehyde leading to 32 was followed by an electrocyclization in refluxing xylenes in the presence of palladium on carbon, providing the carbazole 33. Subsequent benzylic bromination gave 34, which was subjected to annulation with aqueous ammonia in THF, followed by a Cadogan cyclization, eventually rendering the natural product 29 after removal of the protective group (Scheme 7).61,62 A recently published intricate synthesis of K-252c (29) featuring a E


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Scheme 8. Approach to Arcyriaflavin A Relying on Nitrene Insertion for Synthesis of an Indolo[2,3-a]carbazole Key Intermediate

remarkable assemblage of various C−H functionalization reactions did also include a high-yielding Cadogan cyclization to finalize the construction of the heterocyclic framework.63 A related nitrene insertion has also been used as the final ringforming step in a synthesis of arcyriaflavin A (35). The sequence commenced with a Michael addition of (indol-2-yl)methanol (36) to dimethyl acetylenedicarboxylate giving the adduct 37, oxidation of the alcohol to the corresponding aldehyde, and a Wittig olefination to provide the intermediate 38. After an iodine-mediated electrocyclization to the carbazole 39, and subsequent cyclization to the indolo[2,3-a]carbazole 40, the natural product 35 could eventually be obtained after construction of the maleimide ring (Scheme 8).64 In another study, a similar cyclization was included as the final step of a rather complex sequence, providing a Boc-protected arcyriaflavin derivative in moderate yield using the reagent combination MoO2Cl2(dmf)2 (25 mol %)/PPh3 in toluene at 90 °C.65 The arsenal of different strategies toward indolo[2,3a]carbazoles utilizing 2,2′-biindolyls as starting materials summarized in our previous reviews1,2 has been expanded further, as a palladium-catalyzed oxidative cyclization of the 2,2′biindolyl 41 with alkynes in the presence of oxygen was demonstrated to provide, for instance, the indolo[2,3-a]carbazoles 42a−b in respectable yields (Scheme 9). Several examples with symmetrically substituted diphenylacetylenes were also reported. All successful examples were based on Nsubstituted 2,2′-biindolyls.66 In a thorough study of indium-catalyzed annulation of 2-aryland 2-heteroarylindoles with propargyl ethers, the 2,2′biindolyls 41 and 43 served as building blocks for the indolo[2,3-a]carbazoles 44a−b (Scheme 10). A control experiment with 1-deuterio-3-(hexyloxy)-1-propyne and 41 gave a product with the deuterium atom exclusively incorporated in the

Scheme 10. Indium-Catalyzed Cyclization Approach to Indolo[2,3-a]carbazoles Employing 2,2′-Biindolyls and Methyl Propargyl Ethers As Reactants

methyl group at C-5. This supports a suggested mechanism accounting for incorporation of the three carbon fragment, featuring an initial addition of one indole fragment to the more crowded carbon atom of the alkyne fragment, followed by cyclization via a SN2 mechanism with the corresponding alcohol acting as a leaving group, and a final aromatization of the newly formed central ring of the heterocyclic core.67 Following the repetition of a well-known procedure exploiting the facile conversion of 2,2′-biindolyl (43) into the cyanoacetyl derivative 45,68 a diazotization provided the intermediate 46, which finally underwent cyclization to the indolo[2,3-a]carbazole 47 via a sequence featuring a photoinduced carbene formation, followed by a C−H insertion reaction (Scheme 11).69 Compound 47 is a previously known synthetic precursor70 of the indolo[2,3-a]carbazole natural products 48 and 49, originally isolated from the blue-green alga Nostoc sphaericum (strain EX-5-1).71 Similar chemistry was used for synthesis of two additional related N-methylated indolo[2,3a]carbazoles,69 including compound 50, which has also been previously reported as an intermediate en route to the alkaloid 49 (Figure 5).72,73 Further related compounds derived from the scaffold 47 have been prepared and included in a screening for antibacterial properties, displaying moderate potencies at best.74 In a recent report, routes to two alkaloids have been described based on the 2,2′-biindolyl derivative 51 as the common intermediate. To begin with, a cyanide-catalyzed cyclization of the aldimine 52 (available from the condensation of 2aminocinnamate with 1-benzylindole-2-carboxaldehyde), provided compound 51, which via N-benzylation, addition to ethyl glyoxylate and oxidation underwent conversion to the cyclized precursor 53. The central ring of the indolo[2,3-a]carbazole core was thereafter crafted by a base-mediated intramolecular condensation, which was followed by dehydration to an intermediate anhydride, and subsequent reaction with ammonium acetate, providing the indolo[2,3-a]pyrrolo[3,4-c]-

Scheme 9. Preparation of Indolo[2,3-a]carbazoles from a 2,2′-Biindolyl Derivative and Alkynes by PalladiumCatalyzed Oxidative Cyclization

F


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Scheme 11. Synthesis of the Indolo[2,3-a]carbazole 47 Based on Generation of a Carbene Intermediate, and Subsequent C−H Insertion

time, employing reagents such as I2/hν,12,78 DDQ (2,3-dichloro5,6-dicyano-1,4-benzoquinone)/TsOH,79 PIFA [phenyliodine(III) bis(trifluoroacetate)]/BF3·OEt2,80 Pd(OAc)2 (5 mol %)/CuCl2/air,81 Pd(O2CCF3)2,82 PdCl2,83 or CuCl284 to effect the oxidative cyclization, and the following discussion will provide examples of some new applications and variations. In a bioactivity study of pyrazole analogues of K-252c, the βketoester 60 obtained by coupling of an anion of Boc-protected ethyl (indol-3-yl)acetate with the Boc-protected chloride of indole-3-carboxylic acid, was converted to the pyrazolone 61 by heating with hydrazine hydrate. Subsequent irradiation in the presence of excess iodine gave the fused indolo[2,3-a]carbazole 62 in modest yield. The intermediate 61 was also converted to the corresponding triflate, which was thereafter treated with ammonium formate and palladium acetate as the catalyst, providing the pyrazole derivative 63. Finally, a similar cyclization using iodine and irradiation by a 400 W medium pressure mercury lamp afforded the ring system 64, which displayed moderate cytotoxic effects (Scheme 15).60 Moreover, glycosylated derivatives of 64 have been prepared recently using variations of these routes.85 An additional application of the UV-light mediated cyclization in the presence of catalytic amounts of iodine was used for stepwise conversion of the precursor 65 to the fused indolo[2,3a]carbazole derivative 66, which displayed cytotoxic effects against colon carcinoma (HCT-15) and renal cancer (ACHN, CAKI-1, and UO-31) cell lines. Other conditions screened for this particular cyclization (e.g., Pd(OAc)2 in DMF or AcOH), or alternatively PhI(OAc)2 in CH2Cl2 failed to give the desired product. The required intermediate 67 was obtained by condensation of compound 65 with guanidine carbonate in the presence of sodium methoxide (Scheme 16).86 During studies toward indolo[2,3-a]carbazoles fused to quinoxalines as anion-sensing molecules, several examples of intramolecular coupling reactions between the C-2 atoms of two

Figure 5. Indolo[2,3-a]carbazole alkaloids (48 and 49) isolated from the blue-green alga Nostoc sphaericum (strain EX-5-1), and a closely related synthetic compound (50).

carbazole 54. After a final debenzylation, the natural product arcyriaflavin A (35) was obtained in a good overall yield (Scheme 12). Likewise, compound 51 served as a precursor for the indolo[2,3-a]carbazole 55 in a different route after an initial saponification, followed by annulation and Vilsmeier formylation. Protection of the NH- and OH-functionalities with methoxymethyl groups,75 followed by adaptation of a previously established oxidation/hydrolysis/condensation sequence,76 and a final debenzylation completed a total synthesis of the alkaloid calothrixin B (56) (Scheme 13).75 A synthetic route to a series of quino[2,3-a]carbazoles was extended by two examples of indolo[2,3-a]carbazoles, wherein 1-ethylindole-3-acetonitrile (57a) or the related ethyl indol-3acetate (57b) initially underwent condensation with 2-chloro-1ethylindole-3-carboxaldehyde (58), followed by a palladiumcatalyzed annulation to provide the products 59a−b in reasonable yields (Scheme 14).77 A group of strategies for construction of the indolo[2,3a]carbazole core rely on formation of a bond between the C-2 positions of two indole fragments present in 3,4-bis(indol-3yl)maleimides or related readily available precursors as the key operation. Numerous variations have become available over

Scheme 12. Total Synthesis of Arcyriaflavin A Involving 2,2′-Biindolyl Derivatives As Intermediates

G


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Scheme 13. Synthesis of an Indolo[2,3-a]carbazole from a 2,2′-Biindolyl Derivative En Route to the Alkaloid Calothrixin B (56)

Scheme 14. Construction of Indolo[2,3-a]carbazoles by a Palladium-Catalyzed Annulation

Scheme 15. Synthesis of Pyrazole-Fused Indolo[2,3-a]carbazoles

Scheme 16. Additional Example of the UV-Light Mediated and Iodine-Catalyzed Cyclization Approach to Fused Indolo[2,3a]carbazoles

adjacent indole fragments using trifluoroacetic acid and DDQ have been reported,87−89 constituting some new variations of these old procedures originally developed for synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles.79,90 The conversions of 2,3-di(indol-3-yl)quinoxalines 68a−b to the receptors 69a−b for sensing fluoride and acetate ions serve as representative examples (Scheme 17).87 As an extension of a study mainly devoted to synthesis of benzo[a]carbazoles from 3-aryltetramic acids, the 3-(indol-3yl)-tetramic acid 70 was allowed to react with 1-methylindole producing the intermediate 71, which could in turn be annulated to the indolo[2,3-a]pyrrolo[3,4-c]carbazole derivative 72 (Scheme 18).91

A variation has been proposed as a complement to the previously reported transition metal mediated or catalyzed cyclization approaches, as exemplified by the efficient conversion of the 3,4-bis(indol-3-yl)maleimide derivatives 73a−b to the indolo[2,3-a]pyrrolo[3,4-c]carbazoles 74a−b in the presence of catalytic amounts of palladium(II) trifluoroacetate (10 mol %) and Cu(OAc)2 (3 equiv) (Scheme 19). Both electron-withdrawing and -releasing groups at various positions were well-tolerated in a set of four examples.92 As mentioned above, bromination of indolo[2,3-a]carbazoles usually occurs at the C-3/C-8 positions. By employing a typical procedure, the parent system 1 was initially N-alkylated for achieving better solubility, producing 11,12-dibutyl-11,12dihydroindolo[2,3-a]carbazole (75). Upon exposure of 75 to H


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then in turn serve as the substrate for the next step toward rebeccamycin, which relies on the tryptophan amino acid oxidase RebO for forming the indole-3-puruvic acid imines (86a/86b R = Cl, Scheme 22), which are then converted into the intermediate 87 (R = Cl) by RebD.100 On the basis of studies involving indole-3-pyruvic acid and StaD (a heme-containing peroxidase-like enzyme), wherein it was established that the dimerization of two molecules of indole-3-pyruvic acid proceeds through the enol form rather than the keto form, it was suggested that the enamine form 86b (R = H) is the substrate for StaD. Two enamines 86b can thereafter undergo coupling mediated by StaD. The resulting unstable dimer 87 (R = H) spontaneously releases ammonia, producing chromopyrrolic acid (CPA) (88, R = H).101 The cyclization of CPA (88, R = H) to an indolo[2,3-a]pyrrolo[3,4-c]carbazole is catalyzed by StaP, an enzyme belonging to the cytochrome P450 family. On the basis of crystal structures of both CPA-bound and free forms of StaP, the C−C bond formation leading to 89 (R = H) was suggested to involve an initial one-electron oxidation. The resulting indolyl cation radical intermediate can then form the C−C bond in an intramolecular radical coupling,102 which is in agreement with a previous mechanistic study.103 Each of the enzymes StaP and its counterpart RebP are effective in any of the two pathways (R = H or Cl), which has been exploited for combinatorial biosynthesis of new indolo[2,3-a]pyrrolo[3,4c]carbazoles.104 Labeling experiments with H218O or 18O2 in incubations of CPA (88, R = H) with StaP/StaC and StaP/ RebC showed that the incorporated amide oxygen in K-252c (29) and both imide oxygens in arcyriaflavin A (35) originated from the labeled dioxygen. Moreover, StaC and RebC control the selectivity, as StaP on its own transforms CPA into a mixture of the aglycons 29, 90, and 35. Introduction of RebC promoted the formation of arcyriaflavin A (35), whereas upon addition of StaC, K-252c (29) was the predominant product. None of the evaluated combinations of StaP, StaC, and RebC could interconvert any of the three aglycons 29, 90, and 35, which further supports the pathways depicted in Scheme 22.103 Preparation of the dimethyl ester derivative of 89 (R = H), followed by treatment of this intermediate with lithium hydroxide in methanol/water, did not give the expected diacid 89 (R = H). Instead, a set of products was observed, featuring compound 91 (R = H) and the adduct 92 (R = H) as the major components in a ratio of 3:1, indicating that enzymes may not be required for facilitating such reactions of the diacid 89. Nonetheless, the molecule 92 was not an intermediate toward any of the final aglycons 29, 90, or 35 in this study.105 By investigating the role of the redox cofactor FAD (flavin adenine dinucleotide) in the enzymatic mechanisms of RebC and StaC, a clear correlation between FAD-binding affinities and the catalyzed reaction was noted, with Kd on the nanomolar level

Scheme 17. Construction of Receptors for Anion Sensing by Cyclization of 2,3-Di(indol-3-yl)quinoxaline Intermediates Using DDQ in Trifluoroacetic Acid

1.0 equiv of NBS in DMF, the 3-bromo-derivative 76 was obtained in excellent yield. Likewise, the use of 2.1 equiv of NBS under similar conditions provided convenient access to the 3,8dibrominated product 77. Both halogenated indolo[2,3-a]carbazoles were subsequently used as partners in Suzuki coupling reactions.55 Further bromination is possible with 4.5 equiv NBS in CH2Cl2/AcOH (1:1), leading to the tetrabrominated product 78 (Scheme 20).56 In a sequence illustrating some further options in functionalization at the nitrogen atoms leading to the rather elaborate derivative 79 en route toward materials for organic lightemitting diode (OLED) applications, an initial N-arylation of the parent system 1 with iodobenzene in the presence of copper(I) iodide gave the intermediate product 80. Subsequent deprotonation using sodium hydride, followed by nucleophilic displacement of two chlorine atoms in cyanuric chloride (81) afforded the intermediate 82, which eventually provided practical access to the target molecule 79 via a final Suzuki coupling with 4-biphenylboronic acid (83) (Scheme 21).40 2.2. Indolo[2,3-a]carbazole Natural Products: Occurrence and Biosynthesis

2.2.1. Biosynthesis and Isolation of Indolo[2,3-a]carbazole Natural Products. The biosynthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazole natural products is a relatively well-studied topic, which has been reviewed in detail up to 2006.16 In addition, a few focused overviews touching upon certain specific aspects are also available.93−96 Consequently, only a brief overview of the recent findings is included in this text, supported by selected older key references. As elucidated previously, the fundamentals of the biosynthetic routes to rebeccamycin97,98 and staurosporine (or its aglycon K252c, 29)99 share many common features. The biosynthesis of rebeccamycin aglycon (1,11-dichloroarcyriaflavin A, 84) commences with chlorination of tryptophan (85a) at C-7 (Scheme 22).98 The resulting 7-chlorotryptophan (85b) can

Scheme 18. Approach to an Indolo[2,3-a]pyrrolo[3,4-c]carbazole Relying on a Cyclization Mediated by the Reagent Combination PIFA/BF3·Et2O

I


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Scheme 19. Palladium(II) Trifluoroacetate-Catalyzed Conversion of 3,4-bis(indol-3-yl)maleimides to Indolo[2,3-a]pyrrolo[3,4c]carbazoles

Scheme 20. Synthesis and Bromination Reactions of 11,12-Dibutyl-11,12-dihydroindolo[2,3-a]carbazole

Scheme 21. Preparative Route to the Material 79 Featuring Sequential N-Arylation and Nucleophilic Substitution Reactions Starting from 11,12-Dihydroindolo[2,3-a]carbazole

for binding to RebC (a net 8-electron oxidation of CPA) and substantially weaker binding (Kd on micromolar level) with StaC (a net 4-electron oxidation of CPA). Crystallization experiments identified K-252c-7-carboxylic acid (93) (R = H) as the substrate of StaC.106 Previously, the same molecule 93 was found to be a substrate of RebC. Moreover, strong evidence was provided supporting the view that RebC is a flavin-dependent hydroxylase was presented in the same work.107 With both enzymes sharing a common substrate, the different enzymatic product outputs were suggested to be an effect of preferential binding of either of the tautomers 93 or 91 (R = H) to the enzyme-active site. The nonplanar keto tautomer 93 binds to the StaC enzyme, whereas RebC binds the planar tautomer 91 (R = H). The sp3 hybridized C-7 carbon in 93 (R = H) can accept

electrons from the decarboxylation, which is not possible in the enol form with sp2 hybridization at C-7. However, the hybridization in the RebC substrate 91 (R = H) can be changed through a FAD-dependent oxidation introducing a hydroxyl group at C-7, which may then be followed by a decarboxylation.106 The role of FAD in StaC catalysis remains to be resolved,108 although it has been suggested that it contributes in the catalysis of the decarboxylation step via steric or electrostatic interactions.106 By substitution of two specific active site residues in RebC for those present in StaC, a complete switch in product selectivity to K-252c (29) was achieved.109 The structure of the rebeccamycin pyranose 4′-O-methyltransferase (RebM) responsible for a final O-methylation to form rebeccamycin has been determined. On the basis of data from J


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Scheme 22. Biosynthetic Pathways to the Indolocarbazole Cores of K-252c (staurosporine aglycon, 29), Arcyriaflavin A (35), and Rebeccamycin Aglycon (1,11-Dichloroacyriaflavin A, 84)

Figure 6. Indolotryptoline natural products.

affinity may prove useful for accessing new biosynthetic targets.111,112 By screening a previous archived soil DNA library by polymerase chain reaction (PCR) using degenerate primers designed to recognize oxytryptophan dimerization genes, one cosmid (AB1650) was found to contain the entire set of conserved genes necessary for the indolocarbazole biosynthesis (abeO, -D, -C, and -P), as well as two monooxygenases (abeX1 and -X2), and three methyltransferases (abeM1, -M2, and -M3). The unprecedented finding of the monooxygenases and methyltransferases in this new gene cluster inferred that

the crystal structure, a binding model implicated nonspecific hydrophobic interactions consistent with findings that RebM may methylate a range of different indolocarbazoles.110 Molecular cloning, followed with sequence analysis of genes from Nocardiopsis sp., supported by biotransformation experiments in E. coli, have provided additional insight into the enzymes and routes involved in biosynthesis of the indolo[2,3a]carbazole natural product K-252a (6) and its analogues. Particularly, the expression and functionalization of an Nglucosyltransferase displaying distinctly promiscuous substrate K


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Scheme 23. Suggested Biosynthetic Pathway for the Oxidative Rearrangement of Arcyriaflavin A (35) to Cladoniamide C (101)

containing a similar gene cluster to that which encodes for the transformation of an indolo[2,3-a]carbazole precursor to BE54017 (94). Apart from indolo[2,3-a]pyrrolo[3,4-c]carbazole biosynthetic genes (borO, -D, -C, and -P), one halogenase gene (borH), as well as two oxidoreductase genes (borX1, borX2) were found, the latter being responsible for the indolotryptoline formation from an indolocarbazole substrate. An additional unique oxidoreductase gene (borX3) was also identified. Genemodified Streptomyces albus was used for effecting increased production of metabolites in quantities amenable to characterization, resulting in the discovery of the borregomycins A−D (116−119) (Figure 8), together with the corresponding

metabolites bearing oxidized, rearranged, and/or methylated functionalities could be anticipated as biosynthetic products. This was indeed the case, as one major metabolite BE-54017 (94), and four minor clone-specific metabolites 95−98 were isolated and identified from cultures of Streptomyces albus transformed with the eDNA-derived cosmid AB1650 (Figure 6).113 The biosynthetic pathway to the natural products 94− 98113 and the related cladoniamides A−G (99−105) isolated from Streptomyces uncialis114 was proposed to follow a sequence illustrated by formation of the metabolite cladoniamide C (101) (Scheme 23), where the precursor arcyriaflavin A (35) first undergoes oxidation to a cis-diol 106 (an isolated natural product, see below), which after N-methylation of the maleimide ring nitrogen atom leading to 107 is further oxidized to an oxirane intermediate 108. Subsequent ring-opening to the intermediate 109 is accompanied by a flip of the indole ring and a final ring-closure at the indole nitrogen atom, forming the core of the indolotryptolines. A final O-methylation of the resulting intermediate 110 eventually leads to cladoniamide C (101).115 Chemical syntheses of BE-54017 (94), 116 as well as cladoniamides G (105)117−119 and F (104)118 have been reported, confirming their structures. The indolo[2,3-a]carbazole derivatives 106 and 111−115 were identified as the products from the strain Streptomyces coelicolor YD52 with an engineered biosynthetic cluster (Figure 7). Subsequent experiments could confirm that the metabolites 113−115 were the result of nonenzymatic ring expansion of 106 and 111−112.115 By expanding the homology-guided metagenomics screening to another soil eDNA library by searching for oxy-tryptophan dimerization gene homologues, a cosmid clone was found

Figure 8. Structures of borregomycins A−D (116−119).

dichlorinated chromopyrrolic acid. The biosynthesis of borregomycin A (116) may partly follow a route similar to the one outlined in Scheme 23, followed with additional methylations and oxidations.120 Brady and co-workers expanded their homology guided exploration of tryptophan dimer gene clusters, leading to the discovery of an additional set of metabolites named erdasporines A−C (120−122) from the culture broth of E. coli BL21 cells expressing various combinations of a refactored gene from the cluster AB339 identified in the same work (Figure 9). A biosynthetic pathway was proposed for the erdasporines. The carboxylic acids corresponding to 121 and 122 are intermediates in the staurosporine aglycon (K-252c) pathway (Scheme 22). Erdasporine C (122) is a product from spontaneous oxidation of 121.121 In another study, the unique pyrrolinium-fused indolo[2,3-a]carbazole reductasporine (123) was found (Figure 9), and its structure was verified by X-ray crystallography. The ionic compound 123 displayed moderate antifungal activity.122 Arcyriaflavin E (1-hydroxyarcyriaflavin A) has been isolated

Figure 7. Natural products (106 and 111−112) and nonenzymatic products 113−115 from S. coelicolor. L


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ma, and breast adenocarcinoma was noted for both natural products.127 Reinvestigation of the strain Actinomadura melliaura ATCC 39691 led to the isolation of four new metabolites, including a new member belonging to the small class of disaccharide-substituted indolocarbazoles.128 During a recent study of extracts from the Streptomyces sp. A68 and its Rifampicin-resistant mutant strain R-M1, the N-acetylated metabolite 129 was isolated along with its 3′-epimer and a related N-formyl derivative. The structure of 129 was verified by X-ray crystallography.129 2.2.2. Indolo[2,3-a]carbazoles by Combinatorial Biosynthesis. Combinatorial biosynthesis gives access to indolo[2,3-a]pyrrolo[3,4-c]carbazoles which would otherwise be difficult to prepare by standard synthetic methods, introducing another level of diversity into this thoroughly studied compound class. A review is available covering the advances in combinatorial biosynthesis of antitumor indolo[2,3-a]carbazoles.19 A series of novel glycosylated indolo[2,3-a]carbazoles has been prepared by combinatorial biosynthesis, which led to the identification of 130 as a very potent and selective inhibitor of Ikkb, a kinase involved in inhibition of the NF-kB pathway (Figure 11). Moreover, the related compound

Figure 9. Structures of erdasporines A−C (120−122) and reductasporine (123).

from a coculture of Streptomyces cinnamoneus NBRC13823 and the mycolic acid-containing bacterium Tsukamorella pulmonis.123 Streptocarbazoles A and B (124−125) have been isolated from the marine actinomycetes strain FMA, a Streptomyces sp. from mangrove soil. Both alkaloids feature an unusual arrangement of the glycosidic unit, which is connected via its C-1 and C-3 carbon atoms to the K-252c core (Figure 10). Both

Figure 11. Examples of novel indolo[2,3-a]pyrrolo[3,4-c]carbazoles obtained via combinatorial biosynthesis, including EC-70124 (130).

