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Review Cite This: J. Nat. Prod. 2017, 80, 3060-3079

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Natural Products with Heteroatom-Rich Ring Systems Emma K. Davison and Jonathan Sperry* School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand ABSTRACT: This review focuses on all known natural products that contain a “heteroatom-rich” ring system, specifically a five-, six- or seven-membered ring that contains three or more heteroatoms. The isolation and biological activity of these natural products is discussed, along with the biosynthetic processes that Nature employs to assemble these rare heterocyclic frameworks.

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guanine phosphoribosyl transferase in Plasmodium falciparum,10 thus inhibiting [3H]hypoxanthine uptake (IC50 6.6 μM) and therefore inhibiting parasite growth (IC50 18 μM), making it a potential lead compound in the development of novel antimalarial agents.10 Additionally, 1 was recently discovered to inhibit growth of the pathogenic bacterium Leptospira sp., with 53% of leptospiral isolates showing complete growth inhibition when incubated with 1 (225 g L−1).11 A biosynthetic pathway to 1 from guanine (2) has been proposed (Scheme 1).12,13 Guanosine triphosphate 8-formylhydrolase (GTP-

INTRODUCTION Heterocycles are present in a large proportion of natural product structures and are particularly common in alkaloids, polyketides, phenylpropanoids, and vitamins.1 The heterocycles present in these natural products typically contain one or two heteroatoms,2,3 most commonly nitrogen and/or oxygen but occasionally sulfur. Natural products harboring heterocycles with more than two heteroatoms are much less abundant but constitute a fascinating group of compounds with a vast degree of structural diversity and range of biological activities. This review embraces all known natural products that contain a “heteroatom-rich” heterocycle, specifically a five-, six-, or sevenmembered ring that contains more than two heteroatoms (any combinations of nitrogen, oxygen, and sulfur). The isolation and biological activity of these natural products are discussed, along with the unique biosynthetic processes that Nature employs to assemble these frameworks. Heterocycles that are part of fused and spirocyclic systems are included, but bridged heterocycles, such as endoperoxides and thiodiketopiperazines, are not covered in this review.

Scheme 1. Proposed Biosynthesis of 8-Azaguanine (1)12,13

formylhydrolase) catalyzes the extrusion of carbon 8 from guanine (2) as formic acid, forming triaminopyrimidin-7-one (3), which undergoes annulation with an external nitrogen source to form 8-azaguanine (1). The first report of the 1,2,4-triazole motif in Nature was in the isolation of L-1,2,4-triazole-3-alanine (4) in 1985 from Streptomyces sp. KM-10329 in a soil sample collected from Joetsu City, Niigata Prefecture, Japan.14 Amino acid 4 was previously known by synthesis15 and shown to inhibit the growth of Salmonella typhimurium (histidine auxotroph, strain his-203) by approximately 40% at 30 μg mL−1.16 L-1,2,4Triazole-3-alanine (4) was proposed to exert its antibacterial activity by acting as a histidine analogue, both through incorporation into proteins and as a repressor for histidine biosynthetic enzymes.16 Ribonucleoside 5 contains a triazolone motif and was known by synthesis17 prior to its isolation in 2000 from the actinobacterium Actinomadura.18 The triazolone

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STRUCTURAL TYPES Triazoles, Tetrazoles, Trioxolanes, and Derivatives. 8Azaguanine (1), also known as pathocidin, was first isolated from the fermentation broth of Streptomyces albus var. pathocidicus in 1961 and was found to possess the triazolo[4,5-d]pyrimidin-7-one structure 1.4 The extensive biological properties of 1 are covered in a detailed review,5 so only a brief discussion is included herein. 8-Azaguanine (1) displays antimicrobial and cytotoxic properties against a wide range of bacteria, viruses, fungi, and human cancer cell lines.5,6 8Azaguanine (1) exerts this cytotoxic activity following conversion to a nucleotide derivative that inhibits nucleic acid and protein synthesis.5,7,8 Not included in the aforementioned review are the early investigations into the applications of 1 to treat human malignancies; these efforts were hindered by issues with administration, dosing, and resistance, leading to further investigations being abandoned.9 8-Azaguanine (1) has also recently been found to act as a substrate of hypoxanthine © 2017 American Chemical Society and American Society of Pharmacognosy

Received: July 4, 2017 Published: November 14, 2017 3060

DOI: 10.1021/acs.jnatprod.7b00575 J. Nat. Prod. 2017, 80, 3060−3079

Journal of Natural Products

Review

triazoles A (8) and B (9) were isolated from the marine-algaderived endophytic fungus Penicillium chrysogenum EN-118.23 X-ray crystallographic analysis of the p-bromobenzoate derivative of chrysotriazole A confirmed the presence of a 1,2,4-triazole.23 Biological assays were carried out to determine their cytotoxicity against an array of human cancer cell lines (MCF-7, SW1990, HepG2, NCI-H460, A-549, HeLa, and Du145); however, no activity was observed. Moreover, chrysotriazoles A (8) and B (9) also failed to show antibacterial activity against both Escherichia coli and Staphylococcus aureus.23 The biosynthesis of penipanoid A (7) is proposed to begin with tyrosine (10) (Scheme 2B),22 which is converted to phydroxyphenylacetamide (11) through sequential decarboxylation and oxidation reactions. Condensation of phenylacetamide 11 with anthraniloyl-CoA would generate quinazolinone 12, which, upon hydrolysis, gives amidine 13. Methionine-derived formamide (14) would then undergo condensation with amidine 13 to forge the 1,2,4-triazole and hence penipanoid A (7). This proposed biosynthesis is likely to be relevant to chrysotriazoles 8 and 9 due to their structural similarity. 6-Azidotetrazolo[5,1-a]phthalazine (15) is a metabolite of the dinoflagellate Gymnodinium breve, a protist implicated in the production of red tides.24 The only known tetrazole natural product, 15, contains an unprecedented five contiguous nitrogen atoms separated by a single carbon atom from an azide group. This remarkable structure was assigned using X-ray crystallography.24 6-Azidotetrazolo[5,1-a]phthalazine (15) was reported to exhibit ichthyotoxicity (LD100 of 0.4 μg mL−1), although no details were given regarding the names and/or numbers of fish species tested against.24 3,3-Dimethyl-1,2,4-trioxolane (16) was isolated as a mixture of diastereomers (ratio unspecified) from the dried and fresh aerial parts of the shrub Senecio selloi (Asteraceae) collected

5 exhibited potent phytotoxicity, causing >70% visual injury following post-emergent application of 5 to Helianthus annuus, Ipomoea hederacea, Echinochloa crus-galli, Abutilon theophrasti, Amaranthus retrof lexus, Setaria faberi, and Alopecurus myosuroides at a rate of 4.0 kg ha−1.18 The mode of action for the observed phytotoxicity is proposed to be via inhibition of adenylosuccinate synthetase following bioactivation of 5 by phosphorylation of the C-5′ position.18 The triazolopyrimidine essramycin (6) was isolated in 2008 from marine-sedimentderived samples of Streptomyces sp. Merv8102 collected from the Platinum Coast in the Egyptian Mediterranean Sea.19 Natural 6 allegedly displayed antibacterial activity with minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg mL−1 against both Gram-positive (Bacillus subtilis, Staphylococcus aureus, and Micrococcus luteus) and Gramnegative (Escherichia coli and Pseudomonas aeruginosa) bacteria.19 The structure of 6 was confirmed by two separate concise, two-step syntheses,20,21 but synthetic 6 did not possess any antibacterial activity.20 The original isolation authors subsequently attributed the erroneous data to using a crude sample of the natural product in the antibacterial assays.20