131 showed promising selectivity in a panel of kinases, for instance as a JAK2 inhibitor with an IC50 value of 0.53 nM (see also Section 2.3).130 By expanding the scope of combinatorial indolocarbazole biosynthesis in a bioengineered Streptomyces albus strain, several new derivatives of rebeccamycin were isolated. The use of K-252c and 9-chloro-K-252c as the substrates provided the two new indolo[2,3-a]pyrrolo[3,4c]carbazoles 132a−b via conversion by the enzyme ClaX1.131 Modification of pyranosylated indolocarbazoles by enzymatic catalysis using the system rebeccamycin C4′-O-methyltransferase (RebM) combined with human methionine adenosyltransferase II (hMAT2), in conjunction with SAH-hydrolase to prevent product inhibition, and S/Se-alkylated methionine/ selenomethionine analogues as the alkyl transfer agents, enabled preparation of the four O-alkylated indolo[2,3-a]carbazoles 133 (Figure 12) in 40−67% yield from the corresponding glucopyranosylated arcyriaflavin A derivative.132 It has been demonstrated that enzymes belonging to the dimethylallyl tryptophan synthase (DMATS) family, such as FgaPT2 from Aspergillus fumigatus or 5-DMATS from Aspergillus clavatus can catalyze prenylation of indolocarbazoles utilizing dimethylallyl pyrophosphate (DMAPP) as the reagent. With the substrate 7hydroxy-K-252c (90, R = H) (Scheme 22), prenylation gave conversion to 134 as the single product (42.2% area in HPLC), whereas K-252c (29) and 6-methylarcyriaflavin A as the substrates gave either low conversion or product mixtures containing mono- and diprenylated species.133

Figure 10. Structures of streptocarbazoles A and B (124−125), fradcarbazole A (126), oxygenated staurosporine derivatives from Cystodytes solitus (127−128), and a metabolite of a Streptomyces sp. strain A68 of marine origin (129).

compounds possessed moderate cytotoxic effects against several cell lines.124 Further derivatives of K-252c have been obtained from a mutant strain of the actinomycete Streptomyces fradiae 007M135 isolated from a marine sediment sample. The mutant strain displayed enhanced indolocarbazole production, enabling isolation and characterization of the cytotoxic fradcarbazole A (126), as well as two related metabolites.125 A biomimetic semisynthesis of fradcarbazole A (126) starting from staurosporine has been reported, thereby confirming the assigned structure.126 The oxygenated staurosporine derivatives 127−128 were isolated from the marine ascidian Cystodytes solitus by bioassay-guided fractionation. It is however not clear whether these compounds are produced by the tunicate itself or by microorganisms associated with this species. Significant cytotoxicity against human lung carcinoma, colorectal carcinoM


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activity, in contrast to erythroid cells from healthy controls, which were not significantly affected.135 In a recent phase I dose escalation study with lestaurtinib (135) (Figure 13), clinical activity was reported in patients with myelofibrosis harboring the JAK2 V617F mutation, although with common gastrointestinal adverse effects in the patient group.136 Limited therapeutic effects have also been noted in a phase II study of 135 in patients with polycythemia vera or essential thrombocythemia with the JAK2-V617F mutation.137 Early established as an inhibitor of FMS-like tyrosine kinase 3 (FLT3) displaying cytotoxicity toward leukemia cells in vitro and in vivo, and suggested as a potential treatment for acute myeloid leukemia (AML) with FLT3-activating mutations,138 the indolocarbazole 135, in combination with additional chemotherapy, however failed in prolonging survival of patients in a clinical study targeting this particular disease.139 On the other hand, midostaurin (136, Rydapt) which is a staurosporine derivative, has recently been approved in the USA for treatment of FLT3 mutation-positive AML in combination with cytarabine and daunorubicin. Additional indications included advanced systemic mastocytosis. The topic has been covered in a recent review, providing a concise account of the development of this drug.140 The antitumor compound becatecarin (137), early identified as a DNA intercalator,141 is a water-soluble derivative of rebeccamycin known since 1990.142 It has been evaluated in clinical phase II trials for metastatic renal cell cancer (modest activity),143 metastatic colorectal cancer (inactive),144 as second line therapy against nonsmall cell lung cancer (no significant activity),145 refractory advanced breast cancer (modest activity),146 in children with relapsed CNS and non-CNS solid tumors (limited effects),147 and relapsed small cell lung cancer (active as a single agent but without prospects for attaining

Figure 12. Alkylated indolo[2,3-a]pyrrolo[3,4-c]carbazoles derived via chemoenzymatic routes.

2.3. Selected Synthetic Bioactive Indolo[2,3-a]carbazoles

The indolo[2,3-a]pyrrolo[3,4-c]carbazoles occupy the position as the most intensely studied group of indolocarbazole derivatives and are featured in a multitude of journal articles and patents. Consequently, this subject has been reviewed in much detail over the years, covering topics ranging from natural occurrence and biosynthesis, 14,16,19,21 chemical synthesis,4,14,15,22 to biological effects and therapeutic applications.4,17,23,93 Hence, only a selection of representative examples described in scientific journals will be presented, illustrating some directions of research, bearing in mind that a comprehensive account of this intensely researched area (which is particularly evident from the vast patent literature) is beyond the scope of this text. Lestaurtinib (135) has been subjected to numerous extensive studies, including clinical trials.134 It has for example been demonstrated that compound 135 suppresses proliferation of primary erythroid cells from patients with myeloproliferative disorders, via inhibition of mutant Janus kinase 2 (JAK2)

Figure 13. Selected bioactive indolo[2,3-a]pyrrolo[3,4-c]carbazoles: lestaurtinib (135), midostaurin (136), becatecarin (137), edotecarin (138), Gö6976 (139), and the rebeccamycin derivative 140 isolated from the Pseudonocardia strain BCI2. N


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better outcomes than existing therapies).148 In a phase I study in patients with refractory solid tumors, becatecarin in combination with oxaliplatin displayed some activity but not as a single agent.149 Induction of single strand DNA-cleavage mediated by topoisomerase I has been observed for J-107088 (edotecarin, 138) a long time ago, accounting for its efficacy in an in vivo nude mouse model xenografted with various human cancer cell lines.150 Further examples of the antitumor activity of 138 were demonstrated in a study involving pediatric and adult CNS tumor xenografts in athymic nude mice.151 The development of the topoisomerase I inhibitor edotecarin (138) toward phase I and II clinical studies has been reviewed.152 Gö6976 (139) has long been recognized as a powerful inhibitor of the Ca2+ dependent protein kinase C (PKC) isoenzymes α and β1 at nanomolar concentrations.153 It has also been established that 139 is a potent inhibitor of DNA-damageinduced S and G2 cell cycle checkpoints at concentrations significantly lower than required for inhibition of PKC, efficiently abrogating cell cycle arrest, which was suggested to result from inhibition of the checkpoint kinase Chk1 and possibly also Chk2.154 In a later study, it was demonstrated that Gö6976 (139) is capable of causing mitotic abnormalities and chromosome alignment defects via inhibition of the mitotic spindle checkpoint, eventually causing apoptosis in various human cancer cell lines due to the resulting aberrant progression of mitosis. The Aurora-A and Aurora-B kinases were identified as the protein targets for 139.155 Gö6976 (139) is, just like K252a and staurosporine, a potent inhibitor of leucine-rich repeat kinase 2 (LRRK2), with implications potentially relevant for late-onset Parkinson’s disease.156 Additional activities of 139 include for instance cytotoxic effects against leukemia cells with FLT3 internal tandem duplication mutations via inhibition of the antiapoptotic proteins survivin and MCL-1157 and promotion of apoptosis in EGF-receptor mutant nonsmall cell lung cancer cells independently of PKC inhibition.158 Rapid and reversible inhibition of guanylyl cyclases-A and -B has been reported previously as the first examples of nonkinase targets of Gö6976 (139).159 The wide array of biological effects of 139 provide an illustration of the potential challenges that could be encountered with regard to selectivity during the development of indolo[2,3-a]pyrrolo[3,4-c]carbazoles for therapeutic applications. Combinatorial biosynthesis provided access to a series of novel indolocarbazoles, for instance EC-70124 (130) (Figure 11), which displayed powerful inhibition of IKKβ and JAK2 kinases, with IC50 values of F− > Br−. The strong solvation of the fluoride ion in aqueous solution accounts for the higher association constant observed for Cl− compared to F−, as opposed to measurements involving the related system 159b in DMSO/MeOH (4:1, v/v), where the observed order was F− > Cl− > Br− > I−. The ROESY spectra of similar compounds incorporating only one or two indolo[2,3a]carbazole cores remained unchanged upon addition of sodium halides.177 Further investigations of related structures containing indolo[2,3-a]carbazoles interspaced by ethynyl bridges led to identification of compound 160 as a selective host for the sulfate ion [Ka = 6.4 × 105 M−1 in MeOH/MeCN (10% v/v)], resulting from strong hydrogen bonding between the anion and a total of eight hydrogen-bonding sites featuring six N−H and two hydroxyl groups arranged favorably within a helical structure.178 A similar expanded ion receptor incorporating longer butadiynyl spacers instead of the ethynyl units between the three indolo[2,3-a]carbazole motifs underwent folding into a helical conformation with a more spacious cavity with preferential binding to the dihydrogen phosphate ion [Ka = 2.61 × 105 M−1 in MeOH/MeCN (10% v/v)].179 In a subsequent study, it was demonstrated that the helical sense of the foldamer 160 can be controlled by binding to the chiral organic anions (R)-10-camphorsulfonate and adenosine cyclic 3′,5′-monophosphate (cAMP). Addition of trifluoroacetic acid to the complex of foldamer 160 with cAMP worked as an off switch for the CD signal, as the cyclic phosphate was converted to the corresponding phosphoric acid, leading to dissociation of the complex. The complex could be regenerated by addition of DABCO, as indicated by reappearance of the CD signal.180 The foldamer 161 shows distinctly different CD spectra depending on the polarity of the solvent. In nonpolar solvents such as S


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Figure 16. Selected indolo[2,3-a]carbazole-based materials.

yield of ca. 40%. In contrast, the other cocrystals were photostable.189 The indolo[2,3-a]carbazole-containing material 79 (Figure 16, Scheme 21), featuring distorted π-conjugation and separated HOMO and LUMO levels due to steric crowding around the central 1,3,5-triazine acceptor core, displayed very small energy gap between its singlet and triplet excited states, enabling efficient up-conversion of triplet excitons into singlet excited states, thereby resulting in efficient thermally activated delayed fluorescence (TADF), in turn leading to high electroluminescence efficiency with potential for organic light-emitting diode (OLED) applications.40 During work toward orange-emitting phosphorescent OLEDs, four structurally related systems incorporating two indolo[2,3-a]carbazole units each differing in the substitution of the central 1,3,5-triazine motif have been evaluated as host materials. As a result of its small singlet−triplet energy level split, balanced charge injection and transporting was realized in an OLED based on the system 165, with excellent values for external quantum efficiency of 24.5%, and power efficiency reaching 64.5 lm W−1, while a device utilizing compound 166 displayed the longest extrapolated lifetime in the series when measured at a brightness level of 1000 cd m−2 under constant current.190 Suzuki reactions of brominated indolo[2,3-a]carbazoles have resulted in a series of symmetrically substituted aryl derivatives,55,56 among which the product 167 in particular was identified as a blue emitter both in solution and as a solid film, displaying a wide HOMO−LUMO energy gap, possessing good thermal stability, solubility, and charge transport ability.56 Derivatives of the new ring system indolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazole (22)50 (section 2.1) have been evaluated as potential materials for optoelectronic applications, such as the halogenated or hydroxylated compounds 168 and 169 (Figure 17). The system 168 exhibited characteristics such as a low-lying HOMO level suggesting good air stability,51 which

pyridine fragments interspaced by alkyne units centered around a pivotal benzene or pyridine motif (Figure 15). It was concluded that the interconversion rates between the enantiomeric P and M helices reflect the kinetic stabilities of the helically folded conformations, which rely on the nature of the structural modification of the central 6-membered unit via modulation of local conformational preferences and π-stacking of the aromatic planes.185 Single-crystal X-ray diffraction was used for structure determination of the helically folded oligomeric structure 164a, which was stabilized by hydrogen-bonding interactions with three water molecules arranged in a one-dimensional chain residing in the tubular cavity. Likewise, an extended system featuring five indolo[2,3-a]carbazole cores and four pyridine units accommodated an array of five water molecules within its helical conformation. Also in this case, single-crystal X-ray diffraction proved instrumental for structure determination.186 Control of the helical orientation of a foldamer structurally related to 164a has been efficiently accomplished by changing the absolute configuration of its terminal chiral residues.187 Expanding the size of the cavity by replacing the pivotal pyridine or benzene unit in 164a with a 1,8-naphthyridine motif (through its C-2/C-7 positions) was realized in yet another closely related molecule, enabling binding of monosaccharides into the helix, with the association constants 9.6 × 104 M−1 and 1.0 × 104 M−1 for glucose and galactose, respectively, in DMSO/CH2Cl2 (10% v/v).188 2.5. Miscellaneous Studies Involving Indolo[2,3-a]carbazoles

In recent years, there have been relatively few applications of indolo[2,3-a]carbazoles reported in areas outside those focusing on biology or medicinal chemistry (sections 2.2 and 2.3), or design of anion receptors (section 2.4). Nonetheless, some miscellaneous studies evaluating new aspects of this class of compounds have emerged. A single-crystal X-ray study of the parent indolo[2,3a]carbazole 1 paved the way for design of discrete double, triple, and quadruple stacks of trans-1,2-bis(4-pyridyl)ethylene (4,4′-bpe) organized in the solid state by the system 1 via hydrogen bonds between the indolo[2,3-a]carbazole N−H groups and the nitrogen atoms of the pyridine moieties within the cocrystals of 12(4,4′-bpe)2·2(MeCN), 12(4,4′-bpe)3, and 12(4,4′-bpe)4, respectively. The compositions and structures of all cocrystals were determined by 1H NMR spectroscopy and single-crystal X-ray diffraction. By virtue of the proximity of the alkene units within the stacks in the 12(4,4′-bpe)4 cocrystals, a [2 + 2] photodimerization between the two inner disordered 4,4′bpe molecules within the quadruple stack in the solid state took place upon UV-irradiation, as deduced from the observed dimer

Figure 17. Selected materials and a copolymer featuring the indolo[2,3a][1,2,5]thiadiazolo[3,4-c]carbazole core. T


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Scheme 28. Approach to 5,12-Dihydroindolo[3,2-a]carbazole Involving a Final Palladium-Catalyzed Cyclization Step

Scheme 29. Biomimetic Route to the Natural Product Racemosin B (179) and Other Related Indolo[3,2-a]carbazoles

is in line with previous estimations for other N-alkylated derivatives of 22.50 In addition, the copolymer 170 together with a related material bearing 2-ethylhexyl substituents on the fused silole ring have been prepared by Stille coupling between the appropriate N-alkylated 3,9-dibromoindolo[2,3-a][1,2,5]thiadiazolo[3,4-c]carbazole derivatives (section 2.1) and suitable stannylated silolo[3,2-b:4,5-b′]dithiophene (dithienosilole) monomers. Both materials were subjected to absorption and emission measurements, as well as electrochemical studies and DFT calculations.52

a new route to the parent indolo[3,2-a]carbazole 2 (Scheme 28).192 Although this preparative route is inferior compared to an old method for synthesis the unsubstituted system 228 due to the poor atom economy, it may nevertheless have potential in future synthetic applications aiming at, for instance, unsymmetrically substituted derivatives. In a biomimetic approach, the N-phthaloyltryptophan esters 174 were initially allowed to react with various indoles 175a−d, providing the 2,3′-biindolyls 176. Subsequent cleavage of the phthaloyl group afforded the tryptophan derivatives 177, which could then be converted to the indolo[3,2-a]carbazoles 178 in two steps, including the natural product racemosin B (179) (section 3.2), via the unstable keto ester intermediates 180, obtained by a transamination reaction with sodium glyoxylate monohydrate. Saponification of the methyl ester derivatives 178, followed by decarboxylation, provided the final products 181. However, in the final step of the sequence, the harsh decarboxylation conditions were not compatible with brominated substrates (Scheme 29). When 5,6-(methylenedioxy)indole was used as the indole reactant in the sequence, a direct annulation to a methyl indolo[3,2-a]carbazole-6-carboxylate derivative was observed in the transamination step.193 As a part of a work on benzannulation of indole derivatives to carbazoles, an extension of the methodology proved useful for the total synthesis of the natural product (182) (Section 3.2). In an intriguing sequence, the γ-keto ester 183 served as the starting point, as it was converted to the peroxide intermediate 184, which was in turn annulated with 6-bromoindole (185), providing the carbazole 186. The series of events leading to 186 was suggested to involve an acid-induced rearrangement of the peroxide via migration of a phenyl group to the adjacent oxygen

3. INDOLO[3,2-A]CARBAZOLES 3.1. Synthesis and Reactions

A number of new synthetic routes targeting indolo[3,2a]carbazoles have appeared recently, offering access to derivatives with new substitution patterns and functional groups, significantly expanding the previously known repertoire of methods. The simple derivative 5,12-dihydro-5,12-dimethylindolo[3,2a]carbazole has been obtained in moderate yield as a single example from a Fischer indolization between 1,2,3,9-tetrahydro9-methyl-4H-carbazol-4-one and 1-methyl-1-phenylhydrazine hydrochloride,45 constituting an extension of old Fischer indolization-based approaches to 5,12-dihydroindolo[3,2-a]carbazole (2) itself.38,191 As a part of a study toward fused heterocycles employing an intramolecular palladium-mediated annulation as the key transformation, the cyclization precursor 171 was first constructed by a substitution reaction involving the reactants 172 and 173. Subsequent cyclization in the presence of catalytic amounts of palladium acetate and triphenylphosphine provided U


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Scheme 30. Total Synthesis of the Naturally Occurring Indolo[3,2-a]carbazole 182

Scheme 31. Application of the Cadogan Cyclization for Preparation of Indolo[3,2-a]carbazoles

Scheme 32. Illustration of a Route to Indolo[3,2-a]carbazoles Relying on a Microwave-Assisted Cadogan Reaction

atom and elimination of tert-butanol forming an intermediate oxycarbenium ion, which is thereafter trapped by the indole. After N-benzylation and saponification, the carboxylic acid derivative 187 was obtained and was then subjected to a Curtius rearrangement followed by acetylation, providing the acetamide intermediate 188. An ensuing annulation with phenyliodine(III) bis(trifluoroacetate) (PIFA) produced the indolo[3,2-a]carbazole 189, which was eventually deacetylated with sulfuric acid, and simultaneously debenzylated and demethylated with BBr3, to furnish the target natural product 182 in 10.9% overall yield (Scheme 30).194 The Cadogan cyclization has proven to be a useful tool for the synthesis of the indolo[3,2-a]carbazole core, as shown by the preparation of the products 190a−b from the carbazoles 191a− b, with concomitant formation of the side products 192a−b (Scheme 31), as an extension of a study mainly focusing on a route to indolo[2,3-a]pyrrolo[3,4-c]carbazoles.62 Further applications of the Cadogan reaction have been reported in connection with syntheses of N-alkylated indolo[3,2-a]carbazole derivatives, including several extended fused systems.195 Microwave-assisted Cadogan cyclization of the carbazole 193 has been demonstrated to give the indolo[3,2-a]carbazole 194

in good yield, illustrating one of the three examples (yields 58− 67%) included in the study. The cyclization precursor 193 was accessed through a one-pot, three component CAN-catalyzed reaction between the chalcone 195, ethyl acetoacetate, and butylamine (Scheme 32).196 In an extension of a synthesis of 2,3′-biindolyls by NBSinduced dimerization of a series of indoles, treatment of indole with NBS under slightly modified conditions gave,197 not unexpectedly, the previously described indolo[3,2-a]carbazole 196 (Scheme 33).198 The acid-catalyzed reactions between 3bromoindoles and indoles have long been known to provide an Scheme 33. Formation of an Indolo[3,2-a]carbazole Derivative from Indole in the Presence of NBS

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efficient route to 2,3′-biindolyls,199 and the sequence of events leading to 196 features an initial bromination of indole giving 3bromoindole, which may then undergo a reaction with indole itself, providing a 2,3′-biindolyl intermediate after elimination of hydrogen bromide.199 The 2,3′-biindolyl will subsequently react with 3-bromoindole yielding a trimer, which finally gives the product 196 after an acid-induced cyclization followed by ringopening of one of the indole moieties as proposed in detail by Bocchi and Palla.198 In the new work, the use of indoles functionalized at C-4 or C-7 afforded the corresponding substituted derivatives of 196 in yields ranging between 35% and 66%, with halogenated substrates being the most successful.197 A one-pot protocol giving access to a series of 7-phenylindolo[3,2-a]carbazoles 197 has been developed, involving various indoles and nitrostyrenes as the reactants (Scheme 34). Yields

An approach to a series of indolo[3,2-a]pyrrolo[3,4-c]carbazoles 200 relying on two consecutive Heck reactions and a final thermal electrocyclization has been described, based on a selection of indoles and maleimides (Scheme 36). The yields Scheme 36. Synthesis of Indolo[3,2-a]pyrrolo[3,4c]carbazoles from Indoles and Maleimides by Consecutive Heck Reactions and Ensuing Thermal Electrocyclization