The 1,2,4-triazole penipanoid A (7) was isolated from Penicillium paneum SD-44, a marine-sediment-derived fungus collected from the South China Sea in 2011.22 The structure of penipanoid A (7) was assigned using X-ray crystallography.22 Penipanoid A (7) displayed cytotoxic activity against the SMMC-7721 cell line with an IC50 value of 54.2 μM; however, no antimicrobial activity was observed against an array of fungi and bacteria.22 In 2013, the 1,2,4-triazole alkaloids chryso-

Scheme 2. (A) Penipanoid A (7) and Chrysotriazoles A (8) and B (9); (B) Proposed Biosynthesis of Penipanoid A (7)22

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concentrations as low as 0.1 μM, 100% inhibition of CXCL12induced cell migration of GH4C1 wt cells, and ∼50% inhibition of CXCL12-induced DNA synthesis of GH4C1 wt cells at 10 μM.30 The exemplary biological properties of 18 make it a promising lead compound for the potential treatment of CXCL12-implicated diseases. A biosynthetic pathway to these alkaloids has been proposed (Scheme 3). Coupling of indole-3Scheme 3. Phidianidines A (18) and B (19) and their Proposed Biosynthesis27

from Rio Grande do Sul in Southern Brazil.25 The presence of the unusual trioxolane ring in 16 was assigned using a combination of experiments. The IR spectrum of 16 showed C−O stretching vibrations (∼1100 cm−1) but not CO or O−H bands, indicating that all four oxygen atoms of the natural product existed in ether-like bonds.25 The 13C NMR shifts of C-24 and C-25 in 16 (epimeric mixture; δC 104.5/104.6 ppm and 108.48/108.53 ppm, respectively) are characteristic of trioxolanes.25 Mass spectrometry fragmentation experiments also supported a trioxolane structure, with signals M+ − 74 (M+ − C3H6O2, m/z 400) and M+ − 117 (trioxolane beta fission, m/z 315) being particularly informative. The natural product 16 provided a positive result on a TLC color test for peroxides.25 Trioxolane 16 failed to exhibit antimalarial activity against Plasmodium falciparum (NF 54) in vitro at 5 μg mL−1.25 In 2012, triterpene trioxolane 17 was isolated as a 1:1 mixture of diastereomers from rabbit-head wormwood, Artemisea lagocephala, collected in South Sikhote-Alin, Primorsky Territory, Russia.26 The mixture of trioxolane diastereomers 17 was found to exhibit moderate antifungal activity against Aspergillus niger, Fusarium oxysporum, and Cercospora sojina with inhibition zones of ∼2 mm at 100 μg/hole.26 Oxadiazoles, Thiadiazoles, and Derivatives. Phidianidines A (18) and B (19) are 1,2,4-oxadiazole-linked indole natural products isolated in 2011 from the eolid opisthobranch Phidiana militaris, a shell-less mollusk, collected off the coast of Hainam Island in the South China Sea.27 The 1,2,4-oxadiazole regioisomer was assigned through careful comparison of the experimental 13C NMR data with synthetic literature examples; the two 13C NMR signals in 1,2,4-oxadiazoles generally appear δC ∼10 ppm further downfield than in the 1,3,4-oxadiazole regioisomer.27 The cytotoxicity of both 18 and 19 was evaluated against an array of both tumor and nontumor cell lines. Phidianidines A (18) and B (19) both displayed high cytotoxicity, especially 18, against nontumor 3T3-L1 murine embryonic fibroblasts (IC50 0.14 μM) and a tumor C6 HeLa (IC50 1.5 μM) cell line.27 Synthetic 18 and 19 both inhibit the dopamine transporter protein (101% and 96% inhibition at 10 μM, respectively) and showed only weak inhibition of the norepinephrine transporter protein (68% and 45% inhibition at 10 μM, respectively) and minimal inhibition of the serotonin transporter protein (22% and 16% inhibition at 10 μM, respectively).28,29 Both 18 and 19 displayed complete inhibition of the μ-opioid receptor (103 and 97% inhibition, respectively), with no discernible activity at the δ- and κ-opioid receptors.28,29 Phidianidine A (18) was found subsequently to be a potent ligand of CXCR4, a chemokine receptor involved in several pathologies including rheumatoid arthritis, HIV, cancer development, and metastasis.30 Phidianidine A (18) exhibited inhibition of CXCL12-dependent ERK1/2 phosphorylation at

acetic acid precursors (20a and b) with alkyl bisguanidine 21 followed by oxidation would afford intermediate hydroxyguanidines 22, which upon cyclodehydration forms phidianidines A (18) and B (19).27 This biosynthesis was validated through three biomimetic syntheses of 18 and 19.31−33 In 2001, lycoposerramine A (23) was isolated from the club moss Lycopodium serratum, collected from the Boso Peninsula

in Japan. The presence of the 1,2,4-oxadiazolidin-5-one motif was confirmed by X-ray crystallographic analysis.34 Lycoposerramine A (23) did not inhibit acetylcholinesterase (from bovine erythrocytes) at 200 μM; however, no other biological data were reported for this natural product.34 The absolute configuration of 23 was not determined, but was proposed to be the same as other Lycopodium alkaloids such as fawcettimine (24), from which 23 could be biosynthetically derived (Scheme 4).34 Fawcettimine (24) exists mainly as the hemiaminal 24a, which is in equilibrium with a minor amount of the ketoamine tautomer 24b.35,36 N-Methylation of the minor ring-opened tautomer 24b and conversion of C-5 and C-13 ketones to a hydroxylamine and imine, respectively, would afford 25, which upon transannulation would form diaminoacetal 26. Formation of the 1,2,4-oxadiazolidin-5-one would then occur through incorporation of an external carbonyl unit, affording lycoposerramine A (23).34 3062



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190 ppm (C-5) and δC ∼170 ppm (C-3) (as observed for 29 and 30).55 The structures of polycarpathiamines 29 and 30 were later confirmed by synthesis.56 Polycarpathiamine A (29) showed potent cytotoxic activity against L5178Y mouse lymphoma cells in vitro with an IC50 value of 0.41 μM, while polycarpathiamine B (30) was inactive. 55 A proposed biosynthetic pathway to the polycarpathiamines 29 and 30 involves an interesting skeletal rearrangement (Scheme 5A). The biosynthetic precursor 31 is the monomeric derivative of the disulfide alkaloid polycarpine (32), present in the same ascidian.55,57 Oxidation of the 2-amino-4-thioimidazole 31 followed by hydrolysis and ring-opening would give N3thioacylguanidine 33, which upon oxidative heterocyclization would afford the 1,2,4-thiadiazole and hence polycarpathiamines A (29) and B (30). The natural products 34 and 35 also found in P. aurata resemble the hypothetical biosynthetic intermediates and thus support this proposed pathway.55,57

Scheme 4. Proposed Biosynthesis of Lycoposerramine A (23)34

L-Quisqualic acid (27) is an amino acid with a 1,2,4oxadiazolidin-3,5-dione side chain isolated in 1972 from the seeds of Quisqualis indica, more commonly known as Chinese honeysuckle,37 but also from the petals from the zonal geranium Pelargonium × hortorum.38 The Japanese beetle, Popillia japonica, is rapidly paralyzed following consumption of these flower petals, with 27 demonstrated to be the compound responsible for this phenomenon.38 Biological studies on 27 have been extensive; it is able to act as an agonist at multiple excitatory amino acid receptors in the central nervous system, with a particularly high affinity for AMPA, metabotropic, and kainate receptors.39−43 Quisqualic acid (27) also inhibits the Ca2+/Cl−-dependent glutamic acid uptake system in the synaptic plasma membrane and inhibits a peptidase that cleaves the brain dipeptide Ac-Asp-Glu-OH.40 Quisqualic acid (27) produces an action potential in the muscle fibers of crayfish and is 500−1000 times more potent than glutamic acid in this regard.44 Quisqualic acid (27) is excitotoxic and selectively causes lesions of cholinergic neurons.45 As such, it is used in neuroscience research to selectively destroy neurons in the CNS of animals to study the resulting cognitive effects associated with Alzheimer’s disease and aging.45−49 Quisqualic acid (27) is thought to be derived from albizziin, a natural amino acid isolated from several species of Fabaceae, a large family of flowering plants, although further details surrounding the biosynthesis of 27 from albizziin appear to be lacking.50−52