Scheme 34. Reactions of Indoles with Nitrostyrenes in the Presence of Tin(II) Chloride Dihydrate and MnO2 for Construction of a Series of 7-Phenylindolo[3,2-a]carbazoles

were generally good,201 constituting an improvement compared to an earlier facile synthesis of several examples of this ring system directly from indole and maleimides in acetic acid at 95 °C.202 In yet another route relying on palladium catalysis, the precursors 201 accessed via double Buchwald−Hartwig coupling between 2,4-dibromobenzoic acid or its methyl ester with anilines (in the former case followed by Fischer esterification) underwent double oxidative palladium-catalyzed cyclization, rendering an extensive set of indolo[3,2-a]carbazoles 202 bearing different combinations of substituents. This appears to be a fairly general and efficient method, as both electron-withdrawing and -donating groups were tolerated, the latter giving the lowest yields. A mixture of two isomeric products was obtained when R1 = Ac at the meta-position to the amino group and R2 = H, with preferred cyclization at the more sterically hindered position, in contrast to the reaction of a similarly substituted precursor bearing a trifluoromethyl group which proceeded selectively on the less hindered site (Scheme 37). The natural product racemosin B (179) was obtained as one of the products in the series.203

were at best moderate, the reaction failed with nitroindoles or 5,6-dimethoxyindole, while methoxyindoles gave the best results. The presence of MnO2 as the oxidant was crucial for acceptable yields. Despite its limitations, this approach is still attractive for practical reasons, as it offers easy access to rather complex products from simple and readily available building blocks. A mechanistic rationale was proposed featuring initial formation of 2,3′-biindolyls, which undergo conjugate addition to the nitrostyrenes, followed by a dehydrogenation with MnO2, and finally electrocyclization and aromatization.200 Palladium-catalyzed oxidative cycloaromatization of various 2-phenyl- or 2-heteroarylindoles with alkyne derivatives provided a set of benzocarbazoles and indolocarbazoles, featuring the system 198 as the only example of an indolo[3,2a]carbazole, which was obtained in excellent yield from the reaction of the 2,3′-biindolyl 199 with diphenylacetylene (Scheme 35).66 Two indolo[3,2-a]carbazoles have also been reported as products in modest yields from annulation reactions of the 2,3′-biindolyl 199 with propargylic ethers in the presence of indium nonafluorobutanesulfonate as the catalyst.67

Scheme 37. Double Oxidative Palladium-Catalyzed Cyclization As a Route to Methyl Indolo[3,2-a]carbazole-6carboxylate Derivatives

The indolo[3,2-a]carbazole 203 was obtained in good yield as a single example in an extensive study toward carbazole derivatives based on a rhodium-catalyzed approach, upon cyclization of the precursor 204 in the presence of carbon monoxide (Scheme 38).204 Heating of indoles with substituted benzils in the presence of p-TsOH resulted in the formation of a series (9 examples) of 6,7diphenylindolo[3,2-a]carbazoles 205 in respectable yields (Scheme 39). In contrast, a reaction of indole and biacetyl under such conditions gave 5,12-dihydro-6,7-dimethylindolo[3,2-a]carbazole (206, Scheme 40) in only 12% yield,205 which could be improved to a modest yield of 45% in a later

Scheme 35. Formation of an Indolo[3,2-a]carbazole by Palladium-Catalyzed Oxidative Cycloaromatization of a 2,3′Biindolyl Derivative with Diphenylacetylene

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system 208 (Scheme 40). The use of an excess of 4bromopyridine or iodobenzene led to diarylation in each respective case.207

Scheme 38. Preparation of an Indolo[3,2-a]carbazole by a Rhodium-Catalyzed Reaction Involving Carbon Monoxide

3.2. Indolo[3,2-a]carbazole Natural Products

Since the isolation of ancorinazole (209)210 (Figure 18) from the sponge Ancorina sp., the first example of an indolo[3,2-

Scheme 39. Formation of 6,7-Diphenylindolo[3,2a]carbazole Derivatives by Acid-Induced Reactions of Indoles with Benzils

Figure 18. Indolo[3,2-a]carbazole alkaloids.

a]carbazole natural product, a few additional related compounds derived from marine organisms have been reported. Fractionation of an extract from an unidentified deep-water sponge belonging to the genus Asteropus collected at 131 m depth gave the brominated indolo[3,2-a]carbazole 182, as well as its sulfated conjugate 210.211 A total synthesis of the alkaloid 182 has been reported (section 3.1).194 Racemosin B (179) isolated from an ethyl acetate soluble fraction during studies of components from the green alga Caulerpa racemosa displayed some effects in a neuro-protective assay,212 and its structure was later confirmed by total synthesis (section 3.1).193

development which featured RuO2 nanoparticles as the catalyst in refluxing 1,4-dioxane.206 Nevertheless, the latter product proved to be a useful partner in sequential palladium-catalyzed N-arylation reactions with iodobenzene and 4-bromopyridine toward materials for phosphorescent OLEDs (section 3.3).207 An additional application of the annulation method mentioned above, involving 1-(1H-indol-3-yl)-2-phenylethane-1,2-diones and indoles as the reaction components, furnished a set of 5,12dihydro-6-(1H-indol-3-yl)-7-phenylindolo[3,2-a]carbazole derivatives (four examples) in modest yields.208 In a study of rather limited scope, 5,12-dihydro-6,7-diphenylindolo[3,2-a]carbazole has been reported as a product in 71% yield from the reaction of benzil and indole in the presence of catalytic amounts of Bi(NO3)3·5H2O in acetonitrile at 120 °C, whereas a similar reaction involving indoline instead of indole gave the same product in 40% yield with coformation of three other components.209 In contrast to ring synthesis, the reactivity and modification of indolo[3,2-a]carbazoles are scantily studied topics. Apart from some examples included in the text above, which all can be considered as standard transformations, a study reporting selective palladium-catalyzed N-arylation is available. The starting material 206 prepared according to a known method as outlined above,205 underwent a selective reaction at N-12 with 4-bromopyridine (1.1 equiv), providing the intermediate 207, which was subsequently arylated at N-5, affording the

3.3. Applications of Indolo[3,2-a]carbazoles as Functional Materials

As might be anticipated for a relatively unexplored compound class, there are relatively few publications concerning applications of indolo[3,2-a]carbazoles, apart from the triazatruxenes, a group of extended star-shaped derivatives incorporating an additional indole unit fused to the central benzene ring. This particular topic has been treated recently in several reviews,36,37,213 and it will therefore not be discussed in this account. During a quest for new host materials for red, green, and blue (RGB) phosphorescent OLEDs and white OLEDs, compound 211 (Figure 19) was prepared in 43% yield by a double Narylation of 5,12-dihydro-6,7-dimethylindolo[3,2-a]carbazole (206) (section 3.1) with 4-bromopyridine. With 211 as the host, efficient RGB phosphorescent OLED devices could be fabricated, displaying excellent electroluminescent performance, with maximum external quantum efficiencies reaching 27%. Additionally, a white OLED based on the host 211 exhibited a high external quantum efficiency of 20.3% and power efficiency of 50.9 lm W−1 in conjunction with good color stability. The low efficiency roll-off observed for the devices was ascribed to the

Scheme 40. Sequential N-Arylation Reactions of 5,12-Dihydro-6,7-dimethylindolo[3,2-a]carbazole

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been utilized en route to indolocarbazole-based organogelators capable of emitting blue light (Scheme 41). As an example, coupling of the boronic acid 214 with 1,5-dibromo-2,4dinitrobenzene (215) gave the intermediate 216, which underwent Cadogan cyclization in refluxing triethyl phosphite, affording the indolo[2,3-b]carbazole 217. A double N-alkylation finally gave the target 218.59 Further variations of this strategy have been implemented for synthesis of an extended indolo[2,3b]carbazole system,195 or indolo[2,3-b]carbazole-based sensors for gaseous nitroaromatics.216 The Cadogan reaction has also been employed successfully during construction of the indolo[2,3-b]carbazole core of some persistent aminyl biradicals.217 Despite the low to moderate yields generally experienced, the routes relying on sequential Suzuki and Cadogan reactions are nonetheless quite attractive, offering practical access to elaborate structures in a limited number of operations. A new route has also been reported involving a double annulation strategy relying on the Buchwald−Hartwig reaction. For example, a Suzuki coupling of N,N-(4,6-dibromo-1,3phenylene)bisacetamide (219) with 2-(chlorophenyl)boronic acid (220) gave the intermediate 221, which was cyclized under Buchwald−Hartwig conditions to 5,7-dihydroindolo[2,3-b]carbazole (3). After alkylation under standard conditions, the resulting product 222 was subjected to low-temperature bromination providing compound 223, which served as an intermediate for ensuing consecutive stannylation, Stille coupling, and acetal hydrolysis eventually leading to the system 224 (Scheme 42), a precursor for a dye for a solar cell application. The 2,10- and 3,9-dimethyl derivatives of 3 could also be obtained using this methodology.218 An extension of a synthetic protocol toward a series of carbazoles relying on palladium-catalyzed intramolecular oxidative C−H amination gave access to 5,7-dihydro-5,7-di(p-toluenesulfonyl)indolo[2,3b]carbazole in 72% yield as the single example belonging to its class.219 As a part of an approach to a series of carbazoles and related heteroaromatics, the indolo[2,3-b]carbazole 225 was obtained in good yield upon reaction of the substrate 226 with 1hexylindole in the presence of zinc bromide as the Lewis acid (Scheme 43). It was proposed that the cascade leading to this outcome involves a Friedel−Crafts reaction, electrocyclization, and aromatization. The building block 226 was accessed from the corresponding N-protected 3-methylindole-2-carboxalde-

Figure 19. Selected materials for OLED applications based on the indolo[3,2-a]carbazole core.

presence of the 4-pyridyl structural elements which are capable of facilitating balanced carrier transport in the resulting bipolar material.207 The related indolo[3,2-a]carbazole 212 bearing an electron-accepting 1,3,5-triazine motif had previously been evaluated for OLED applications as a luminescent material with very small energy difference between the S1 and T1 excited states.214 In a very recent study, the material 213 revealed promising characteristics toward roll-off-free thermally activated delayed fluorescence organic light-emitting diodes (TADFOLEDs), as demonstrated by its external quantum efficiency and power efficiency of 26.2% and 69.7 lm W−1, respectively, at 5000 cd m−2 brightness level with a modest voltage of 3.74 V recorded for a green TADF-OLED incorporating 213 as the host. Moreover, when evaluated as the emitter in a device, 213 displayed a photoluminescence quantum yield of 0.93, as well as a maximum external quantum efficiency of 25.1%.215 On the basis of such promising data, there is a good chance that further refined indolo[3,2-a]carbazole derivatives will be explored during the quest for new efficient organic functional materials.

4. INDOLO[2,3-B]CARBAZOLES 4.1. Synthesis and Reactions

The for a long time rather elusive indolo[2,3-b]carbazole ring system has recently enjoyed more attention, primarily due to the development of several new practical synthetic methods. The Cadogan reaction has been used previously for synthesis of the parent indolo[2,3-b]carbazole 3, representing one of the first reliable preparative routes.30 Following this path, a strategy based on Suzuki cross-coupling and Cadogan cyclization has

Scheme 41. Construction of the Material 218 Using a Double Cadogan Cyclization As the Key Transformation

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Scheme 42. Application of a Double Intramolecular Buchwald−Hartwig Reaction for the Synthesis of 5,7-Dihydroindolo[2,3b]carbazole, and Its Subsequent Elaboration into the System 224

reaction of the Staudinger product 230 with the diazo compound 231 (Scheme 45), exhibited the highest quantum

Scheme 43. Synthesis of the Indolo[2,3-b]carbazole Derivative 225 by a Sequence Featuring a Friedel−Crafts Reaction, Electrocyclization, and Aromatization

Scheme 45. Preparation of an Extended Indolo[2,3b]carbazole System from the Staudinger Product 230 and a Ketene Intermediate

hyde by an acetylation/bromination sequence in good overall yield.220 In some related work involving the indole-3-carboxaldehyde derivatives 227 and indoles as the reaction partners, a set of indolo[2,3-b]carbazoles 228 was prepared using a copper triflate-catalyzed heteroannulation (Scheme 44). The authors suggested a mechanistic rationale accounting for the formation of the products, supported by trapping and isolation of a key intermediate under modified reaction conditions.221 Extended systems based on the indolo[2,3-b]carbazole core featuring additional fused benzene or fluorene units have been included in a study focusing on benzo[b]carbazoles displaying photoluminescent properties with potential applications in optoelectronics. Among the indolo[2,3-b]carbazoles investigated, the derivative 229 obtained in good yield from the

yield (48.9%) with an emission maximum at 441 nm. The sequence was proposed to include a Wolff rearrangement of the diazo ketone 231 rendering a ketene intermediate, followed by an aza-Wittig reaction with 230, a biradical cyclization, and finally a 1,5-H shift.222 A protocol for construction of indolo[2,3-b]carbazoles 232 in modest yields from β-ketoesters and indoles mediated by iodine has been reported (Scheme 46). The reactions resulted in moderate yields with methyl- or ethyl benzoylacetate derivatives, whereas ethyl acetoacetate or dibenzoylmethane failed to give any products. An initial α-iodination of the β-ketoester component, followed by a Kornblum oxidation with DMSO to a 1,2,3-tricarbonyl species, which then, in turn, may undergo condensation with two equivalents of indole forming a 3,3′-

Scheme 44. Copper Triflate-Catalyzed Annulation Approach to Indolo[2,3-b]carbazoles

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Besides the contributions outlined above, which all provide access to structurally more or less elaborate indolo[2,3b]carbazoles in a few synthetic steps, there are a few additional studies worth mentioning in this context. In a route of limited scope relying on Fischer indolization as the final step, a set of methyl-substituted 5,6,7,12-tetrahydroindolo[2,3-b]carbazole6-ones was prepared in moderate yields.226 It should also be noted that there has been some controversy concerning a claimed preparation of 6,12-disubstituted indolo[2,3-b]carbazole derivatives by condensation of indoles with aromatic aldehydes in the presence of iodine as the catalyst,227 as the results could not be repeated in a later study, which instead demonstrated rigorously that the products were in fact the isomeric indolo[3,2-b]carbazoles.228 Hydroiodic acid liberated in the initial reaction of an indole with iodine is the likely reagent accounting for this outcome, as it promotes a rearrangement of an intermediate 3,3′-diindolylmethane to a 2,3′-diindolylmethane. This was illustrated by the preparation of an extensive series of 6,12-diarylindolo[3,2-b]carbazole derivatives from indoles and aromatic aldehydes catalyzed by HI, with a final dehydrogenation step using iodine in refluxing acetonitrile (section 5.1).228 The rather fast and inexorable isomerization of 3,3′-diindolylmethanes to 2,3′-diindolylmethanes in the presence of mineral acids229 must be kept in mind in connection with application of any approach to indolo[2,3-b]carbazoles starting from simple electron-rich indoles and carbonyl compounds involving acidic reagents, and very strict control of the reaction conditions may be required in order to achieve the desired outcome.

Scheme 46. Iodine-Mediated Synthesis of Indolo[2,3b]carbazoles from Indoles and β-Ketoesters

diindolylmethane as the key intermediate, followed by a cyclization with a second equivalent of the 1,2,3-tricarbonyl compound, was proposed as a possible mechanistic rationale accounting for the observed outcome in this peculiar sequence. The structure of one of the products 232 (Ar = Ph, R1 = CO2Et, R2 = H) was verified by X-ray crystallography.223 A different sequence, which was also suggested to involve the intermediacy of 3,3′-diindolmethanes has been developed recently, wherein reactions between indoles and phenyl glyoxal catalyzed by copper(II) triflate, and subsequent cyclization with 1,3-dicarbonyl compounds or their equivalents (for instance malononitrile as shown in Scheme 47) in the presence of Scheme 47. Example Highlighting an Approach to Indolo[2,3-b]carbazoles from Indoles, Phenyl Glyoxal, and 1,3-Dicarbonyl Compounds or Their Equivalents

4.2. Bioactive Indolo[2,3-b]carbazoles

Bearing in mind that the indolo[2,3-b]carbazoles are a relatively unexplored class of molecules, and practical procedures for their preparation have not become available until recent years, it is not surprising that only a limited number of derivatives have been subjected to biological studies, with very strong focus on SR13668 (9) (Figure 20) and its promising applications in cancer chemoprevention.32 As new synthetic methods emerge, further derivatives are likely to be included in biologically oriented studies.

DABCO, provided access to a series of nine indolo[2,3b]carbazoles in comparable yields, such as the product 233. The structure assignment of the product 233 was supported by a single-crystal X-ray study.224 Annulation of the 3,3′-diindolylmethane 234 with ethyl acrylate to provide the indolo[2,3-b]carbazole product 235 in good yield was accomplished as an example probing the scope of a new intricate approach to acenes and related systems (Scheme 48). The structure of the indolo[2,3-b]carbazole 235 was Scheme 48. Palladium(II)-Catalyzed Synthesis of an Indolo[2,3-b]carbazole from a 3,3′-Diindolylmethane Bearing a Carboxylic Acid As a Traceless Directing Group

Figure 20. Structure of SR13668 (9) and two related indolo[2,3b]carbazoles.

On the basis of inspiration from the cancer chemopreventive properties of 3,3′-diindolylmethane, a condensation product of the naturally occurring unstable indole-3-carbinol,230 the closely related indolo[2,3-b]carbazoles 236−237 were evaluated besides compound 9. Although all these compounds displayed comparable in vivo antitumor effects in an MCF tumor model with IC50 values as low as 0.09 μM, indolo[2,3-b]carbazole 9 was selected for further studies and was found to exhibit potent oral antitumor activity in PC-3 prostate and SKOV-3 ovarian cancer cell models when administered in combination with Taxol.

confirmed by X-ray crystallography. The carboxylic acid functionality in the substrate 234 was suggested to participate in a directed formation of a palladacycle intermediate and is eventually lost during the decarboxylative aromatization of the central ring.225 AA


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Figure 21. Selected indolo[2,3-b]carbazole materials.

organogels was observed upon ultrasound treatment of the indolo[2,3-b]carbazole 218 (section 4.1), involving formation of nanofibers capable of emitting blue light. Exposure of a xerogel-based film of compound 218 to gaseous 2,4,6trinitrotoluene (TNT) caused fluorescence quenching, thereby suggesting that such materials could act as sensors for detection of explosives.59 Similar behavior was noted for the structurally related system 239, which was also prepared employing double Cadogan cyclization.216 In a recent study, compound 240 was employed as host in a green TADF-OLED with external quantum efficiency of 19.2% and power efficiency of 53.5 lm W−1, although its [3,2-a]-isomer displayed an even more impressive performance.215 As judged from those examples, it is not too farfetched to assume that further studies will follow, exploring new molecular designs and application areas.

Moreover, SR13668 (9) was shown to inhibit the AKT kinase signaling pathway.32 In this context, it is interesting to note that down-regulation of AKT signaling has been proposed as a strategy for cancer prevention.231 A safety study indicated that SR13668 (9) was not genotoxic,232 and no significant toxicity was observed in a 14-day toxicity study with Sprague−Dawley rats even at 600 mg kg−1 day−1. In addition, no kinase inhibition was noted for SR13668 in a broad kinase screen.32 The risk for drug−drug interactions of SR13668 was determined as low based on an in vitro study of cytochrome P450 enzymes induction in primary cultures of human hepatocytes.233 Much effort has been devoted to improving the oral bioavailability of SR13668 (9), which has poor solubility in water. In a phase 0 clinical chemoprevention trial of SR13668, the vehicle Solutol HS15 was found to provide the highest bioavailability of the investigated formulations,234 following results of studies on the use of permeation enhancers (in particular the combination PEG400/Labrasol, 1:1 v/v), which enabled a markedly improved bioavailability of SR13668 in rats,235 or formulation of SR13668 with the lipid-based surfactant Solutol HS15, resulting in bioavailability of 14.6% and 7.3% in dogs and monkeys, respectively.236 Enhanced bioavailability compared with a Labrasol formulation was demonstrated in a mouse model by using poly(lactic-co-glycolic acid) (PLGA) nanoparticles with narrow size distribution, capable of encapsulating SR13668 with a high drug loading (33.3% w/w).237 A later pharmacokinetic study detailing SR13668-PLGA nanoparticles administered to beagle dogs at 2.8 mg kg−1 with enhanced bioavailability compared with two alternative formulations has also been disclosed.238

5. INDOLO[3,2-B]CARBAZOLES 5.1. Synthesis and Reactions

The indolo[3,2-b]carbazoles have been intensely studied as synthetic targets due to their diverse biological effects and numerous applications in materials chemistry. As a result, many useful routes for ring synthesis and functionalization are now available. This section will focus predominantly on ring synthesis and key strategies addressing challenging functionalization issues, illustrating the major directions of current research. The double Fischer indolization still constitutes one of the most reliable and practical methods for accessing structurally simple indolo[3,2-b]carbazoles. Following its first application in the synthesis of the parent system 4 by Robinson,3 it has been used extensively ever since. The reliability of this procedure (sometimes in slightly modified form)239 is demonstrated by its recent application in conversion of the hydrazones 241−242 into 5,11-dihydroindolo[3,2-b]carbazole (4),240,241 and the useful building block 2,8-dibromo-5,11-dihydroindolo[3,2-b]carbazole (243),241−245 respectively (Scheme 49), as well as for the synthesis of 2,8-dialkylated derivatives displaying enhanced solubility.246 All these Fischer syntheses involving the use of unsubstituted or 4-substitued phenylhydrazines proceed in yields which are moderate at best but are still synthetically very useful. With m-substituted phenylhydrazines as the starting materials, the resulting bis(phenylhydrazone) intermediates have the possibility to undergo cyclization at two different positions on each side, leading to isomeric side-product formation, and consequently significantly lower yields of the

4.3. Miscellaneous Applications and Studies

The indolo[2,3-b]carbazole core has only relatively recently been considered as a target for development of new organic materials. As one of the first examples, the system 229 (section 4.1) was included in a study of the photophysical properties of a series of related fused nitrogen heterocycles and was shown to absorb light at 421 nm. On the basis of its emission at 441 nm with a quantum yield of 48.9%, it was suggested that such materials may prove useful for applications in optoelectronic devices.222 The organic dye 238 (Figure 21) with the ability to anchor efficiently onto a TiO2 surface has been designed and synthesized by condensation of cyanoacetic acid with the dialdehyde 224 (section 4.1) and was further employed as a sensitizer in a dye-sensitized solar cell (DSSC), displaying a power conversion efficiency of 6.02%.218 Formation of stable AB