In 2012, an unnamed scalemic mixture of thiadiazole alkaloids 36a and 36b (2:1) was isolated from the root of the

herbaceous plant Isatis indigotica, which is commonly used in traditional Chinese medicine for the treatment of various diseases.58 Both 36a and 36b showed comparable antiviral activity against the Herpes simplex virus 1 (HSV-1) cell line, with IC50 values of 33.3 and 25.9 μM, respectively; however, only 36a exhibited activity against influenza virus A/Hanfang 359/95 (H3N2), with an IC50 of 33.3 μM.58 Two proposed biosynthetic pathways to 36a and 36b are shown in Scheme 6.58 The putative biosynthetic precursors, epiprogoitrin (37a), progoitrin (37b), and glucobrassicin (38), are present in cruciferous plants, including I. indigotica.58 Myrosinasecatalyzed hydrolysis of glucosinolate precursors 37a, 37b, and 38 would afford thiohydroximate-O-sulfonates 39a, 39b, and 40, respectively. Path A proceeds via a heterocyclization between nitrile 41a or 41b and imidothioate 42a or 42b (known decomposition products of thiohydroximate-O-sulfonate 39a or 39b) followed by dehydration to yield 1,2,4thiadiazole 43a or 43b.58 The authors proposed a Diels− Alderase-mediated cycloaddition of 1,2,4-thiadiazole 43a or 43b with 3-thioxoindolin-2-one (44) (a known decomposition product of indole thiohydroximate-O-sulfonate 40), followed by double-bond rearrangement as the final step in the biosynthesis of natural products 36a and 36b.58 Alternatively, path B would involve a heterocyclization between nitrile 41a or 41b with imidothioate 45 (from 40), to afford 1,2,4-thiadiazole 46a or 46b. Indole epoxidation and subsequent epoxide opening by the putative plant metabolite 3-mercaptopropanal

The only thiadiazole regioisomer known to occur naturally is 1,2,4-thiadiazole; dendrodoine (28) was the first to be isolated in 1980 from the marine tunicate Dendrodoa grossularia collected off the coast of North Brittany, France.53 The 3amino-5-acyl-1,2,4-thiadiazole structure of 28 was established by X-ray crystallography and later confirmed by synthesis.53,54 Dendrodoine (28) showed cytotoxic activity against the lymphoma LI210 cell line.53 Polycarpathiamines A (29) and B (30) were isolated in 2013 from the ascidian Polycarpa aurata, a marine invertebrate commonly referred to as the ox heart ascidian, the gold-mouth sea squirt, or the ink-spot sea squirt due to its vibrant purple and orange colors.55 The polycarpathiamines contain the 3-amino-5-acyl-1,2,4-thiadiazole motif also present in dendrodoine.53,55 The 13C NMR data confirmed the presence of the 1,2,4-thiadiazole, the only viable heterocycle where the two carbon atoms resonate at δC 180− 3063