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ing acid-induced dimerization of adducts derived from indole, aromatic aldehydes, and N,N-dimethylbarbituric acid has also been described,253 although it has later been reported by other workers that much longer reaction times than those originally reported may be required.254 A questionable report claiming preparation of indolo[2,3b]carbazoles by the condensation of indoles with aromatic aldehydes in the presence of iodine as the catalyst227 was soon proven incorrect by Dehaen and co-workers based on a detailed experimental investigation featuring X-ray crystallography as the key analytical technique, eventually setting the stage for an alternative practical protocol for synthesis of 6,12-diarylsubstituted indolo[3,2-b]carbazoles,228 which has been subsequently used for preparation of, for instance, 5,11-dihydro6,12-di(1-naphthalenyl)indolo[3,2-b]carbazole.255 On the basis of the results emerging from the work by the Dehaen group, it could be concluded that the reaction of indole with aromatic aldehydes in the presence of HI (20 mol %) in refluxing acetonitrile for 14 h provides a mixture of the tetrahydroindolo[3,2-b]carbazoles 253 and fully aromatic systems 254, which can subsequently be completely converted to 254 upon heating with iodine as the oxidant in overall yields ranging between 40 and 60% (Scheme 52).228 The reaction time in the initial condensation step is crucial, as shorter or longer reaction times gave lower yields. This could be attributed to the required acid-induced rearrangement of the initially formed 3,3′diindolylmethanes to the corresponding 2,3′-diindolylmethanes, which are the precursors for the indolo[3,2-b]carbazole products observed.256 Intermediates such as 253, which can easily be isolated due to their limited solubility (in high yields when the reaction is performed at room temperature as noted for 253 bearing phenyl substituents), may also undergo alkylation on both nitrogen atoms with alkyl halides257 prior to final dehydrogenation using for instance DDQ258−260 or PCC259 as the oxidants. It is noteworthy that dialkylation of compound 253 (R = Ph) with iodomethane or 1-bromopropane in DMSO was accompanied by spontaneous dehydrogenation, in contrast to reactions involving longer chain alkyl halides.257 From a practical synthetic perspective with consideration to safety and environmental aspects, the Deahen sequence involving HI/I2228 appears to be the most attractive one as it avoids the use of toxic chromium reagents or DDQ, which may be difficult to remove completely from the product. By replacing hydroiodic acid with the combination tetrabutylammonium iodide/aqueous HBF4 (48% w/w), yields can be improved in some cases. This particular modification has been used for instance in the

Scheme 49. Synthesis of 5,11-Dihydroindolo[3,2-b]carbazole and 2,8-Dibromo-5,11-dihydroindolo[3,2-b]carbazole by Double Fischer Indolization

3,9-disubstituted indolo[3,2-b]carbazoles. For example, 3,9dichloro- and 3,9-dibromo-5,11-dihydroindolo[3,2-b]carbazole have been prepared in this manner in yields of 9% and 7.5%, respectively.242 Fischer indolization of the bis-hydrazone derived from 2,5-dimethylcyclohexane-1,4-dione and phenylhydrazine provided 5,11-dihydro-6,12-dimethylindolo[3,2-b]carbazole in 80% yield.247 Obviously, high yields may be encountered with certain substrates. Fischer indolization is also a powerful tool for construction of larger-sized, fused derivatives of indolo[3,2-b]carbazole. In a recent study, the starting hydrazine 244 was prepared from 1,4diiodobenzene (245) and could thereafter participate in a double Fischer indole synthesis with the tetralone 246, providing the partially saturated system 247 (along with an isomer, not depicted). Subsequent dehydrogenation with DDQ, followed by cleavage of the benzyl carbamate protective groups with TBAF, gave the extended indolocarbazole 248 in respectable overall yield.248 Functionalization of 248 with various alkyl groups (C5−C16) was investigated for achieving better solubility characteristics, with optimal properties observed for the derivative 249 (Scheme 50).249 Application of a known protocol for construction of indolo[3,2-b]carbazoles directly from indoles and aromatic or aliphatic aldehydes in the presence of sulfuric acid229,247 provided access to the system 250 when indole and compound 251 were employed as the reactants and was followed by an alkylation eventually giving the product 252 in a study aiming at new materials for OLED devices (Scheme 51).250 Similar strategy was employed for synthesis of a platinum(II) complex based on the triphenylamine-substituted indolo[3,2-b]carbazole core 250251 as well as 5,11-dihydro-6,12-bis(4-methylphenyl)indolo[3,2-b]carbazole.252 A conceptually related approach to 6,12-disubstituted 5,11-dihydroindolo[3,2-b]carbazoles involv-

Scheme 50. Approach to Extended Indolo[3,2-b]carbazole Systems Involving Double Fischer Indolization As the Key Transformation

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Scheme 51. Sequence Featuring a Direct Synthesis of an Indolo[3,2-b]carbazole by the Acid-Mediated Reaction between an Aromatic Aldehyde and Indole

Scheme 52. Synthesis of Indolo[3,2-b]carbazole Derivatives from Indole and Aromatic Aldehydes Catalyzed by Hydroiodic Acid, and Aromatization of the Intermediate Products

Scheme 53. Sequence Based on the Acid-Catalyzed Reaction of Indoles with Aldehydes Involving an Intermediate Alkylation Step for the Synthesis of Thienyl-Substituted Indolo[3,2-b]carbazoles

at best,256,261 these procedures are attractive nonetheless as they offer quick access to compounds which would otherwise have to be constructed by rather laborious routes. One of the old synthetic approaches relying on the rearrangement of 3,3′-diindolylmethane (259) to 2,3′-diindolylmethane under the acidic cyclization conditions involving triethyl orthoformate for the annulation262 has been used for preparation of the parent system 4 en route to N-substituted indolo[3,2-b]carbazoles with DNA intercalating properties, for example 260 and 261, the latter having the strongest apparent affinity (Scheme 55),263 N-alkylated systems toward polymeric materials for UV−vis and photoluminescence studies,264 or indolo[3,2-b]carbazole-based hole transporting materials for perovskite solar cells.265 A stepwise synthesis featuring an iodine-mediated rearrangement of the 3,3′-diindolylmethane 262 (conveniently available from the reaction of indole with pyridine-2-carboxaldehyde) provided access to the indolo[3,2-b]carbazole derivative 263, which could, in turn, be converted to the boron complexes 264 and 265 (Scheme 56), which displayed absorption extending over a substantial part of the visible spectrum.266 Further synthetically useful rearrangements involving 3,3′-diindolyl-

synthesis of the system 255, which was prepared in three steps from indole and thiophene-2-carboxaldehyde through the intermediates 256 and 257 (Scheme 53).259 The techniques outlined above may also be used in modified form for preparation of indolo[3,2-b]carbazoles bearing only one substituent on the central ring via the intermediacy of 2,3′diindolylalkanes,256 which has been utilized for the construction of, for instance, 3,9-dibromo-6-hexyl-5,11-dihydroindolo[3,2b]carbazole (258) from 6-bromoindole (185) and heptanal (ca. 0.5 equiv), followed by a final annulation with triethyl orthoformate (Scheme 54).261 Although the yields are moderate Scheme 54. Synthesis of Indolo[3,2-b]carbazole 258 from 6Bromoindole by Two Consecutive Reactions under Acidic Conditions with an Aliphatic Aldehyde and Triethyl Orthoformate, Respectively

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Scheme 55. Acid-Mediated Rearrangement of 3,3′-Diindolylmethane and Subsequent Cyclization with Triethyl Orthoformate As an Efficient Route to 5,11-Dihydroindolo[3,2-b]carbazole (4)

Scheme 56. Synthesis of Two Boron Complexes Featuring an Iodine-Catalyzed Rearrangement of a 3,3′-Diindolylmethane Intermediate for Construction of the Indolo[3,2-b]carbazole Core

Scheme 57. New Synthesis of 2,3′-Diindolylmethane and Its Conversion to the Indolo[3,2-b]carbazole 266

Scheme 58. Alternative Synthetic Route to FICZ (8)

methanes leading to indolo[3,2-b]carbazoles have previously been performed with iodine in refluxing acetonitrile.267,268 A common strategy toward indolo[3,2-b]carbazoles from 2,3′-diindolylmethane derivatives used previously on numerous occasions269−271 has been employed in a new sequence the known indolo[3,2-b]carbazole 266 [a known precursor to FICZ, 8269] from the 2,3′-diindolylmethane 267 mediated by methanesulfonic acid, as an illustration of the potential applicability of the many substituted 2,3′-diindolylmethanes

prepared in this work by a platinum-catalyzed reaction between indoles and propargylic ethers such as 268 (Scheme 57).272 Cyclization of 2,3′-diindolylmethane derivatives with triethyl orthoformate in the presence of methanesulfonic acid has also been exploited en route to 2-bromo- and 3-bromo-5,11dihydroindolo[3,2-b]carbazole as building blocks for materials intended for organic field-effect transistors (OFETs).273 Since its discovery in 1987,25 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (8, FICZ) has attracted much AE


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was expanded with an example where the precursor 277 was selectively converted to the indolo[3,2-b]carbazole 278 in moderate yield (Scheme 61).284

attention, predominantly in biologically oriented studies (section 5.2.3), but there are however only a few publications available focusing on the synthetic aspects.269,274,275 Supplementing the previously established routes, a new variant involving some new intermediates has been reported. On the basis of an evaluation of different bases for the conjugate addition of the enolate derived from the protected ethyl indole3-acetate 269 onto the indole-3-carboxaldehyde 270, it was established that KHMDS was the best choice for effective formation of the 2,3′-diindolylmethane intermediate 271. Subsequent annulation with concomitant cleavage of the Bocgroups afforded ethyl 5,11-dihydroindolo[3,2-b]carbazole-6carboxylate (266), which was eventually converted to FICZ (8) via a reduction/oxidation sequence (Scheme 58).276 The Cadogan cyclization has previously been recognized on several occasions as a useful tool for indolo[3,2-b]carbazole synthesis30,277,278 and has more recently been employed for the synthesis of compound 272 bearing alkyl ether substituents from the precursor 273 (Scheme 59). The structure of the product

Scheme 61. Synthesis of an Indolo[3,2-b]carbazole Derivative by a Double Copper-Catalyzed Intramolecular C− N Bond Formation

The alkaloid malasseziazole C (279) originally isolated from the human pathogenic lipophilic yeast Malassezia furfur285 has been prepared using a sequence involving a palladium-mediated double cyclization for construction of the indolocarbazole core as the key step (Scheme 62)286 essentially following a previously described route,247 except for the final step. The required precursor 280, synthesized from aniline and diethyl cyclohexane-1,4-dione-2,5-dicarboxylate, was heated with 2.2 equiv of palladium(II) acetate in acetic acid as described previously, providing the known diethyl 5,11-dihydroindolo[3,2-b]carbazole-6,12-dicarboxylate (281).247,286 Attempts to effect the cyclization with catalytic amounts of Pd(OAc)2 gave only a low yield of 281.286 After a selective reduction of 281 with LiAlH4 (2.0 equiv) followed by oxidation with DDQ according to known procedures,247 a saponification of the remaining ester functionality eventually gave the natural product 279 in good overall yield.286 A synthetic approach to carbazoles relying on SNAr-type reactions of benzo[b]thiophene-1,1-dioxide derivatives with anilines was extended with a few elegant examples of larger systems. For instance, the precursor 282, available via Diels− Alder chemistry from the relatively simple system 283, was eventually converted in modest yield to the fused and densely decorated indolo[3,2-b]carbazole derivative 284 (Scheme 63) as well as an even more crowded system bearing two tert-butyl units at each N-phenyl substituent, neatly illustrating elegant ways to achieve considerable structural complexity in a few synthetic steps.287 Prior to this work, some additional examples of this extended indolo[3,2-b]carbazole ring system have been prepared by an equally intricate sequence featuring a Pummerertype cyclization and an SmI2-mediated cyclization.288 Two examples of indolo[3,2-b]carbazoles have been included in a quite substantial study toward fused carbazoles and analogous heterocycles. Annulation of the 2-(bromomethyl)indole derivatives 285a−b (readily available from the corresponding 2-methylindole-3-carboxaldehydes) with 1-hexylindole in the presence of zinc bromide provided the products 286a−b in moderate yields with concomitant loss of diethyl

Scheme 59. Microwave-Assisted Double Cadogan Cyclization for Synthesis the Indolo[3,2-b]carbazole 272

272 was corroborated by X-ray crystallography.279 Similar strategy was used by the same group for preparation of the closely related 5,11-dihydro-6,12-dimethoxy-5,11dimethylindolo[3,2-b]carbazole, which was also subjected to a single-crystal X-ray study.280 In this context, it is also worth mentioning that a single example of an indolo[3,2-b]carbazole has been reported as a minor product in low yield from a conceptually related palladium-catalyzed reductive cyclization of a nitroaromatic precursor in the presence of hydrogen.281 An extensive set of extended indolo[3,2-b]carbazoles obtained using a sequence involving double Suzuki and Cadogan reactions has been reported. In a representative example, the coupling of the carbazole 274 with phenylboronic acid, followed by cyclization of the resulting intermediate 275 under microwave-assisted Cadogan conditions, provided the product 276 in respectable yield (Scheme 60). With conventional heating at 230 °C for 24 h, the yield in the Cadogan cyclization leading to the product 276 was only 25%.282 The double intramolecular copper-catalyzed Ullmann-type coupling has previously been employed as a powerful tool for crafting of extended indolo[3,2-b]carbazole systems.283 A different copper-catalyzed intramolecular C−N bond formation protocol toward an extensive series of carbazoles disclosed later

Scheme 60. Application of a Double Microwave-Assisted Cadogan Reaction for the Synthesis of an Extended Indolo[3,2b]carbazole System

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Scheme 62. Synthesis of the Alkaloid Malasseziazole C

Scheme 63. Strategy for Preparation of a Densely Substituted Indolo[3,2-b]carbazole System Relying on Diels−Alder and SNArType Reactions

Scheme 64. Preparation of Two Indolo[3,2-b]carbazoles Using a Common Approach from Differently Functionalized Starting Materials

Scheme 65. Construction of the Indolo[3,2-b]carbazole 291 Using a Cu(OTf)2-Catalyzed Annulation Reaction

malonate (Scheme 64).289 The use of a Boc-protected analogue of 285a as the reactant resulted in loss of the Boc-group during the cyclization, providing access to 5-hexyl-5,11-dihydroindolo[3,2-b]carbazole. Similar chemistry leading to the product 286a or its pentyl-analogue involving a similar 2-(acetoxymethyl)indole substrate, or alternatively a closely related 2(bromomethyl)indole compound derived from 1,3-dimethylbarbituric acid instead of diethyl malonate, has also been described.290 Likewise, cyclization of the diacetoxy intermediates 287a−b under similar conditions also resulted in formation of indolo[3,2-b]carbazoles 286a−b, albeit in better yields, providing a further variation of this methodology.220

As an extension of work focusing on the synthesis of a series of indole-2-carboxaldehydes bearing aryl- or alkynyl groups at C-3, compound 288 was prepared in two steps from the protected 2aminobenzaldehyde 289 via the intermediate 290 in good overall yield. Subsequent annulation of 288 with 1-methylindole in the presence of Cu(OTf)2 as the catalyst, followed by cleavage of the Boc-group with TBAF in refluxing THF, afforded the indolo[3,2-b]carbazole 291 (Scheme 65).291 In connection with the routes relying on ring synthesis, it can also be mentioned that flash vacuum pyrolysis of 1-(3-phenyl1H-pyrazol-4-yl)-1H-benzotriazole has been reported to give 5,11-dihydro-6,12-diphenylindolo[3,2-b]carbazole in 19% yield,292 a result which is merely of academic interest as much AG


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Scheme 66. Strategy for Selective N-Alkylation of 5,11-Dihydroindolo[3,2-b]carbazole

Scheme 67. N-Alkylation of 3,9-Dibromo-5,11-dihydroindolo[3,2-b]carbazole Followed by Borylation via Halogen−Metal Exchange

Scheme 68. Conversion of 3,9-Dibromo-5,11-dihydroindolo[3,2-b]carbazole into the System 300 via a Sequence Featuring Alkylation, Palladium-Catalyzed Borylation, Suzuki Coupling and Annulation

containing indolo[3,2-b]carbazole units in the side-chains (Scheme 66).293 Double Boc-protection of indolo[3,2-b]carbazoles may also be used as a tool for efficient chromatographic purification of these notoriously poorly soluble compounds247 and for facilitating solubility during subsequent synthetic modification by, for instance, Suzuki or Stille reactions.294 Even better results in terms of enhanced solubility of a copolymer for organic solar cells was realized through monomer synthesis by initial attachment of branched N-alkyl substituents, as demonstrated by the reaction of 3,9-dibromo-5,11dihydroindolo[3,2-b]carbazole (294) with 7-(bromomethyl)pentadecane in the presence of aqueous sodium hydroxide and triethylammonium chloride in DMSO/THF (2:1), which proceeded in 89% yield affording the product 295. Subsequent double halogen−metal exchange was followed by quench of the resulting dilithio-derivative with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, giving access to the boronic ester building block 296 in respectable yield (Scheme 67).295 Similar alkylation−borylation sequences relying on reactions employing 9-heptadecanol-9-(p-toluenesulfonate)296 or 11-heneicosanol11-(p-toluenesulfonate)297 as the alkylating reagents have also been reported. For larger scale operations, alkylations using hydroxide bases (often under phase transfer conditions) are

more efficient and practical syntheses of such derivatives are available. As might be expected from a field that has reached a certain level of maturity, numerous successful modifications of the indolo[3,2-b]carbazole core have been accomplished to date. Many of the approaches rely on standard methodologies, for instance N-alkylation, transition metal catalyzed couplings, and various other fundamental functional group transformations, in analogy to other indole-containing compound classes. Some strategies are however unique or quite specifically useful for the indolo[3,2-b]carbazoles and will therefore be treated in more detail in the following discussion. As many indolo[3,2-b]carbazole derivatives having free NH groups while lacking any flexible or lipophilic substituents at other positions are rather poorly soluble in common organic solvents, N-alkylation is often used for improving solubility and thus also reactivity. Direct selective monoalkylation of indolo[3,2-b]carbazoles having free NH-groups is not practically feasible, leading to mixtures of products. Adaptation of a previously published strategy239 enabled straightforward synthesis of 5,11-dihydro-5-octylindolo[3,2-b]carbazole 292 from the parent compound 4, via its di-Boc-derivative, which was monodeprotected selectively providing the intermediate 293, eventually leading to the target product after N-alkylation and removal of the second Boc-group en route to styrene polymers AH


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accessible by introduction of bromine atoms into an already existing indolo[3,2-b]carbazole system at a later stage. As an example, treatment of the partially saturated compound 305 (available from the reaction of indole with benzaldehyde in the presence of HI at room temperature, followed by alkylation) with 4 equiv of NBS in acetic acid was accompanied by aromatization, rendering the product 306 in good yield. As anticipated, this indolo[3,2-b]carbazole was an excellent substrate for Suzuki reactions. Furthermore, a halogen−metal exchange, followed by quenching with DMF provided the formylated product 307 (Scheme 71).257 The fact that all compounds in this sequence bear N-alkyl groups again highlights a typical feature of many other routes toward indolo[3,2-b]carbazole-based materials, as this is often a prerequisite for attaining satisfactory solubility and reactivity. Bromination of the indolo[3,2-b]carbazole 308 with 1.1 equiv of NBS in refluxing CCl4 provided the 2-bromo derivative 309,258 whereas the use of 3 equiv of the same reagent enabled an alternative synthesis of the 2,8-dibromo product 306 (Scheme 72), which also subsequently participated in Suzuki reactions.302 Monobromination of a 6,12-disubstituted indolo[3,2-b]carbazole at C-2 has also been accomplished with good conversion using NBS (9.4 equiv) in methylene chloride (0 °C to rt).260 Previously, it has been demonstrated that treatment of 5,11-dihydro-6-pentylindolo[3,2-b]carbazole with 3 equiv FeBr3 in THF/water gives the corresponding 6-bromo-12pentyl-derivative in excellent yield.256 The C-6 and C-12 positions of the central ring of the indolo[3,2-b]carbazole core are obviously the most reactive sites toward electrophilic species. As mentioned above, brominated indolo[3,2-b]carbazoles readily participate in transition metal catalyzed coupling reactions, for instance Suzuki and Stille reactions, which work well under standard conditions.303 A practical one-pot sequence featuring halogen−metal exchange, borylation, and Suzuki coupling with the coupling partner 310 has been implemented in conversion of the reactant 309 into the system 311, which served as a precursor to the dye 312 during a study toward new materials for DSSC applications (Scheme 73).304 A similar strategy was employed for construction of a related materials from an analogue of 309 bearing branched N-alkyl substituents.305 It has also been demonstrated that bromo-substituted indolo[3,2-b]carbazoles are good substrates in Heck reactions with 2-vinylpyridine306 or 4-(N,N-diphenylamino)styrene.298 Techniques are now also available for selective formylation and acylation of indolo[3,2-b]carbazoles, opening additional opportunities for further practical elaboration into more complex structures. Formylation of simple indolo[3,2-b]carbazoles takes place preferentially at C-6/C-12. As an example, Vilsmeier formylation of the previously known 5,11-dialkylated substrate 313307 provided the carboxaldehyde 314 in moderate

obviously the methods of choice, although sodium hydride is sometimes still used in small scale laboratory procedures. In an additional illustrative sequence featuring a double Nalkylation with 1-bromohexadecane followed by a palladiumcatalyzed borylation, the product 297 was prepared from 3,9dibromo-5,11-dihydroindolo[3,2-b]carbazole (294) via the intermediacy of the derivative 298. An ensuing Suzuki coupling with 1-bromo-2-(methylsulfinyl)benzene provided compound 299 in respectable yield, which eventually underwent a cyclization to the fused system 300 (Scheme 68).298 Alkylation of the readily available 5,11-dihydro-6pentylindolo[3,2-b]carbazole256 (301) with an excess of epichlorohydrin (used as reagent and cosolvent with THF) gave an excellent yield of the product 302 (Scheme 69), a Scheme 69. Alkylation of 5,11-Dihydro-6-pentylindolo[3,2b]carbazole with Epichlorohydrin

monomer for construction of polymers via oxirane ring opening with thiophenol derivatives.299 Likewise, exhaustive N-alkylation of 3,9-dibromo-6-hexyl-5,11-dihydroindolo[3,2-b]carbazole (258) obtained from 6-bromoindole and heptanal by following the same established protocol mentioned above256 has been reported to take place in the presence of bromohexane and sodium hydride as the base in DMF solution, to provide a product displaying good solubility.261 Similarly, 2,8-dibromo5,11-dihydro-6-pentylindolo[3,2-b]carbazole has been alkylated efficiently at both nitrogen atoms with excess 3-(bromomethyl)3-methyloxetane, potassium carbonate, and potassium hydroxide under phase transfer conditions, and the resulting product subsequently served as a substrate in Suzuki or Buchwald− Hartwig reactions.300 Alkylation has also been accomplished utilizing the Michael addition, as treatment of the parent indolo[3,2-b]carbazole 4 with butyl acrylate in the presence of DBU provided access to the diester 303, which could subsequently be converted to the dicarboxylic acid 304 in good overall yield (Scheme 70).301 Several routes are available to brominated indolo[3,2b]carbazoles, which are useful building blocks for more advanced structures. Apart from the derivatives harboring bromine substituents inherited from the starting materials used in construction of the heterocyclic core, certain systems are

Scheme 70. Michael Addition as a Tool for N-Alkylation of 5,11-Dihydroindolo[3,2-b]carbazole

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Scheme 71. Simultaneous Bromination and Aromatization of Compound 305 and Subsequent Formylation Utilizing a Halogen− Metal Exchange Reaction

Scheme 72. Bromination of the Indolo[3,2-b]carbazole 308 with NBS under Different Conditions

Scheme 73. Synthesis of the Dye 312 Illustrating Some Useful Techniques for Elaboration of Indolo[3,2-b]carbazoles

yield (Scheme 74). The structure of the product 314 was verified by a single-crystal X-ray study.308 These formylation conditions

5,11-dihydro-12-pentylindolo[3,2-b]carbazole-6-carboxaldehyde.256 Likewise, 5,11-diethyl-5,11-dihydro-12-pentylindolo[3,2-b]carbazole-6-carboxaldehyde has been prepared in the same manner, albeit in a higher yield of 71%.309 Vilsmeier formylation of 5,11-dihexyl-5,11-dihydro-6-pentylindolo[3,2b]carbazole with the preformed reagent from POCl3 (1 equiv) and DMF (1 equiv) at 80 °C without any additional solvent gave 5,11-dihexyl-5,11-dihydro-12-pentylindolo[3,2-b]carbazole-6carboxaldehyde in 40% yield, whereas the use of 4.8 equiv of the Vilsmeier reagent under such conditions gave a separable mixture of products bearing formyl groups at C-2/C-6 and C-6/ C-8 in modest yields.310 Under forcing conditions (10 equiv of the Vilsmeier reagent in refluxing 1,2-dichloroethane), the indolo[3,2-b]carbazole 255 undergoes formylation at C-2 and C-8, leading to mixtures of

Scheme 74. Vilsmeier Formylation of an N-Alkylated Indolo[3,2-b]carbazole

were similar to those used in a previously reported transformation of 5,11-dihydro-6-pentylindolo[3,2-b]carbazole into

Scheme 75. Formylation Reactions of the Indolo[3,2-b]carbazole 255

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Scheme 76. Nitration Reactions of the Indolo[3,2-b]carbazole 308

Scheme 77. Nitration Reactions of the Indolo[3,2-b]carbazole 319

mono- and diformylated products. However, selective monoformylation of this substrate at C-2 under Vilsmeier conditions was feasible at ambient temperature using PCl5/DMF, providing the product 315 in moderate yield. For efficient diformylation at C-2/C-8, the reagent combination n-C5H11OCH2Cl/SnCl4 provided an useful alternative, leading to compound 316 (Scheme 75).259 Nevertheless, 2-fold Vilsmeier formylation at C-2/C-8 with 100 equiv of POCl3/DMF in refluxing methylene chloride has been used to prepare 5,11-dihexyl-5,11-dihydro6,12-bis(4-methylphenyl)indolo[3,2-b]carbazole-2,8-dicarboxaldehyde in 60% yield.311 The indolo[3,2-b]carbazole 308 is readily nitrated at C-2 and C-8 with 5 equiv of acetyl nitrate generated in situ in methylene chloride leading to the product 317, providing an illustration of representative conditions applicable on a series of related 6,12disubstituted, N-alkylated substrates. The use of 1.3 equiv of acetyl nitrate under otherwise similar conditions gave access to the mononitrated system 318 (Scheme 76). The regioselectivity during nitration resembles that observed during halogenation, demonstrated by the reaction of 319 with 1.3 equiv of acetyl nitrate, which provided the 6-nitro-derivative 320 in respectable yield, while the use of 5 equiv of this nitrating agent gave 5,11dihexyl-5,11-dihydro-6,12-dinitroindolo[3,2-b]carbazole (321) (Scheme 77). Further nitration of 321 at C-2 and C-8 was also possible, but the reaction was unfortunately accompanied by formation of several side products inseparable from the desired tetranitro-derivative. Compound 321 served as an intermediate for further new products, for instance the formyl-derivative 322 and the brominated product 323, which could be further converted to 2,8-dibromo-5,11-dihexylindolo[3,2-b]carbazole (324) (Scheme 78). The latter reaction was rationalized in terms of initial formation of an intermediate quinone diimine, which can undergo hydrolysis under the acidic reaction conditions and then a final reduction to afford the observed product. Likewise, other N-alkylated indolo[3,2-b]carbazoles displayed these reactivity patterns, including 5,11-diethyl-5,11dihydroindolo[3,2-b]carbazole, eventually allowing corroboration of the structures of several of its nitration/bromination products by single-crystal X-ray diffraction. Synthetically useful examples of displacement reactions of the nitro groups at C-6 and/or C-12 by thiolate salts or nitrogen nucleophiles were also included in this thorough study, which addresses a previously poorly explored but potentially important facet of the chemistry of indolo[3,2-b]carbazoles.312

Scheme 78. Reactions of 5,11-Dihexyl-5,11-dihydro-6,12dinitroindolo[3,2-b]carbazole

As illustrated above (Scheme 71), formyl derivatives are also accessible by means of halogen−metal exchange, followed by quenching of the resulting lithiated species with DMF, enabling introduction of the formyl group into indolo[3,2-b]carbazoles at C-2,243,273 C-3,273 and simultaneously at C-2/C-8.244,257 In a sequence relying on a selective halogen-metal exchange as the key transformation, the readily available indolo[3,2-b]carbazole 324 (prepared by Fischer indolization and subsequent Nalkylation) was converted to the formyl derivative 325 in good yield. Benzothiazole formation gave the intermediate 326, which was eventually subjected to a second metalation, providing the material 327 (Scheme 79).313 The closely related material 328 bearing a diphenylamino motif instead of a dimesitylboryl unit has been obtained in respectable yield from the intermediate 326 by a Buchwald−Hartwig coupling.243 The Friedel−Crafts acylation at C-2 and C-8 in a series of 6,12-diaryl- or 6,12-diheteroaryl-substituted indolo[3,2-b]carbazoles has been described, as exemplified by conversion of compound 329 into the product 330 (Scheme 80). Substrates bearing either electron-donating or -withdrawing groups in the aryl substituents were well-tolerated. Propionic anhydride, as well as the anhydride of 2-(4-methoxyphenyl)acetic acid also reacted under these conditions, providing further C-2/C-8 disubstituted products, thus widening the scope of this approach.314 Further functionalization at the acetyl groups at C-2 and C-8 by double iterative Vilsmeier formylation and successive cyclization with methyl thioglycolate or 2,5dihydroxy-2,5-dimethyl-1,4-dithiane in the presence of triethylAK


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Scheme 79. Synthetic Routes to the Materials 327 and 328 via a Common Intermediate

Scheme 80. Acylation of the Indolo[3,2-b]carbazole 329

Scheme 81. Condensation Reaction of 5,11-Diethyl-5,11-dihydroindolo[3,2-b]carbazole with 2,2-Bis(4methoxyphenyl)acetaldehyde

parent system 4) in the presence of (±)-camphor-10-sulfonic acid (CSA), provided direct access to the hole transporting material 332 (Scheme 81).265 The indolo[3,2-b]carbazole 333, easily available in two steps from 2-chlorobenzaldehyde and indole, has been subjected to a copper-catalyzed double intramolecular cyclization, affording the ring system 334 (Scheme 82), a new electron donor with high thermal stability.317 In addition, there are many examples of Cu-mediated N-arylations under Ullmann-type conditions involving the parent indolo[3,2-b]carbazole 4,241,307,318,319 as well as substituted derivatives241,256,320,321 described over the years.

amine (Fiesselmann thiophene synthesis) provided a new entry to various indolo[3,2-b]carbazoles flanked by oligothiophene units.315 Acylation of 6,12-disubstituted and N-alkylated indolo[3,2-b]carbazoles at C-2 and C-8 with 2-iodobenzoyl chloride mediated by SnCl4 has been reported to proceed in excellent yields, and the resulting products served as substrates for double palladium-catalyzed intramolecular C−H arylation reactions, offering access to new extended systems consisting of nine fused rings.316 A condensation reaction between 2,2-bis(4-methoxyphenyl)acetaldehyde and 5,11-diethyl-5,11-dihydroindolo[3,2-b]carbazole (331) (obtained in high yield by alkylation of the AL


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Scheme 82. Intramolecular N-Arylation of an Indolo[3,2b]carbazole Leading to the Fused System 334

Scheme 83. Biosynthesis of Indolo[3,2-b]carbazole (ICZ, 4) from Glucobrassicin (336) via Indole-3-carbinol (335)a

5.2. Naturally Occurring and Bioactive Indolo[3,2-b]carbazoles: Biosynthesis and Metabolism

5.2.1. Introduction and Background. In recent years, more and more efforts have been invested to clarify the physiological roles of the aryl hydrocarbon receptor (AHR). To this end, the focus of the research has moved toward using naturally occurring nonhalogenated bioactive AHR ligands instead of toxic exogenous ligands such as the persistent environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).322−324 One such group of highly potent ligands and bioactive molecules are the indolo[3,2-b]carbazoles, especially 6-formylindolo[3,2-b]carbazole (FICZ, 8) and the parent ring system indolo[3,2-b]carbazole (ICZ, 4) itself. Consequently, many biologically oriented studies involve the use of these compounds, investigating the diverse effects mediated by the resulting AHR responses in vitro and in vivo. The following section aims at providing a comprehensive, but still focused account of the occurrence, biosynthesis, metabolism, and biological effects of indolo[3,2-b]carbazoles. 5.2.2. Indolo[3,2-b]carbazole (ICZ). 5.2.2.1. Occurrence and Biosynthesis. Indole-3-carbinol (I3C, 335) is an autolysis product of glucobrassicin (336),325,326 a glucosinolate present in several species of the Brassica genus, such as broccoli, Brussels sprouts, kale, cabbage, cauliflower, and kohlrabi.327,328 HPLC analyses of acid condensation products after acid treatment of water solutions of I3C in vitro demonstrated the formation of 5,11-dihydroindolo[3,2-b]carbazole (ICZ, 4) and 3,3′-diindolylmethane (259) among other products (Scheme 83).24,329 By identification of ICZ in the gastrointestinal tracts of Sprague− Dawley rats treated by oral intubation with I3C, it was shown that these reactions also occur in vivo.24 Anderton and coworkers developed an HPLC method for the quantification of I3C and its acid condensation products including ICZ in serum. The method was then applied in a series of experiments in which female CD-1 mice were administrated I3C (250 mg kg−1) orally. ICZ was not detected in plasma, lung, heart, or brain but was tentatively determined in the liver, 6 and 24 h after the I3C administration.330 Another source of ICZ and related indolo[3,2-b]carbazoles is the biosynthesis by microorganisms. Of particular interest is the lipophilic yeast Malassezia furfur, constituting a part of the normal skin microbiota. Growing M. furfur on agar medium with tryptophan as the single nitrogen source gives rise to a number of bisindoles and related degradation products. The first bisindole to be described was malassezin.331 Later a number of indolo[3,2b]carbazoles were identified (e.g., malasseziazoles A, B, and C) (337−338 and 279, Figure 22) (cf. below).285 In addition, when M. furfur isolates from human healthy skin or from seborrheic dermatitis (SD) lesions were compared, significant quantities of ICZ were detected only in the isolates from the SD skin.332

a

Also depicted is 3,3′-diindolylmethane (259), another important degradation product of glucobrassicin.

Figure 22. Indolo[3,2-b]carbazoles from M. furfur: malassezioles A, B, and C (337−338, 279).

Gaitanis and co-workers have presented the chemical structures of all the tryptophan-derived indoles produced by M. furfur identified until 2012.333 Further analytical work by Magiatis and co-workers demonstrated the presence of ICZ in extracts of clinical M. furfur strains originating from diseased skin [SD, folliculitis, and pityriasis versicolor (PV)], with ICZ levels ranging from 0.26 to 3.27 μg per mg extract, whereas no ICZ was detected in the corresponding extracts from healthy skin. Skin scales were also collected, and the authors noted that samples from patients with SD and PV were between 10 and 1000 times more potent inducers of AHR-dependent luciferase reporter activity compared to samples from healthy controls. The skin scales were extracted with ethyl acetate and analyzed with LC− MS/MS to identify possible bioactive substances. ICZ was detected in 2 out of 10 SD and PV samples and malassezin in 4 out of 10 samples. In the same report, a comparison of extracts was carried out from 13 types and reference Malassezia species strains and analyzed by HPLC/UV. ICZ could only be detected in strain CBS1878, and the quantification showed the amount of 0.42 ± 0.03 μg ICZ per mg extract.334 ICZ has also been identified as one of chromophores in aged lignin-free bacterial cellulose.335 5.2.2.2. Metabolism. There are relatively few articles describing the metabolism of ICZ. Bjeldanes and co-workers reported the first indications of a metabolic clearance of ICZ.24 In their comparison of ICZ and TCDD as an inducer of cytochrome P450 1A1 (CYP1A1) activity [by measuring the 7ethoxyresorufin-O-deethylase, (EROD) activity] in Hepa cells, they noted that after 48 h incubation the EC50, value for ICZ was 7000-fold higher than for TCDD, which was not expected since AM


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intracellular formation of FICZ in human keratinocyte (HaCaT) cells after UVB irradiation. To be able to reach the detection limit (15 pM) of the HPLC-MS/MS system used in the study, the cells were first starved for tryptophan for 6 h and subsequently incubated with 1 mM [13C1115N2]-tryptophan 1 h before irradiation with a high UVB dose. After 10 min, the cells were harvested after removal of extracellular tryptophan, and the cell extract was analyzed by HPLC-MS/MS. The results demonstrated formation of approximately 80 pM 13C15Nlabeled FICZ.344 Since the Malassezia cultures from diseased skin produced FICZ and other indole derivatives more efficiently than cultures from healthy skin, extracts from patients’ skin scale samples were analyzed. FICZ was identified in two of the skin scale extracts from the six SD patients, although not the same samples that contained ICZ. The amount of FICZ was quantified as 0.5 and 11 pmol/mg skin extract, respectively. No FICZ was detected in the skin samples from healthy subjects.334 Another approach was used by Schallreuter and co-workers. They analyzed epidermal suction blister tissue from the skin of patients with vitiligo, which is characterized by a massive induction of oxidative stress and produces and accumulates H2O2 levels in the 10−3 M range in the skin. The presence of FICZ was demonstrated by MS-analysis. The authors hypothesized that FICZ could be formed via oxidation of tryptophan by H2O2 in vitiligo skin.345 In addition, metabolites of FICZ have been demonstrated in human urine (section 5.2.3.2).342 Not only the microbial flora of the skin has the capacity to synthesize indolocarbazoles and other indole-related products. The gastrointestinal tract is a rich source of microorganisms and a favorable environment for formation of similar substances. Although FICZ itself has not yet been identified in mouse cecum extract or fecal pellets, other indole derivatives that are precursors of FICZ (e.g., indole-3-pyruvate and tryptamine) have been found (Scheme 84).343,346−348 5.2.3.2. Metabolism. In earlier studies, Rannug and coworkers suggested that FICZ both could induce and inhibit the CYP1A1 enzyme.349,350 In follow up studies, when human lymphoblast microsomes, selectively expressing the human CYP1A1 enzyme, were exposed to FICZ or ICZ, the CYP1A1 activity (measured as EROD activity) was observed to first be inhibited by 70% with both compounds. The inhibition was sustained for a longer period with FICZ than ICZ, when the compounds were added in the concentration range 5−30 nM, even with a 40-fold higher amount of added 7-ethoxyresorufin.337 That the inhibition disappeared with time indicated metabolic conversion to products that are inferior as substrates for the CYP1A1 enzyme. This was confirmed in a later follow-up study where the induction of CYP1A1 mRNA by FICZ was compared in two mouse Hepa-1 cell lines, one wild type (wt) and one deficient cell line (c37) having no CYP1A1 enzymatic activity. As expected, a low concentration of FICZ gave only a transient induction of CYP1A1 mRNA in the wt cells, while the induction in the c37 cells was sustained. This difference was explained by the metabolism of FICZ as confirmed by HPLC analyses showing metabolism of FICZ by rat liver S9 or S9 fractions from the wt cells but not from the c37 cells.351 Furthermore, the metabolism was NADPH-dependent and was blocked by the CYP1A1 inhibitor ellipticine. Concurrently with the disappearance of FICZ in the S9 system, FICZ metabolites were detected. The metabolite profile showed three fractions that appeared in a time-dependent manner with the first fraction forming rapidly and thereafter a successive formation of more

their binding affinities to the AHR protein were similar. The authors suggested that one reason for this difference could be metabolic degradation of ICZ. Later, Bjeldanes and co-workers demonstrated a rapid loss of the inhibitory effect of ICZ when the substance was preincubated with hepatic microsomes, or in TCDD-induced Hepa cells.336 In 1998, Wei and co-workers, analyzed the inhibition of CYP1A1 in lymphoblast microsomes selectively expressing the human CYP1A1 enzyme.337 Their results showed that the inhibition disappeared with time for both FICZ and ICZ as a result of a CYP1A1-catalyzed clearance. In a later metabolism study, Bergander and co-workers incubated ICZ in an Aroclor-induced rat liver S9 mixture that was extracted at different time points with ethyl acetate and analyzed with HPLC. ICZ showed a similar time course and metabolism profile as FICZ (cf. below). Three major and one minor metabolite were detected indicating successive hydroxylations of the peripheral rings, resulting in metabolites with increased polarity.338 The exact positions of the hydroxyl groups were not determined. Later Schiering et al. in 2017 confirmed that ICZ is efficiently metabolized by recombinant human CYP1A1.339 To our knowledge, no further metabolism studies of ICZ have been reported to date. 5.2.3. 6-Formylindolo[3,2-b]carbazole (FICZ). 5.2.3.1. Occurrence and Biosynthesis. In 1987, photo-oxidized derivatives of tryptophan were found to bind to the AHR with very high affinity and were suggested to be endogenous signal substances. At least three different compounds with binding affinity were detected after UV irradiation of tryptophan solutions, two of which were studied in detail. MS analyses gave molecular ions (M+) of 284 and 300, respectively, and MS quantifications demonstrated that the concentrations that displaced 50% of the added high affinity ligand TCDD were very low, giving Kd values of 0.07 nM (M+ 284) and 0.44 nM (M+ 300).25 In a later study, the chemical structures of these two photoproducts were determined. One of the substances is the symmetrical 5,11-dihydroindolo[3,2-b]carbazole-6,12-dicarboxaldehyde (also known as 6,12-diformylindolo[3,2-blcarbazole, 339, dFICZ, Figure 23) and the other is 5,11-

Figure 23. Structure of dFICZ (339).

dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (6formylindolo[3,2-blcarbazole, FICZ, 8).26 Further studies on the formation of FICZ were carried out and clarified that not only UVA and UVB but also visible light could generate FICZ from tryptophan.340−342 Thus, it is reasonable to assume that any solution or media containing tryptophan can generate FICZ if exposed to light. In addition, it has been demonstrated that Malassezia yeasts produce FICZ and related products. In 2005, Irlinger and coworkers isolated malasseziazole C (279) from cultures of Malassezia furfur. The chemical structure of this substance corresponds to dFICZ (339), in which one of the CHO-groups has undergone oxidation.285 Later, FICZ itself was identified from such cultures.334,343 Fritsche and co-workers demonstrated AN


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Scheme 84. Summary of Major Pathways during Formation and Metabolism of 6-Formylindolo[3,2-b]carbazole (FICZ, 8)a

a

See text for details.

polar metabolites. These results demonstrated for the first time that FICZ, via the AHR, controls the expression of CYP1A1, resulting in an efficient auto regulatory negative feedback.337,351 Further studies followed to elucidate the role of CYP1A1 and the metabolism of FICZ in more detail, with determination of the chemical structure352 of the major metabolites in the three HPLC-fractions found earlier.351 By means of LC−MS (negative ion electrospray mode) and NMR spectroscopy (1H NMR, COSY, and NOESY), five metabolites 340−344 were identified (Scheme 84). The molecular weights of the five metabolites were 300 and 316, which would correspond to mono- and dihydroxylated FICZ derivatives, respectively. Furthermore, the MS spectra showed neutral losses of m/z = 28, 29, and 30, which indicated the presence of the formyl group, also demonstrating a relatively high stability of the metabolites, considering the high cone voltage (70 V) and collision energy (30 eV) applied. The 1H NMR spectra showed that the least polar HPLC-fraction contained two coeluting compounds, the structure of the major component could be assigned as 5,11dihydro-8-hydroxyindolo[3,2-b]carbazole-6-carboxaldehyde (340), while the structure of the minor metabolite (341) differed from 340 in the location of the hydroxyl group.352 The structures of 340 and 341 were corroborated by independent syntheses and comparison of NMR data.269 The next fraction also contained two coeluting substances. In accordance with the 1 H NMR-data, the structure of the major compound was 5,11dihydro-2,10-dihydroxyindolo[3,2-b]carbazole-6-carboxaldehyde (344), while the minor substance was identified as 5,11dihydro-4,8-dihydroxyindolo[3,2-b]carbazole-6-carboxalde-

hyde (342). The most polar metabolite fraction contained only one substance with the structure 5,11-dihydro-2,8dihydroxyindolo[3,2-b]carbazole-6-carboxaldehyde (343). By analyzing the further metabolism of the metabolites, a product− precursor relationship was established and demonstrated that monohydroxylated FICZ derivatives gave rise to the dihydroxylated metabolites and that these reactions were NADPHdependent.352 A time-dependent decrease of the dihydroxylated FICZ metabolites in an NADPH-dependent manner indicated further CYP-metabolism into yet unidentified products. Additional analyses of the further metabolism and degradation of FICZ were made by using both Aroclor-induced and noninduced rat liver S9, as well as human liver S9 fractions as metabolic systems. The induced rat liver system metabolized FICZ faster than the noninduced rat system and the human liver, but the latter two systems produced a more complex metabolite profile. Altogether, five new peaks were seen in HPLC-chromatograms from the human S9 metabolism, three of which were also found in the noninduced rat liver S9, while two were unique to the human system. Under these conditions, one of the new peaks observed in the HPLC chromatogram was found to be less polar than the monohydroxylated FICZ metabolites (340 and 341, Scheme 84). It was, together with the 5,11-dihydro-4,8dihydroxy- and 5,11-dihydro-2,10-dihydroxyindolo[3,2-b]carbazole-6-carboxaldehydes (342 and 344), the predominant peak in the chromatogram from the human liver incubation, while no 5,11-dihydro-2,8-dihydroxyindolo[3,2-b]carbazole-6carboxaldehyde (343) was detected. Furthermore, this metabAO


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olite displayed fluorescence, as well as a shift in the UV spectrum, which indicated that it could be a carboxylic acid derivative. On the basis of these observations, the authors suggested that it was 5,11-dihydroindolo[3,2-b]carbazole-6carboxylic acid (CICZ, 345, Scheme 84),338 the structure of which was later established by comparison with a synthetic sample.342 The predominating role of CYP1A1 in the hydroxylation of FICZ was confirmed by the use of specific CYP inhibitors. The results also revealed that CYP1A2 had an overlapping specificity with CYP1A1, while the further metabolism of the dihydroxylated FICZ derivatives was CYP1B1-dependent. Bergander and co-workers also analyzed glucuronidation and sulfation by adding cofactors for these conjugation reactions (uridine-5′-diphosphoglucuronic acid and 3′-phosphoadenosine 5′-phosphosulfate, respectively), in the metabolism systems. Both glucuronidation and sulfation occurred, and a decrease in the amounts of both mono- and dihydroxylated metabolites was demonstrated, although some of the metabolites were more susceptible to sulfate conjugation. The glucuronidation was confirmed by the addition of βglucuronidase to recover the hydroxylated metabolites338 In further analyses of the metabolism of FICZ, pooled human liver S9 fractions (separated in microsomal and cytosolic fractions, respectively) and bicistronic plasmids encoding human NADPH-P450 reductase together with CYP enzymes 1A1, 1A2, or 1B1 expressed in Escherichia coli were applied. The products from the metabolism were analyzed by LC−MS/MS, and several new metabolites were subsequently identified. Together with the three dihydroxylated metabolites 342−344 (Scheme 84) found earlier, one novel monohydroxylated FICZ derivative was detected, but the position of the hydroxyl group was not determined. The same group also showed that an S9 fraction from human liver in the absence of NADPH, or a corresponding cytosolic fraction, could catalyze oxidation of the aldehyde group in both FICZ and its mono- or dihydroxylated metabolites, giving rise to CICZ (345) and its mono- and dihydroxylated metabolites, respectively. Under these conditions, the oxidation of the aldehyde moiety was the only metabolic step. By applying different oxidase inhibitors, the authors concluded that the cytosolic aldehyde oxidase catalyzed this oxidation.342 The efficiency of the CYP1 family of enzymes to metabolize FICZ was compared to the efficiencies of ethoxyresorufin-Odeethylase (EROD) and methoxyresorufin-O-demethylase (MROD) reactions, the standard methods used for quantifying CYP1 enzyme catalysis. In these experiments, the authors used human recombinant CYP1 enzymes expressed in E. coli, and the efficiencies (Kcat/Km) were found to be 5−50 times higher for FICZ than for the standard substrates. CYP1A1 was shown to be extremely efficient in catalyzing the hydroxylation of FICZ, with Kcat/Km of 8.1 × 107 M−1 s−1, a value close to the limit of diffusion.342 Because the studies by Bergander and co-workers had indicated that sulfoconjugation is an important pathway in the metabolism of FICZ,338 a detailed study of the sulfation using 2- or 8-monohydroxylated FICZ metabolites 341 and 340 as substrates for the six human recombinant sulfotransferases SULT1A1, -1A2, -1A3, -1B1, -1E1, and -2A1 was pursued. SULT1A3 and -2A1 did not catalyze any conjugation, while the other four SULTs exhibited high catalytic efficiencies. In all four cases, the 2-hydroxylated metabolite 341 was more efficiently conjugated than the 8-hydroxylated metabolite 340. A Kcat/Km of 1.1 × 107 M−1 s−1 was obtained with SULT1A2 and the metabolite 341 as substrate which was stated to be higher than

for any other substrate and human SULT form reported in the literature. The dihydroxylated metabolites 342−344 were also converted to their sulfuric acid diesters by SULT1A1, -1A2, and -1B1, with intermediate monosulfoconjugates. The results from the kinetic studies applying recombinant human CYP1 enzymes and sulfotransferases indicated that the sulfate conjugates would be one type of final metabolites in humans. Since the conjugation of the monohydroxylated FICZ metabolites was very rapid, and sulfation of dihydroxylated metabolites proved less favorable, the authors focused their search on monosulfated urinary FICZ metabolites (Mr = 380). Seven 24 h human urine samples were analyzed by LC−MS/MS, revealing that sulfated 5,11-dihydro-8-hydroxyindolo[3,2-b]carbazole-6-carboxaldehyde (346) was present in two of the seven samples, while several other compounds related to FICZ (i.e., compounds having the same Mr = 380 and MS fragments) were also present, although their molecular structures were not determined. The authors concluded that FICZ (1) is a potent activator of AHR and thereby a potent inducer of CYP1 enzymes, (2) is an excellent substrate for the induced CYP1 enzymes, and (3) that the hydroxylated metabolites are excellent substrates for SULT1 enzymes, which convert them to sulfate conjugates that can be excreted.342 5.2.3.3. Mechanisms of Formation. As mentioned above, the high affinity AHR ligand FICZ (8) was first described as a tryptophan photo-oxidation product together with dFICZ (339),25,26 and indole-3-acetaldehyde (I3A, 347) was suggested to be a precursor of both these indolocarbazoles (Scheme 84).26 Smirnova and co-workers examined that hypothesis in detail, with the objective to identify light-independent alternative pathways by which FICZ could be formed and to determine whether I3A is the precursor.343 One of the pathways investigated was the oxidative deamination of tryptamine (348), which is known to yield I3A.353 Human recombinant monoamine oxidases (MAO) A and B obtained from a Baculovirus expression system were used to catalytically form I3A from tryptamine. The products from the enzymatic reactions were then incubated at different temperatures or at different pH values. HPLC and LC−MS analyses demonstrated that while the amount of the precursor I3A decreased with time, FICZ and, subsequently, CICZ appeared. This nonenzymatic rate of formation of FICZ from I3A increased with temperature and was optimal at acidic pH. MAO-catalyzed reactions performed in the presence of the inhibitor phenelzine confirmed that I3A was the precursor. In addition, when an HPLC fraction containing I3A was stored for 5 days at 37 °C in the dark and then analyzed with LC−MS-QqQ (MRM), both FICZ and the oxidation product of I3A, indole-3-acetic acid, were identified and confirmed with authentic standards. In the same article, the addition of H2O2 during UV irradiation of tryptophan (85a) was found to increase the yield of FICZ, while the addition of catalase prevented its formation. In the next step, tryptophan was incubated with different concentrations of H2O2 in the dark for 14 days, and subsequent analyses with HPLC-FL and LC− MS (MRM) confirmed that oxidation of tryptophan with H2O2 could produce FICZ.343 The results showing formation of FICZ in the presence of H2O2 are in accordance with the results reported by Schallreuter and co-workers (section 5.2.3.1).345 The production of FICZ by Malassezia furfur cultures as reported by Magiatis and co-workers334 (section 5.2.2.1) was confirmed by Smirnova et al., who also detected the oxidation product CICZ (345) in the same cultures.343 In 2003, Bradfield and co-workers showed that the enzyme aspartate aminoAP


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Figure 24. FICZ/AHR/CYP1A1 auto regulatory loop. AHR, aryl hydrocarbon receptor; AHRE, AHR response element; ARNT, aryl hydrocarbon receptor nuclear translocator; CYP1A1, cytochrome P4501A1; FICZ, 6-formylindolo[3,2-b]carbazole; HSP90, AIP, and p23 are chaperone proteins.

5.2.4. Indolo[3,2-b]carbazoles as Natural Aryl Hydrocarbon Receptor (AHR) Ligands. 5.2.4.1. Aryl Hydrocarbon Receptor. The AHR is a cytosolic receptor protein belonging to the basic helix−loop−helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors.356 In the absence of ligands, the AHR resides in the cytoplasm as a component of a chaperone complex that includes a dimer of Hsp90 and the cochaperones p23 and AIP. The translocation of AHR into the nucleus is initiated upon ligand binding that allows the AHR to dissociate from its chaperones. In the nucleus, AHR forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT), and this complex binds to AHR response motifs (AHREs) in the promoters of target genes, recruits transcription cofactors and chromatin remodeling proteins, and starts gene transcription (Figure 24). This topic has been reviewed by Beischlag.357 AHR promotes the expression of hundreds of genes involved in normal physiology in the absence of exogenous ligands. The receptor can be activated by many types of low molecular-weight compounds in a broad range of affinities ranging from 10−13 to 10−3 M. The gene that is most highly up-regulated in response to the activated AHR codes for CYP1A1, a member of the cytochrome P450 superfamily of enzymes. CYP1A1 is widely recognized for its role in mediating oxidative metabolism of many exogenous as well as endogenous substrates.358 Although the AHR is not essential for survival, without it, aging starts early and AHR-deficient mice spontaneously develop lesions in several organs359−363 and exhibit high sensitivity to inflammatory stimuli.364−366 The original assumption, based on toxicological findings, was that the AHR is a receptor for and a mediator of metabolism of exogenous substances.367,368 Later findings, such as, the high degree of evolutionary conservation of the AHR,369,370 in

transferase with tryptophan as the amino donor compound generated substance(s) that activated the AHR. Indole-3pyruvate (I3P, 349) which was formed in these reactions yielded the AHR-activating substance(s) upon aerobic incubation at pH 7.4 and 37 °C.354 Later, Chowdhury et al. identified two of these products. One was 1-(1H-indol-3-yl)-3(3H-indol-3-ylidene)propan-2-one and the other was malassezione,355 which had been previously identified in crude extracts of Malassezia furfur cultures.285 No other substances with AHR activating properties were mentioned or identified.355 Likewise, no other substances with AHR activating properties were mentioned or identified by Chowdhury and co-workers, but they reported that an incubation of I3A under the same conditions gave the same two substances. They therefore suggested that decarboxylation of I3P yields I3A, which then undergoes several reactions to yield the identified substances.355 Smirnova and coworkers repeated the procedure described by Chowdhury et al.355 and analyzed for the presence of FICZ. Both HPLC-FL and LC−MS (QToF) analyses verified the production of FICZ from I3P.343 A mechanism for the formation of FICZ via the common intermediate I3A was suggested based on the results discussed above and supported by control experiments using I3P as the starting material. HPLC-FL demonstrated the formation of FICZ and CICZ in these control experiments, and MRM confirmed their identity. The other expected product dFICZ (339) was not detected, but its oxidation product malasseziazole C (279) was tentatively identified as a major product. Scheme 84 provides a summary of the major biosynthetic pathways generating FICZ and its metabolites identified to date, emphasizing the major role of tryptophan and with I3A as a common denominator.343 AQ


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combination with the fact that the AHR regulates the constitutive expression of genes involved in, for example, cell growth and differentiation, strongly argue for important endogenous functions.371−373 The fact that the high affinity ligand TCDD is a highly toxic chemical322−324 infers that AHRmediated responses can be deadly if not strictly controlled. Already in the early 1980’s, Daniel Nebert and colleagues presented a hypothesis that implicated an endogenous ligand and a feedback control mechanism for AHR-dependent regulation of CYP1A1 gene expression and enzyme activity.374,375 The tryptophan-derived molecules FICZ and dFICZ that were discovered in the late 1980’s were found to bind to the receptor with higher affinity than that described for all other molecules, even higher than that of TCDD, and were proposed to be endogenous signal substances.25 Also ICZ exhibits very high AHR-binding affinity.342 In contrast to the binding mode of TCDD, the binding mode of FICZ to AHR is evolutionarily well-conserved.376−379 5.2.4.2. Biological Effects of Indolo[3,2-b]carbazole Ligands for the AHR. 5.2.4.2.1. Toxicity. Activation of the AHR by FICZ is strictly controlled via the FICZ/AHR/CYP1A1 feedback loop that maintains low intracellular FICZ levels via the inducible CYP1 enzymes.338,342,351,380 At low concentrations, FICZ causes rapid and transiently elevated expression of many AHR-regulated genes,337,342,380,381 and when applied topically on mouse ear skin, it leads to systemic induction of CYP1A1.380 FICZ as well as ICZ have generally been considered to be nontoxic AHR agonists. Both ligands have, however, been shown to possess antiestrogenic activity in fish hepatocytes, and ICZ was found to be antiestrogenic in human breast cancer cells.382,383 In two studies with cultured chicken hepatocytes, reduced viability has been documented with estimated median lethal concentrations of 9.4 μM and 14 μM FICZ, respectively, and transient oxidative effects of FICZ have been observed in different cell types.384,385 Increased formation of reactive oxygen species (ROS) and stimulated apoptosis signaling were recorded when FICZ was added together with the CYP1A1 inhibitor 3′methoxy-4′-nitroflavone.384 Furthermore, recent studies performed with zebrafish embryos and with chicken and Japanese quail embryos showed that FICZ can be embryotoxic.386−388 The toxic manifestations in zebrafish embryos occurred only when the CYP1A metabolism was inhibited in embryos that were either injected with morpholino antisense oligonucleotides targeting CYP1A or in embryos coexposed to the potent CYP1A-inhibitor α-naphthoflavone.387 When FICZ was tested for embryo-toxicity in chicken and Japanese quail embryos, air sac injection of FICZ led to dose-dependent mortality with median lethal doses of FICZ that were below 20 μg kg−1. Furthermore, the toxicity increased when FICZ was applied together with the antifungal drug ketoconazole, which inhibits chicken CYP1A4- and CYP1A5-catalyzed metabolic degradation of FICZ.388 Regular rodent toxicity studies with high doses of FICZ have not been performed in adult animals, but no signs of pathology were mentioned in mice treated intraperitoneally (i.p.) three times, 3 days apart with 500 μg FICZ kg−1.389 In another study, no toxicity was observed when FICZ was administered to adult mice via subcutaneously implanted pumps that delivered FICZ at a rate of 10 μg kg−1 h−1. FICZ treatment was also performed with pumps that delivered FICZ at the same rate for 9 days in animals that lack CYP1A1 activity. Also in these animals, no FICZ-related toxicity was observed.390

In 2002, a study of the acute toxicity of ICZ was performed. ICZ has similar AHR binding affinity as TCDD, but there were none of the typical signs of TCDD toxicity reported in rats administered 508 μg ICZ kg−1 subcutaneously for 5 days.391 This may not be surprising because ICZ, like FICZ, is very efficiently metabolized via the induced CYP1 enzymes.337 5.2.4.2.2. Cellular Responses. FICZ Interferes with Homeostatic Maintenance, Self-Renewal, and Differentiation of Stem/Progenitor Cells. Significant data show that the AHR is involved in the growth homeostasis of stem cells and in particular regulates the balance between quiescence and proliferation.392−399 Accordingly, AHR activation by FICZ has been reported to modulate growth of progenitor cells.400−403 FICZ Modulates Immune Cell Differentiation and Responses. Activation of the AHR by FICZ appears to play critical roles in mammalian innate and adaptive immune defenses against external pathogens, and important properties of FICZ have been revealed in the intestine, skin, and airways constituting the physical and immunological entry barriers. In the gut, FICZ may be formed by bacteria since the microbiome is known to form several indole derivatives which are weak AHR ligands by themselves,348 and as described in section 5.2.3.1, some of these indoles are precursors for the formation of FICZ.343 Gut immunity to bacterial infection is promoted by the cytokine interleukin 22 (IL-22), which is produced primarily by innate lymphoid cells (ILCs), and Qiu and co-workers have shown that FICZ could increase IL-22 production and protect against mortality in mice infected with the intestinal pathogen Citrobacter rodentium.404 A Japanese study reported that FICZ could drastically reduce the mortality from infection by the intestinal pathogen Listeria monocytogenesis.405 FICZ was also found to produce IL-17 as well as IL-22 in peritoneal T cells when injected i.p. together with heat-killed Mycobacterium tuberculosis.406 Recently, it was demonstrated that the CYP1A1 enzyme in the intestinal epithelial cells carry out a vital role in the intestinal immunity by controlling the availability of FICZ.339 FICZ was first reported only to act pro-inflammatory in mice by enhancing the differentiation of subsets of CD4+ T helper cell 17 (Th17) that express the cytokines IL-17, IL-17F, and IL22, and to block the formation of anti-inflammatory regulatory T cells.407,408 Subsequent studies performed in mouse cells and human cells in vitro supported the finding that FICZ stimulates the production of IL-17 and IL-22339,409−415 but not regulatory T cells.416,417 Induction of regulatory T cells or other antiinflammatory T cell types by FICZ has, however, been reported in other studies.418−426 The conflicting data on T cell differentiation with some studies showing that FICZ induces only the pro-inflammatory Th17 cells and other studies finding that FICZ can also induce regulatory T cells that can suppress the immune responses are most certainly explained by FICZ degradation via the FICZ/AHR/CYP1A1 feedback loop that impacts the effective dose of FICZ. FICZ and ICZ also influence the sensitivity toward allergens and viruses through regulation of dendritic cell maturation. The phenotypical alterations generated by FICZ and ICZ in dendritic cells were similar to those generated by TCDD.427−431 Furthermore, like TCDD, but not to the same extent, FICZ was reported in four studies to activate expression of the tryptophan-degrading enzyme indoleamine-2,3-dioxidase in different human and mouse dendritic cells412,425,432,433 but not in two other studies.434,435 Wheeler and co-workers reported that FICZ, when administered to mice infected with influenza virus could slightly AR


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FICZ could, in fact, ameliorate the pathology of EAE.421 Thus, the dose of FICZ may possibly influence the responses. Psoriasis and Atopic Dermatitis (AD). Treatment of human primary keratinocytes with FICZ in vitro has been shown to induce epidermal differentiation and to upregulate the expression of genes involved in epidermal differentiation supporting a physiological role of AHR in the skin.448,449 It was recently demonstrated that a lack of the AHR in keratinocytes, resulted in increased production of proinflammatory cytokines, including IL-22, and increased skin inflammation in the imiquimod-induced mouse psoriasis model. Daily i.p. administration of 100 μg FICZ kg−1 for 6 days to AHRproficient mice was, furthermore, found to ameliorate imiquimod-dependent skin inflammation.450 In another report, the intracellular quantity of FICZ and of tryptophan, the metabolic precursor of FICZ, in skin immune cells was shown to be regulated by a complex that includes the activation marker CD69 and the membrane transport protein LAT1-CD98. The authors suggested that decreased uptake of tryptophan could reduce IL-22 production in psoriatic skin.451 Mice with constitutively active AHR in keratinocytes develop an AD-like phenotype, but AHR activation in wild type mice daily treated for 4 weeks with 0.5 μg FICZ kg−1 did not result in an AD-like phenotype.452 Diabetes. Abu-Rezq and Millar used a T-cell mediated autoimmune diabetes model where diabetes was induced by multiple low doses of the pancreatic islet β-cells toxin streptozotocin. They found that i.p. coadministration of 5.7 μg FICZ kg−1 together with streptozotocin for 5 days suppressed the induced diabetes.422 The effect of FICZ on wound closure was investigated in a study using wild-type mice and mice that exhibit severe wound healing impairments because of type 2 diabetic phenotypes. Application of a topical ointment containing 0.6 μg FICZ kg−1 was found to effectively promote the wound healing in both normal and diabetic skin. The authors also showed that FICZ could accelerate wound closure in an in vitro assay.453 Systemic Lupus Erythematosus (SLE) and Amyotrophic Lateral Sclerosis (ALS). A role for cutaneous AHR activation by photoproducts such as FICZ in SLE patients was suggested in a study reporting that increased lesional expression of CYP1A1 correlated with the expression of proinflammatory cytokines that contribute to the pathogenesis of SLE.414 Ash and coworkers conducted a study to examine if AHR ligands might affect the risk of ALS by altering the amounts of aggregated TAR DNA Binding Protein-43 (TDP-43) in the central nervous system. They found that addition of FICZ seemed to promote ALS since they observed that FICZ increased the levels of endogenous TDP-43 protein in neuron-differentiated induced pluripotent stem cells derived from an ALS-patient and in human neuroblastoma M17 cells. Moreover, addition of FICZ increased TDP-43 levels, caused improved TDP-43 stability, and significantly increased expression of a number of ALSassociated genes in human H4 neuroglioma cells.454 Thyroid Eye Disease (TED) and Ocular Behcet’s Disease (BD). In orbital fibroblasts explanted from patients with TED, FICZ blocked several of the detrimental effects. FICZ prevented profibrotic signaling via the Wnt/β-catenin signaling pathway and transcription of genes involved in myofibroblast production.455 Decreased expression of AHR was reported in patients with active BD. In peripheral blood mononuclear cells derived from BD patients, AHR activation with FICZ inhibited proinflammatory cytokines but stimulated IL-22 production.456

suppress the adaptive virus-specific T-cell responses in CYP1A1defective mice but not in wild-type mice.390 Likewise, Yamada and co-workers reported that FICZ negatively influenced innate antiviral responses to vesicular stomatitis virus,436 but a study of corneal lesions in ocular herpes simplex virus infected mice found no significant effects after i.p. administrations of FICZ.437 Mast cells (MCs) are critical for the regulation of mucosal immunity and allergic and anaphylactic responses. Sibilano and co-workers studied how FICZ affected degranulation in mouse bone marrow-derived cultured mast cells (BMMCs) during the challenge with antigen-specific IgE (Ag). A single treatment with FICZ boosted MC responses to Ag. However, two pretreatments with FICZ before Ag challenge led to impaired MC degranulation responses.438 Other important results were presented by Zhou and co-workers who found that when FICZ was added to BMMCs during the sensitization step, this molecule displayed a nonlinear dose response and led to increased MC responses only when added at low but not at higher concentrations.439 Also, other studies with MCs have reported that FICZ can increase Ag-mediated degranulation together with increased formation of ROS, as well as endoplasmatic reticulum and mitochondrial stress responses.385,440 Taken together, several studies thus suggest that the endogenously activated AHR can have critical roles in MC homeostasis, but its role depends on the dose and the treatment schedule. Very little is known about the function of AHR in the regulation of immune responses in the CNS, but a recent study suggested anti-inflammatory effects of FICZ by attenuating proinflammatory responses induced by bacterial endotoxins in primary mouse microglial cells.441 In conclusion, FICZ can increase development of both inflammatory Th17 cells and regulatory T cells and thus seems both to have the capacity to aid clearance of infections and to suppress immunity. 5.2.4.2.3. Inflammatory Diseases and Cancer. Inflammatory Bowel Diseases (IBD). In experimental studies of induced colitis in mice treated with dextran sulfate sodium, trinitrobenzenesulfonic acid, or transfer of T cells to recombinaseactivator gene 1 (RAG1)-deficient mice, single or repeated i.p. injections of 50 μg FICZ kg−1 led to activation of AHR. This triggered regulatory signals in the gut, which culminated in the production of IL-22 in colonic tissue and suppression of colitis.442−447 In support of a protective role for FICZ in IBD, addition of FICZ was found to lead to a dose-dependent upregulation of IL-22 expression in lamina propria mononuclear cells from Crohn’s disease patients and from healthy individuals.442 Multiple Sclerosis (MS). In 2008, the laboratories led by Stockinger and Weiner, respectively, tested whether AHR activation with FICZ, when added during induction of experimental autoimmune encephalomyelitis (EAE) in a mouse model of MS, protected against or accelerated the pathology of EAE. In both studies, either if 30 μg FICZ kg−1 was administered in the antigen emulsion together with myelin oligodendrocyte peptide 35−55 (MOG35−55) in complete Freund’s adjuvant (CFA)407 or if 50 μg FICZ kg−1 was injected i.p. 24 h before EAE was induced with myelin antigen in CFA,408 the results indicated that FICZ increased Th17 cell differentiation and aggravated autoimmune pathology. As a contrast, in a follow-up study performed by Stockinger and co-workers, when 10 mg FICZ kg−1 was injected i.p. 24 h before EAE was induced with myelin antigen in CFA, the results indicated that AS


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manner.472 Thus, a dual role for FICZ in tumorigenesis can be postulated. First, high concentrations of FICZ seem to stimulate tumor cell migration and invasiveness through increasing the expression of growth factor genes and genes associated with CSC. FICZ has, however, in other studies been shown to inhibit proliferation of cancer cells through inhibiting the expression of CSC-associated factors, repress cell migration, promote differentiation, and enhance immune cell-dependent control of tumor development. In conclusion, the evidence is accumulating that FICZ can be involved in the etiology of several inflammatory diseases and cancer. The results point to both suppressing and exacerbating effects of FICZ, but it should be stressed that the results at this early stage are incomplete, since in most cases only one treatment protocol has been used. Furthermore, most studies have not considered the rapid metabolic degradation of FICZ. 5.2.4.2.4. Miscellaneous Biological Effects. FICZ is a Powerful Photosensitizer That Can Cause Skin Pigmentation and Skin Aging. FICZ is an endogenous chromophore that at nanomolar concentrations acts as a photosensitizer by potentiating UVA-induced oxidative stress.473 ROS generated by FICZ/UVA combinations cause oxidative damage.473,474 ICZ, on the other hand, does not work as a photosensitizer.473 Instead, ICZ was shown to decrease oxidative DNA damage by activating ROS scavenging functions.475 The UV-stress response in mammalian cells has been reported to be regulated by FICZ,344 and FICZ can also stimulate melanogenesis in human skin cells and in mouse skin.476,477 In addition, FICZ has been reported to reduce collagen synthesis and may therefore be involved in photoaging of the skin.478 FICZ Stimulates Intra Chromosomal Changes and Moves Transposable Elements. At relatively high concentrations, FICZ has been shown to increase sister chromatid conversion and gene conversion in Saccharomyces cerevisiae as well as to cause concentration-dependent increases in sister chromatid exchanges in Chinese hamster ovary cells.350 In 2010, Okudaira and co-workers showed that picomolar levels of FICZ could induce long interspersed nucleotide element-1 retrotransposition (LINE-1) in human hepatocellular carcinoma cells in a manner that did not require the AHR.479 FICZ has also been shown to regulate the transcription of Alu retrotransposons, and when administered through intratesticular injection, 4 μg FICZ kg−1 was found to repress expression of genes that control small noncoding transposable elements that are involved in maturation of germ cells.468,480 FICZ Affects Circadian Rhythms. FICZ has been shown to alter the expression of the clock genes Per1 Cry1, Cry2, and Bmal1 and to decrease phase shifts in response to light.481,482 FICZ Affects Food Preferences. Like TCDD, FICZ can induce a strong and persistent avoidance of novel food items in rats. When 100 μg FICZ kg−1 was administered to Sprague− Dawley rats by gavage, it triggered practically total avoidance of novel chocolate and the avoidance was still clearly present 2 weeks later when chocolate was offered again.483 FICZ Activates Nuclear Hormone Receptors. FICZ has also been found to activate receptors belonging to the superfamily of nuclear hormone receptors including vertebrate vitamin D receptors, the invertebrate pregnane X receptor, invertebrate, and vertebrate liver X receptors (LXRs) including the human LXRα and LXRβ, as well as peroxisome proliferator-activated receptors (PPARs).484−487 5.2.4.2.5. Potential Applications of Indolo[3,2-b]carbazole AHR Ligands in Medicinal Chemistry. The AHR is a potential

Asthma. On the basis of the results from a study of ovalbumin (OVA)-induced allergic asthma in mice, FICZ was suggested to have antiasthmatic effects. The authors reported significantly reduced pulmonary eosinophilia and Th2 cytokine expression in mice that had been injected i.p. with 3 or 30 μg of FICZ kg−1 during the sensitization step.457 Also, data presented in a study by Thatcher et al. suggested that FICZ could be involved in the normal regulation of Th2-mediated immunity in the lung via a dendritic cell-dependent mechanism, since the compound markedly inhibited priming of T cells by mouse lung dendritic cells incubated overnight with lipopolysaccharide (LPS) and OVA.431 However, in another study on the role of AHR activation in allergic asthma, FICZ was shown to stimulate expression of the pro inflammatory Jagged 1 (Jag1)−Notch pathway in mouse bone marrow-derived dendritic cells in an AHR-dependent manner.458 Allergy. Administration of FICZ (100 μg kg−1) together with antigen-specific IgE in a single intravenous (i.v.) injection during the challenge step in a mouse model of systemic anaphylaxis caused significantly increased plasma histamine levels. Repeated administrations of FICZ 3 and 16 h before Ag challenge could, however, protect against the allergic reaction.438 That FICZ could enhance anaphylactic responses upon Ag challenge was also noted in an in vivo study of passive cutaneous anaphylaxis. In mice that had been sensitized by an intradermal injection containing anti-OVA IgE together with 0.03 or 0.3 μg FICZ kg−1, Zhou and co-workers reported significantly increased vascular leakage in the skin.439 Schultz and co-workers studied peanut allergic responses in mice that had been exposed to repeated i.p. or oral treatments with up to 500 μg FICZ kg−1 before and during initiation of sensitization to peanut. FICZ was not found to increase the percentage of the regulatory T cells in peanut-sensitized mice and did not affect peanut extract-induced cytokine production.389 Peritonitis. AHR activation by FICZ suppressed aluminduced peritonitis in C57BL/6 mice when 200 μg FICZ kg−1 was injected i.p. 40 min ahead of the aluminum salt (an aluminum hydroxide/magnesium hydroxide mixture was used in the study). Pretreatment of mouse peritoneal macrophages with FICZ inhibited LPS-induced expression of the pattern recognition receptor NLRP3 and reduced aluminum saltinduced recruitment of inflammatory cells.459 Cancer. Hyper-activation of the AHR with high amounts of FICZ appears to activate cancer-related end points. FICZ has been reported to increase the activity of growth factors,460 increase proliferation of stem cells,402 increase expression of stem cell associated factors in cancer cells,461 stimulate migration in scratch-wound assays,462 and increase tumor breaching of the lymph endothelial barrier.463 However, the AHR can also be antiproliferative to cancer stem cells (CSCs) by down-regulating the activity of stem cell-associated factors.464,465 Accordingly, FICZ has been shown to reduce the expression of stem-cell associated factors in cancer cells466−468 and to cause cell cycle and proliferation arrest.469 Other studies have reported that FICZ could repress cell migration in a wound healing assay and augment signaling events that drive differentiation of leukemia cells.470,471 FICZ was also found to stimulate immune cell antitumor functions by enhancing NK cell-mediated tumor rejection. In mice subcutaneously implanted with murine T-cell lymphoma cells or implanted with melanoma cells, Shin and co-workers showed that three i.p. injections of 3 μg FICZ (about 150 μg kg−1) could significantly inhibit tumor growth in an AHR- and NK cell-dependent AT


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compared to 10−2 cm2 V−1 s−1 for the devices based on the Nsubstituted material, a difference which was ascribed to the ability of 4 to form higher-ordered films where the molecules adopt a head-on orientation in relation to the substrate as judged from interpretation of X-ray diffraction data. It was suggested that the more efficient molecular packing arrangement involving N−H···π interactions between molecules of 4 enables more efficient charge transport, thereby accounting for the observed differences in field-effect performance.240 In a later study, OFET devices fabricated from 2,8-dichloro-5,11-dihydroindolo[3,2b]carbazole (351) displayed no field-effect performance, whereas the charge carrier mobility of the devices based on the N,N-dialkylated derivative 352 was 0.14 cm2 V−1 s−1 or 0.5 cm2 V−1 s−1 for the thin films or single crystals, respectively. It was suggested that introduction of the alkyl chains promotes self-organization causing a shift in molecular packing from herringbone to one-dimensional π−π stacking, thus strongly enhancing the charge transport properties.488 It has previously been reported that organic thin film transistor (OTFT) devices based on 3,9-dichloro-5,11-didodecyl-5,11-dihydroindolo[3,2b]carbazole displayed low field effect transistor (FET) mobility despite the fact that the semiconductor formed a crystalline film, which was rationalized in terms of its failure to sufficiently stabilize the injected hole carriers, whereas OTFTs based on the isomeric 2,8-dichloro-5,11-didodecyl-5,11-dihydroindolo[3,2b]carbazole (353) displayed substantial mobility (0.02−0.03 cm2 V−1 s−1) and a high current on/off ratio (105−106).242 A recent study encompassed 5,11-dihydro-5,11-dimethylindolo[3,2-b]carbazole (354), which also displayed a herringbone packing motif wherein each molecule was surrounded by six neighbors, featuring C−H···π interactions between one of the hydrogen atoms of the methyl substituents with the central ring (distance 2.68 Å), as well as with the peripheral benzene rings (distance 3.01 Å) of the nearly planar heterocyclic core of adjacent molecules. The hole mobility of the material 354 used as the semiconductor layer in an organic thin film transistor was 7 × 10−3 cm2 V−1 s−1.489 The lower mobility limit for 5,11dihydro-5,11-dioctylindolo[3,2-b]carbazole (313) as the semiconductor layer was estimated to 1.5 × 10−5 cm2 V−1 s−1,490 which is in line with previous findings.307 In another recent contribution, p-type OFET devices based on the system 355, in which the alkyl substituents did not disturb the N−H···π interactions, displayed a charge carrier mobility of ≈10−2 cm2 V−1 s−1. The herringbone packing mode adopted by 355 is however disrupted by installation of two additional alkyl chains at the nitrogen atoms of the heterocyclic core, and the resulting material 356 showed a mobility of ≈10−3 cm2 V−1 s−1 but with substantial improvement in solubility and processability.246 The Ullmann reaction has enabled convenient access to a variety of indolo[3,2-b]carbazoles bearing aryl substituents on both nitrogen atoms. All materials mentioned in this paragraph are prepared using routes that involve an Ullmann reaction, for instance the derivative 357 (Figure 26) equipped with multiple alkoxy groups reached a hole drift mobility value of 2.1 × 10−6 cm2 V−1 s−1 (50% sample in bisphenol Z polycarbonate prepared from THF solution).318 It has been demonstrated that the location of a single methoxy group at the N-phenyl substituents attached to the 6-pentylindolo[3,2-b]carbazole core has relatively little influence on the molecular properties, where for instance the neat material 358 as a glassy layer displayed a hole drift mobility of 5 × 10−4 cm2 V−1 s−1 at an electric field of 6.4 × 105 V cm−1 at ambient temperature.321 Among a set of Nsubstituted phenyl-, carbazolyl-, and fluorenyl-derivatives of 6-

clinical target for multiple diseases including cancer and autoimmune dysfunction, and AHR agonists as well as antagonists might effectively block many critical steps that can lead to disease. Given the increasingly important roles described for FICZ in physiologic and pathological processes, there is no doubt that advanced knowledge of FICZ/AHR-mediated molecular signaling will have a significant impact on the development of new therapeutics for humans. Especially, the observations that FICZ can induce regulatory T cells have generated interest in developing treatments for patients with inflammatory disorders, for example, inflammatory bowel disease, multiple sclerosis, psoriasis, diabetes, systemic lupus erythematosus, asthma, and cancer. On the basis of other findings, FICZ might be utilized in, for example, photodynamic therapies, wound healing treatments, and for regenerative therapies by expanding hematopoietic stem cells. Many of the effects reported have so far only been seen in animal models, and in animal and human cell lines, and effects remain to be confirmed in humans. A growing body of research suggests that the biological effects of various types of AHR-activators are very similar, and there seems to be no special mode of action that distinguishes sustained AHR-activation with high doses of FICZ from that of toxic ligands such as TCDD. Therefore, a particularly important aspect when considering medical treatments based on FICZ is the potential interaction with factors that can inhibit the CYP1A1-mediated turnover of FICZ and lead to high doses of FICZ. 5.3. Indolo[3,2-b]carbazoles in Materials Science and Related Applications

The groundbreaking studies identifying indolo[3,2-b]carbazole derivatives as promising semiconductor materials for OLEDs27 or transistor devices as a result of their low-lying HOMOs and large band gaps242,307 have set the stage for many successive efforts aiming at further refining those desirable characteristics by structural modifications. Although most materials studied in this area are extended πsystems where the indolo[3,2-b]core is decorated with various aromatics or heteroaromatics, even structurally quite simple indolo[3,2-b]carbazoles exhibit interesting properties for applications in electronic devices. In order to probe the influence of N−H···π interactions on the charge transport properties, OFET devices were fabricated using either 5,11dihydroindolo[3,2-b]carbazole (4) itself or 5,11-dihydro-5,11bis(4-octylphenyl)indolo[3,2-b]carbazole (350) (Figure 25). The former displayed the higher mobility of ≈0.1 cm2 V−1 s−1

Figure 25. Some structurally simple indolo[3,2-b]carbazole materials. AU


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Figure 26. Selected materials based on N-arylated indolo[3,2-b]carbazoles.

pentylindolo[3,2-b]carbazole, the highest hole drift mobility was observed for compound 359 (as amorphous layer), exceeding 10−3 cm2 V−1 s−1 at an electric field of 3.6 × 105 V cm−1.320 The material 360 based on an indolo[3,2-b]carbazole core as the donor decorated with benzimidazole acceptor motifs interspaced by phenylene units has been employed in red, yellow, and green phosphorescent organic light-emitting diodes as the host doped with iridium-based phosphors as emitters. However, particularly good performance was observed for a red device featuring 360 as the host doped with Os(bpftz)2(PPhMe2)2, which exhibited saturated red phosphorescence with external quantum efficiency and power efficiency of 22% and 22.1 lm W−1, respectively.319 A device relying on compound 361 as the blue light-emitting layer has been fabricated, displaying for example, a turn on voltage of 6.1 V, maximum luminance reaching 5634 cd m−2 and maximum luminance efficiency of 2.96 cd A−1, also providing insight into this particular type of indolo[3,2-b]carbazole derivatives envisioned as materials for OLED applications.241 In a recent study encompassing spectroscopic methods as well as quantum chemical calculations, it was concluded that restriction of the conformational freedom of the substituents is one of the key factors for maintaining high fluorescence yields of indolo[3,2-b]carbazole materials.491 When evaluated in single carrier devices, the material 362 (Figure 27) exhibited a much higher hole mobility than electron mobility (1.02 × 10−5 and 1.83 × 10−9 cm2 V−1 s−1, respectively),255 which is in concurrence with later findings for

Figure 27. Structure of 5,11-dibutyl-5,11-dihydro-6,12-di(1naphthalenyl)indolo[3,2-b]carbazole.

5,11-dihexyl-5,11-dihydro-6,12-di(thien-2-yl)indolo[3,2-b]carbazole.492 A device with low turn on voltage (2.6 V) was fabricated using compound 362 in the form of an undoped thin film as the emitting layer, displaying deep blue emission, whereas application of 362 as a hole transport material and host in conjunction with iridium-based dopants provided high-performance yellow and red phosphorescent OLEDs.255 Materials of this type are readily accessible from acid-induced condensation reactions of indoles with aromatic or heteroaromatic aldehydes as the key step, followed by further suitable modifications (section 5.1). Compound 363 (Figure 28), available in 68% yield by Suzuki coupling between 3,9-dibromo-5,11-dihydro-5,11dioctylindolo[3,2-b]carbazole and phenylboronic acid, has AV


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Figure 28. Selected indolo[3,2-b]carbazole materials bearing phenyl substituents.

dimesitylboryl groups and bearing butyl substituents on the indolocarbazole nitrogen atoms has also been studied as an emitting layer for OLED devices showing blue emission.245 Several conceptually related materials for DSSC applications have been prepared and evaluated. The sensitizer 367 (Figure 30) anchored onto a TiO2 film in a DSSC displayed an overall conversion efficiency of 7.3% under 100 mW cm−2 irradiation.493 Likewise, an overall efficiency of 7.03% was achieved for a DSSC based on compound 368 as the sensitizer. It was also concluded, that the presence of the bridging benzothiadiazole and thieno[3,2-b]thiophene units contributed to improved photostability.258 A subsequent study featured three additional related compounds, from which the relatively photostable dye 312 emerged as the best example, displaying an η value reaching 7.49%.304 The multi donor−π−acceptor type material 369, featuring an indolo[3,2-b]carbazole core as the main donor group reinforced by additional electron-donating motifs, has been identified among a set of four related systems as the most effective photosensitizer in a DSSC device displaying a high efficiency of 8.09% under 100 mW cm−2 irradiation. The diethylaniline unit was instrumental for good light-harvesting ability.260 Likewise, the sensitizer 370 exhibited some promising data in a DSSC application with a conversion efficiency of 8.24% and short circuit current of 15.72 mA cm−2.305 All compounds in these studies were constructed using Suzuki reactions as the key step starting from brominated indolo[3,2-b]carbazole precursors (section 5.1), including a condensation reaction between a carboxaldehyde functionality with 2-cyanoacetic acid. An organic thin film transistor (OTFT) featuring the extended indolo[3,2-b]carbazole-based system 248 (Figure 31) as the semiconductor layer has been devised, displaying decent field effect mobility with good photostability under visible illumination unlike related pentacene-based devices, the latter property being ascribed to the effect of the significant HOMO−LUMO gap of ≈2.95 eV.248 In a further application, a sensitive strain gauge capable of measuring up to ≈2.48% of elastic strain was constructed incorporating two OTFTs based on 248 in an inverter-type circuit, targeting practical applications in strain-sensing in flexible electronics.494 Moreover, a hybrid complementary (hybrid-CMOS) inverter device envisioned for display and pixel electronics has been fabricated on a glass surface featuring a top-gate n-channel MoS2 nanosheet field effect transistor (FET) and a bottom-gate p-channel FET based on the material 248.495 The alkyl derivative 249 exhibits good

previously been identified among a group of related derivatives as an efficient p-type semiconductor when evaluated in FET devices displaying good environmental stability, with hole mobilities as high as 0.2 cm2 V−1 s−1 and on/off current ratio >106.303 In a later study, the excellent performance of 363 was confirmed, exhibiting superior hole mobility compared to, for example, the system 364.273 Good hole mobility (0.22 cm2 V−1 s−1) has also been observed for the material 365 in a FET device. In the same study, it was established that the presence of alkyl chains on both ends of this type of derivative gives rise to a film morphology where the molecules tend to attain a perpendicular orientation to the surface rather than aligning to it in a parallel fashion.294 Compound 366 exhibited good thermal stability, and a maximum luminance efficiency of 3.64 cd A−1 as a hole transporting material in an OLED device.300 To promote intramolecular charge transfer, the unsymmetrical compound 328 has been devised based on a pivotal indolo[3,2-b]carbazole electron donor core flanked by an electron-donating diphenylamino group moiety and a benzothiazole acceptor unit on the opposite side. The material displayed good thermal stability and hole transporting properties.243 The related compound 327 (Figure 29) incorporating an

Figure 29. Structures of the materials 327 and 328.

acceptor dimesitylboryl moiety acted as selective sensor for fluoride ions via interaction with the boron center (switch from an electron acceptor to a donor by changing coordination number from three to four), manifested by a distinct color change.313 The structurally related 2,8-di(benzothiazol-2-yl)5,11-dibutyl-5,11-dihydroindolo[3,2-b]carbazole has been shown to possess a high fluorescence quantum yield in dilute THF solution of 0.38 and good thermal stability, as the onset degradation temperature for 5% weight loss was determined by TGA to 418 °C.244 A variant capped at both C-2 and C-8 by AW


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Figure 30. Selected indolo[3,2-b]carbazole materials equipped with additional heterocyclic motifs.

Figure 31. Examples of extended systems based on the indolo[3,2-b]carbazole core.

Figure 32. Selected materials having alkene spacers between the indolo[3,2-b]carbazole core and the peripheral aryl groups.

yellow photoluminescence in the solid state compared to the blue emission observed in solution.282 In a recent contribution p-type OFETs have been devised using the extended indolo[3,2b]carbazole derivative 300, which exhibited desirable characteristics such as a high hole mobility of 0.17 cm2 V−1 s−1 and current on/off ratio of 1.2 × 106 in combination with a low threshold voltage of −0.8 V.298 Extension of the π-conjugated system may also be achieved by incorporation of alkene spacers between the heterocyclic core and the peripheral aryl units. The compound 332 (Figure 32) bearing diphenylethenyl side arms has been explored as a hole transporting material in a perovskite solar cell displaying a power conversion efficiency of 13.86%.265 An electroluminescent device featuring the material 372 as the emitter exhibited a low turn-on voltage (2.65 V), as well as maximum current efficiency and maximum brightness reaching 7.06 cd A−1 and

solubility in common organic solvents and crystallizes forming single-crystal nanowire arrays via a direct printing method. FETs fabricated using such single-crystal nanowires in the p-type active channel displayed excellent performance with a high field effect mobility of 1.5 cm2 V−1 s−1 (average from 20 individual devices) and good environmental stability as demonstrated by stable operation over 30 days.249 When employed in a layer blended together in equal ratios (w/w) with PC60BM and an organic dye (D149) for enhanced charge transfer, the molecule 249 functioned as a donor material in a photovoltaic device with a power conversion efficiency of 2.51%.496 In a similar application, the high hole transporting ability of 249 was exploited in a solid state perovskite solar cell reaching a power conversion efficiency of 11.26%.497 A different type of extended indolo[3,2-b]carbazoles has been prepared and investigated in detail, as exemplified by the system 371, which displayed bright AX


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Figure 33. Selected indolo[3,2-b]carbazole copolymers.

68729 cd m−2 at 13 V, respectively, with a maximum external quantum efficiency of 2.79%.308 As can be seen from the examples above, there is now a certain fundamental understanding of how the key parameters crucial for device performance may be modulated by molecular design of indolo[3,2-b]carbazole-based materials, although direct comparison of data generated in different studies is challenging for instance due to diverse device configurations. With even better synthetic and analytical methods around the corner, further substantial progress toward highly efficient and durable organic electronics relying on the indolo[3,2-b]carbazole core can be anticipated.

indolo[3,2-b]carbazole core. Both materials were demonstrated to exhibit superior hole mobility in FET devices compared to polyfluorene, while electroluminescence devices relying on 373 or its C3,C9-linked isomer as the emissive layers displayed blue and green colors, respectively.503 Polymerization of a diborylated indolo[3,2-b]carbazole monomer with electron-deficient dibromo-heterocycles using Suzuki coupling has resulted in a set of indolo[3,2-b]carbazole-based donor−acceptor alternating conjugated copolymers, among which the material 374 exhibited the highest power conversion efficiency of 1.40% when used in a photovoltaic cell with PC70BM as the acceptor. In addition, the hole mobility of 374 was measured to 1.89 × 10−4 cm2 V−1 s−1 in a thin film transistor application.504 The copolymer 375 (Figure 34) composed of an indolo[3,2b]carbazole core as the donor motif and electron-accepting 2,2′-

5.4. Indolo[3,2-b]carbazole Polymers

Since the disclosure of the pioneering studies of polyindolo[3,2b]carbazoles more than 10 years ago, which shed light on some of the fundamental aspects concerning their preparation and properties,498−500 this particular research topic has attracted further attention, inspiring a number of sequels. The early developments up to 2007 have been subjected to a thorough discussion in a focused survey.501 Studies of copolymers incorporating various modified indolo[3,2-b]carbazole cores constitute the prevailing direction of current research in this particular area, targeting applications as materials for fabrication of electronic devices. The general synthetic approach relies on Suzuki coupling between borylated indolo[3,2-b]carbazole monomers with halogenated heterocyclic building-blocks. As is evident from the studies cited below, some of the indolo[3,2b]carbazole copolymers display promising properties, but much still remains to be done in order to reach performance levels acceptable for long-term practical applications. Additional publications on this theme can be found in the patent literature, which keen readers may want to explore in case a wider overview is required. The polymerization of indolo[3,2-b]carbazoles with FeCl3 taking place at C-2/C-8498 has been supplemented with new examples involving the additional inclusion of formaldehyde dimethyl acetal as the C1-synthon for conversion of 5,11dihydro-6,12-diphenylindolo[3,2-b]carbazole or the monomer 250 (section 5.1) to hyper-cross-linked microporous polymers, the latter with the ability to store hydrogen (1.68% w/w at 77.3 K and 1.13 bar) and carbon dioxide (3.58 mmol g−1 at 273 K and 1.13 bar) with selectivity for CO2 over N2 reaching 29:1 at 273 K.502 Many of the studies focus on copolymers based on indolo[3,2b]carbazoles with branched N-substituents, which are essential for achieving acceptable solubility. In an early study, the alternating copolymer 373 (Figure 33) containing fluorene and indolo[3,2-b]carbazole motifs was prepared by Suzuki coupling along its isomer linked via the C3,C9-positions of the

Figure 34. Additional selected copolymers incorporating indolo[3,2b]carbazole motifs bearing branched alkyl substituents.

bithiophene and 2,1,3-benzothiadiazole units has been evaluated as a low band gap semiconductor in a solar cell as a mixture with PC60BM (ratio 1:2 w/w), which displayed a power conversion efficiency of 3.6%. The copolymer was constructed following a route relying on Stille and Suzuki cross-couplings, employing the monomer 296 (section 5.1) as one of the building blocks.295 A copolymer featuring the same scaffold, with 1decylundecyl substituents on the nitrogen atoms of the indolo[3,2-b]carbazole components while lacking the aliphatic chains on the thiophene fragments, has also been prepared using the Suzuki reaction and was applied in a photovoltaic device with PC60BM in the active layer, reaching a power conversion efficiency of 2.07%.297 Moreover, in a slightly different molecular design, the 2,2′-bithiophene motifs have been replaced by 4,4dioctyl-4H-cyclopenta[2,1-b;3,4-b′]dithiophene units employAY


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the copolymer 378 as the donor and the fullerene derivative PC70BM as the acceptor (ratio 1:4 w/w) exhibited a power conversion efficiency of 2.54%.507 The indolo[3,2-b]carbazole copolymers 380a and 380b incorporating benzo[d][1,2,3]triazole units in conjunction with thiophene or selenophene motifs have been prepared using cross-coupling reactions and were employed for fabrication of field effect transistors and polymer solar cells. It was demonstrated that the selenophene containing material 380b displayed higher hole mobility compared to its thiophene analogue 380a (0.01 versus 0.0014 cm2 V−1 s−1) in OFET devices, while the power conversion efficiency of solar cell devices relying on blends of 380b and 380a with PC60BM as the active layers (ratio 1:2 w/w) were 2.39% and 1.01%, respectively.509 The random copolymers 381a and 381b (Figure 37) have been prepared using Stille coupling between 3,9-dibromo-5,11-

ing a Suzuki polymerization approach, producing the copolymer 376, which however displayed rather disappointing performance as an active layer with PC70BM in a photovoltaic cell having a power conversion efficiency of 0.39% at best.505 An additional study of a material incorporating indolo[3,2b]carbazole moieties alongside 2,1,3-benzothiadiazole, as well as an extension including its selena-analogue have been realized by construction of the narrow band gap copolymers 377a296 and 377b506 (Figure 35) using the commonly employed Suzuki

Figure 35. End-capped copolymers containing indolo[3,2-b]carbazole units.

polymerization, followed by end-capping with bromobenzene and phenylboronic acid. The power conversion efficiencies in photovoltaic cells based on 377a/PC70BM and 377b/PC60BM (1:2 w/w) were 2.4% under 80 mW cm−2 illumination296 and 1.52% under 100 mW cm−2 illumination,506 respectively. Other studies featured alternative acceptor segments, for instance, quinoxaline in the copolymer 378507 or thieno[3,4b]pyrazine in the copolymers 379a and 379b (Figure 36).508 All these materials were prepared by Suzuki coupling and were subjected to comparative evaluation of their optical and electrochemical properties in photovoltaic devices.507,508 For example, a solar cell device based on an active layer containing

Figure 37. Random copolymers incorporating indolo[3,2-b]carbazole units.

dihydro-5,11-dioctylindolo[3,2-b]carbazole and the suitable dibrominated benzo[c][1,2,5]thiadiazole and 2,5-bis(trimethylsilylstannyl)thiophene by variation of the ratios of the reactants in the monomer feed. When evaluated in photovoltaic solar cells, the combination of copolymer 381b with the acceptor PC70BM (ratio 1:1 w/w) displayed the better performance with an open circuit voltage of 0.54 V and power conversion efficiency of 1.63%.510 In an earlier publication, it has been demonstrated that the electronic and optical properties of the random copolymers 382 (also obtained by Stille coupling polymerization) may be efficiently fine-tuned for applications in photovoltaic solar cells by controlling the ratios of the electrondonating indolo[3,2-b]carbazole/thiophene motifs and pyrazino[2,3-g]quinoxaline acceptor fragments. The best performance was measured for a device based on 382 (ratio m:n = 0.7:0.3) blended with PC70BM (ratio 1:3 w/w) with a power conversion efficiency of 3.24%.261

6. INDOLO[2,3-C]CARBAZOLES 6.1. Synthesis and Reactions

There have been relatively few publications featuring indolo[2,3-c]carbazoles during the main reporting period of this review, continuing the historical trend of this isomer as the least studied of the indolocarbazoles in terms of published work. Nevertheless, a few interesting contributions have appeared, featuring techniques which may prove useful in forthcoming approaches to other targets than those outlined below. In a study focusing on synthesis of pyrrolo[2,3-c]carbazoles from 3-

Figure 36. Indolo[3,2-b]carbazole copolymers incorporating quinoxaline, thieno[3,4-b]pyrazine, or benzo[d][1,2,3]triazole acceptor motifs. AZ


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Scheme 85. Stepwise Conversion of 3-Aminocarbazoles into Indolo[2,3-c]carbazoles

Scheme 86. Synthetic Route to the Parent Indolo[2,3-c]carbazole 5 and One of Its Derivatives

aminocarbazoles, the resulting products could be further converted into indolo[2,3-c]carbazoles. Thus, the pyrrolo[2,3c]carbazoles 383a−b were prepared in good yields from the 3aminocarbazoles 384a−b and ethylene glycol using a SnCl2/ RuCl3-mediated reaction. Subsequent annulation on the pyrrole fragment of 383a−b with acetonylacetone in the presence of ptoluenesulfonic acid gave the indolo[2,3-c]carbazoles 385a−b in good yields (Scheme 85).511 The previously studied parent indolo[2,3-c]carbazole 529,512 has been prepared using a new route, featuring an initial substitution reaction involving the building blocks 386 and 173 in the presence of potassium carbonate as the base, followed by a palladium-catalyzed Heck-type cyclization of the resulting precursor 387 at 140 °C for 6 h, which occurred with concomitant loss of the N-substituents. When the annulation reaction was conducted at 110 °C for 4 h, the N-sulfonyl groups remained untouched, providing access to compound 388 (Scheme 86).192 In a report disclosing preparation and studies of the photoluminescent behavior of an extensive set of fused carbazole derivatives, a single example of an indolo[2,3-c]carbazole, namely compound 389, was reported as a product from the indium-catalyzed cyclization of the 3,3′-biindolyl 390 with methyl propargyl ether (Scheme 87).513 Following a virtual high-throughput screening toward new materials for OLED devices, the system 391 was identified as a promising candidate. In its synthesis, the Cadogan reaction was used for a double cyclization of a precursor accessed by a double Suzuki coupling of 1,2-dibromobenzene with 2-(nitrophenyl)boronic acid. The resulting parent indolo[2,3-c]carbazole 5 underwent a palladium-catalyzed N-arylation with the aryl bromide 392, finally providing the target product 391 (Scheme 88).514

Scheme 87. Indium-Catalyzed Cyclization of a 3,3′-Biindolyl Derivative with Methyl Propargyl Ether Providing the Indolo[2,3-c]carbazole 389

Routes to 5,10-dihydrobenzo[a]indolo[2,3-c]carbazoles relying on nitrene insertion for the formation of one of the indole fragments have been disclosed.515,516 Sonogashira coupling of 2(2-bromophenyl)indole (393) with trimethylsilylacetylene gave 2-(2-ethynylphenyl)indole (394), which underwent a second Sonogashira reaction, affording the cyclization precursor 395. Subsequent gold-catalyzed annulation of 395 gave the benzocarbazole 396, which was cyclized in 1,2-dichlorobenzene at 160 °C either directly, or after N-alkylation, rendering the indolo[2,3-c]carbazoles 397 or 398, respectively. A second Nalkylation gave the derivative 399 (Scheme 89). An alternative variant of this route leading to the key intermediate 396 (presumably also via cyclization of 395, not isolated) employing a gold-catalyzed indole ring formation/annulation of an aniline precursor was also presented in this report.516 In a later study, the N-butyl substituted analogue of 398 was converted to twin donor systems featuring 1,3-propylene or m-xylylene bridges between the benzo[a]indolo[2,3-c]carbazole motifs.517 As a further recent development, chiral hetero[7]helicenes based on the benzo[a]indolo[2,3-c]carbazole core have been prepared and studied.518 Structurally related systems featuring an BA


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Scheme 88. Alternative Approach to 5,8-Dihydroindolo[2,3-c]carbazole (5) and Its Elaboration into the Material 391

Scheme 89. Synthetic Routes to Benzo[a]indolo[2,3-c]carbazoles

indolo[2,3-c]carbazole fused to a quinoline have also been reported as products from a palladium-catalyzed reductive annulation of a bis(2-nitrophenyl)carbazole precursor in the presence of hydrogen.281 In an approach of rather limited scope, the indolo[2,3c]carbazole 400 was obtained as the only successful example upon cyclization of the precursor 401 in the presence of a ruthenium catalyst and tetraethylammonium chloride (Scheme 90). Unfortunately, cyclization attempts with two additional related substrates failed to produce indolocarbazoles.519 Although discussion of extended indolocarbazole systems is beyond the scope of this account, some examples of a tetraaza[8]circulenes incorporating the indolo[2,3-c]carbazole core are included to highlight some new interesting work. In an elegant synthetic route, the expanded porphyrin-like precursor 402, available from 1,2-di(pyrrol-2-yl)benzene (403) after initial dibromination with NBS followed by a cyclization with

Scheme 90. Ruthenium-Catalyzed Cyclization of the Precursor 401 Rendering the Indolo[2,3-c]carbazole 400

1,2-di(pinacolatoboryl)benzene (404) under Suzuki coupling conditions, could be efficiently converted to the product 405 under oxidative conditions using the reagent combination DDQ/Sc(OTf)3 in refluxing toluene. Subsequent modification of 405 via full N-alkylation provided the derivative 406 (Scheme 91), which displayed improved solubility in common organic BB


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Scheme 91. Construction and Alkylation of Tetraaza[8]circulenes

solvents. The structures of both tetraaza[8]circulenes 405 and 406 were rigorously proven by X-ray diffraction analysis.520 Controlled alkylation (sodium hydride, iodobutane, and THF) of the system 405 has also been reported, providing access to three different alkyl derivatives incorporating one, two, or three butyl groups displaying distinct differences in their absorption and emission spectra, as gradual red-shifting was observed with increasing number of alkyl groups. Interestingly, the dibutyl product was obtained as one single regioisomer having the alkyl groups at the opposite nitrogen atoms.521 An alternative approach has also emerged recently, relying on initial exhaustive S-oxidation of tetrathia[8]circulene derivatives with m-CPBA, followed by nucleophilic aromatic substitution with anilines in the presence of KHMDS.522

up to λ = 1200 nm in the vis/NIR region, while the observed emission intensity decreased continuously in the fluorescence spectrum.516 The system 391 (Scheme 88, section 6.1) has been identified as a hit for potential for OLED applications during a computation-driven search of an extensive library of compounds and was indeed found to display a external quantum efficiency of 11.9% in an OLED device based on the synthetic material as the emitter, thus also verifying the predictive power of the screening method.514 Further appropriately modified and structurally more advanced indolo[2,3-c]carbazole derivatives may soon evolve as potential materials for various electronic devices as judged from the recent advances in molecular design and synthetic methodologies.

6.2. Applications and Miscellaneous Studies

7. OVERALL CONCLUSIONS AND PERSPECTIVES Given the remarkable expansion of research activities devoted to indolocarbazoles during the recent decade, spanning widely over such diverse fields as cell biology and medicinal chemistry to molecular receptors and organic electronics, there is a good chance that the current momentum will be maintained, leading to new important discoveries in the near future. In particular, the prospects are promising for further fruitful investigations of the indolo[2,3-a]pyrrolo[3,4-c]carbazole core as a scaffold for drug development, which is also a possible scenario for certain structurally relatively simple indolo[3,2-b]carbazoles, illustrated by, for instance, the parent system itself and its 6-formyl derivative (FICZ), both intensely studied in connection with their powerful biological effects as ligands for the aryl hydrocarbon receptor (AHR). The fact that the three remaining, for a long time rather neglected, isomers are gradually emerging as heterocyclic cores for design of new materials is also particularly encouraging. The significant advances of the past decade also reflect the immense impact of the recent developments in new synthetic methodologies that have enabled practical access to these formerly synthetically quite challenging ring systems. In conclusion, the indolocarbazoles constitute a vital and steadily evolving multidisciplinary research area which is likely to enjoy considerable attention in the future.

On the basis of several theoretical studies, it has been proposed that the parent unsubstituted tetraaza[8]circulene 407 (Figure 38) (a theoretically designed compound which has never been

Figure 38. Parent heterocyclic core of tetraaza[8]circulene.

synthesized) is nonaromatic, with an inner 8-membered antiaromatic ring, sustaining a paratropic ring current, whereas the peripheral 20-membered macrocycle constituting the rim of the core displays aromatic character with a diatropic ring current.523−525 As a consequence of their predicted fluorescence characteristics, several derivatives of tetraaza[8]circulene have been suggested as promising targets for the design of new materials for blue OLED applications.526 It remains to be seen if the future evolution of this particular class of fused nitrogen heterocycles will fulfill these predictions and expectations. It has been demonstrated that the fused indolo[2,3c]carbazole 399 (Scheme 89, section 6.1) displays high fluorescence efficiency (ΦF = 0.71). Moreover, it is capable of forming a relatively stable cation radical salt 399+•, which was isolated as its tetrafluoroborate salt amenable for an X-ray crystallographic study. The redox pair 399/399+• displayed dual electrochromic behavior, as electrochemical oxidation of 399 was accompanied by decreased intensity of the UV bands in the UV−vis/NIR spectrum, with concomitant appearance of signals

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Tomasz Janosik: 0000-0003-4198-6104 Notes

The authors declare no competing financial interest. BC


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Biographies

his Ph.D. at the Karolinska Institutet in 2005 in Professor Jan Bergman’s group, where he was mainly working on cyanoacetylation of pyrroles, indoles, and amines, as well as new synthetic applications of the resulting products. He joined Varian AB in 2005, as a service engineer within analytical instruments, where he worked until 2009. He is currently at KTH Royal Institute of Technology as a research engineer working in the area of dye-sensitized solar cells.

Tomasz Janosik (T.J.) received his Master of Science degree in chemical engineering from the KTH Royal Institute of Technology in Stockholm in 1996. After completing his Ph.D. studies in 2002 under the guidance of Professor Jan Bergman at the Karolinska Institutet, mainly focusing on bisindole and indolocarbazole chemistry, he pursued postdoctoral research in the field of new biologically active synthetic triterpenoids at Dartmouth College (New Hampshire, USA) in the group of Professor Gordon W. Gribble (2002−2003). After returning to the Karolinska Institutet, T.J. remained there until 2008, before continuing his involvement in research within organic and medicinal chemistry as an entrepreneur and employee/consultant at Karo Bio AB in Huddinge, Sweden. In 2015, he joined RISE Surface, Process and Formulation (formerly SP Process Development AB), where he is currently active as a senior scientist and project manager. His main research interest is focused on five- and seven-membered heterocycles, indole-containing natural products, organosulfur chemistry, medicinal chemistry, as well as process chemistry and development, including biomass valorization.

Jan Bergman (J.B.) was born (1941) in Stockholm, Sweden and obtained his Ph.D. in 1971 from the Royal Institute of Technology in Stockholm on a thesis with the title “Synthetic Studies of Indole Derivatives”. The thesis was supervised by Professor Holger Erdtman. J.B. got his first promotion to the rank of Assistant Professor in 1973. In 1976, he spent a period at the University of Waterloo, Canada, where he cooperated with Professor Victor Snieckus. For 6 years in the nineties he served as President-elect, President, and past President of the International Society of Heterocyclic Chemistry. In 1994, he moved to the Karolinska Institutet in Stockholm, where he is still active. Over the years, J.B. has supervised 32 Ph.D. theses and published over 300 papers.

Agneta Rannug completed her B.Sc. in natural sciences in 1973 at Stockholm University and received her Ph.D. in 1984 in genetic toxicology at Stockholm University under the direction of Professor Claes Ramel. After pursuing a postdoc period (1985−1986) at Case Western Reserve University in Cleveland, Ohio, Agneta Rannug joined the Department of Toxicology, National Institute of Occupational Health/NIWL, Solna, and established a research group studying genetic polymorphisms in cytochrome P4501A1 and other biotransformation enzymes. She was appointed Associate Professor in 1990 and moved to the Institute of Environmental Medicine, Karolinska Institutet, in 1997, became a full Professor in 2007, and was a member of the Swedish Criteria Group for Occupational Standards, 2007−2016. Her research activity since the discovery of the endogenous aryl hydrocarbon receptor ligand FICZ has focused on the mechanism of action of this substance.

REFERENCES (1) Bergman, J.; Janosik, T.; Wahlström, N. Indolocarbazoles. Adv. Heterocycl. Chem. 2001, 80, 1−71. (2) Janosik, T.; Wahlström, N.; Bergman, J. Recent Progress in the Chemistry and Applications of Indolocarbazoles. Tetrahedron 2008, 64, 9159−9180. (3) Robinson, B. The Fischer Indolisation of Cyclohexane-1,4-dione Bisphenylhydrazone. J. Chem. Soc. 1963, 3097−3099. (4) Prudhomme, M. Indolocarbazoles as Anti-Cancer Agents. Curr. Pharm. Des. 1997, 3, 265−290. (5) Kase, H.; Iwahashi, K.; Matsuda, Y. K-252a, a Potent Inhibitor of Protein Kinase C from Microbial Origin. J. Antibiot. 1986, 39, 1059− 1065. (6) Kase, H.; Iwahashi, K.; Nakanishi, S.; Matsuda, Y.; Yamada, K.; Takahashi, M.; Murakata, C.; Sato, A.; Kaneko, M. K-252 Compounds, Novel and Potent Inhibitors of Protein Kinase C and Cyclic Nucleotide-Dependent Protein Kinases. Biochem. Biophys. Res. Commun. 1987, 142, 436−440. (7) Sezaki, M.; Sasaki, T.; Nakazawa, T.; Takeda, U.; Iwata, M.; Watanabe, T.; Koyama, M.; Kai, F.; Shomura, T.; Kojima, M. A New Antibiotic SF-2370 Produced by Actinomadura. J. Antibiot. 1985, 38, 1437−1439. (8) Yasuzawa, T.; Iida, T.; Yoshida, M.; Hirayama, N.; Takahashi, M.; Shirahata, K.; Sano, H. The Structures of the Novel Protein Kinase C Inhibitors K-252a, b, c and d. J. Antibiot. 1986, 39, 1072−1078. (9) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J. Total Synthesis of (+)and (−)-K252a. J. Am. Chem. Soc. 1995, 117, 10413−10414. (10) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.; Petsch, D. T. Design and Implementation of an Efficient Synthetic Approach to Furanosylated Indolocarbazoles: Total Synthesis of (+)- and (−)-K252a. J. Am. Chem. Soc. 1997, 119, 9641−9651. (11) Nettleton, D. E.; Doyle, T. W.; Krishnan, B.; Matsumoto, G. K.; Clardy, J. Isolation and Structure of Rebeccamycin - a New Antitumor Antibiotic from Nocardia Aerocoligenes. Tetrahedron Lett. 1985, 26, 4011−4014. (12) Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J. Two Synthetic Approaches to Rebeccamycin. Tetrahedron Lett. 1985, 26, 4015−4018. (13) Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.; Tomita, K. Production and Biological Activity of Rebeccamycin, a Novel Antitumor Agent. J. Antibiot. 1987, 40, 668−678. (14) Gribble, G. W.; Berthel, S. J. A Survey of Indolo[2,3-a]carbazole Alkaloids and Related Natural Products. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier, 1993; Vol. 12; pp 365−409. (15) Pindur, U.; Kim, Y.-S.; Mehrabani, F. Advances in Indolo[2,3a]carbazole Chemistry: Design and Synthesis of Protein Kinase C and Topoisomerase I Inhibitors. Curr. Med. Chem. 1999, 6, 29−69.

Ulf Rannug obtained his Ph.D. in genetics at University of Uppsala and became Associate Professor in genetic toxicology at Stockholm University (1981). He served as a Visiting Associate Professor at the Dept. of Environmental Health Sciences, School of Medicine, Case Western Reserve University, in Cleveland, Ohio, (1985/1986). In 1993, he became full Professor in Genetic Toxicology, Stockholm University, and Head of the Department of Genetic and Cellular Toxicology. His research interests include toxic and genotoxic effects of halogenated substances and their mechanisms of action. His achievements comprise more than 100 publications. After the identification of the endogenous high affinity aryl hydrocarbon receptor ligand FICZ, his research has been focused on the role of FICZ and CYP1A1 in the feedback regulation of the aryl hydrocarbon receptor signaling. Niklas Wahlström obtained his Master Thesis in Chemistry at the department of Organic Chemistry from Umeå University, Sweden, in 1998. He performed his Ph.D. studies with Professor J. Bergman at the Karolinska Institutet and obtained his degree in 2004, working with bisindole chemistry. He then performed postdoctoral research work at University of Oxford, Oxford, UK, in the research group of Professor J. Baldwin (2005−2006) before joining AstraZeneca, Process Research and Development, Pharmaceutical Development in Södertälje, Sweden (2006−2012). In 2012, he joined DuPont (acquired in 2016 and renamed MagleChemoswed, a privately owned company) in Malmö, Sweden, as a research and development chemist. He is the author of 12 publications in international peer-reviewed journals and 2 patents. Johnny Slätt received his Bachelor of Science degree in Environment and Safety from Royal Institute of Technology in 1999. He completed BD


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