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Scheme 5. (A) Proposed Biosynthesis of Polycarpathiamines A (29) and B (30). (B) Natural Products 32, 34, and 35 also Isolated from Polycarpa aurata55,57

tomato. 61,62 Quantitative conversion of 49 to 50 by commercially available xanthine oxidase revealed that AOH (50) is a metabolite of AHX (49).61 Both 49 and 50 increase rice seed yield by a rate of 42.2% and 25.5%, respectively, when grown in soil supplemented with 5 μM of either 49 or 50.61 AHX (49) was found to increase the grain weight (g m−2) of wheat (Norin No. 61) by 20.4% after seeds were soaked in a 1 mM solution of 49,63 indicating potential applications of these natural products in agriculture. A biosynthetic pathway to 49 and 50 has been proposed (Scheme 7A). AHX (49) is postulated to be derived from 5-aminoimidazole-4-carboxamide (AICA) (51), which, in turn, is produced from its ribotide AICAR (52), a common metabolite of the purine and histidine metabolic pathway in animals, plants, and microorganisms.61,62 A feeding experiment was conducted that supplied AICAR to L. sordida. 64 The observed consumption of AICAR and accumulation of AHX following feeding lends experimental evidence in support of the proposed biosynthesis.64 A biomimetic synthesis of 49 from 51 has been achieved (Scheme 7B); however, the mechanism of AICA (51) metabolism to AHX (49) remains unclear.61,65 The 7-azapteridine class of natural products contain a pyrimidotriazine framework, and members include toxoflavin (53), fervenulin (54), reumycin (55), and their derivatives 56− 59. The occurrence and biological activities of 53−57 were collated in 2001 by Nagamatu66 and hence will not be covered in detail here. Not included in the aforementioned review was the recent isolation of 2-methylfervenulone (57) (also known as 2096C or MSD-92) from Streptomyces sp. IM 2096 along with its co-metabolites 2096A (58a), B (58b), and D (59) in 2000.67 2096A (58a) and B (58b) were found to be interconvertible diastereomers due to the acidity of the H-4′ proton effecting epimerization at this stereocenter; however, the absolute and relative configurations of 58a and 58b were undetermined.67 2-Methylfervenulone (57) was shown to inhibit several protein tyrosine phosphatases (PTPs), a family of proteins commonly targeted in several disease therapies.67 Interconvertible diastereomers 58a and 58b did not show any inhibition of PTPs, but were proposed to be biosynthetic

(47) followed by thiopyran formation would result in the thiadiazole alkaloids 36a and 36b.58 The 1,2,4-thiadiazole alkaloid penicilliumthiamine B (48) was isolated from the fungus Penicillium oxalicum gathered from the gut of the Chinese grasshopper, Acrida cinerea, collected from Chinese Big-Nine-Lake National Wetland Park in Hubei Province.59 The structure of penicilliumthiamine B was assigned as 48 and was confirmed by synthesis.59 Penicilliumthiamine B (48) inhibits the growth of the HCG-27 cell line (IC50 of 172.3 μM after 48 h) and also inhibits the phosphorylation of Akt/protein kinase B (PKB) (Ser 473), a key signaling component in one of the most frequently activated pathways in cancer, in the same cell line.59 This result inferred that the observed cytotoxicity of 48 could result from targeting Akt/PKB, making it a valuable lead in the search for new chemotherapeutic agents.

Triazines and Derivatives. The imidazotriazine 2azahypoxanthine (AHX) (49) was first isolated from the “fairy ring”-instigating fungus Lepista sordida in 2010.60 Fungi tend to grow outward from the point of spore germination, resulting in circular colonies. These fungal colonies, and the associated zones of darker green and faster growing turfgrass, are commonly referred to as “fairy rings”.60,61 This phenomenon had previously mystified the scientific community, until the discovery of AHX (49) as the active compound responsible for the observed rapid grass growth commonly associated with fungal “fairy rings”.60 AHX (49) was found to promote the growth of bentgrass seedlings (Agrostis palustris) and of rice (Oryza sativa cv. Nipponbare) belonging to the same family as turfgrass, by both direct contact between L. sordida and the roots and secretion from the fungus to the soil.60 In 2014, the imidazotriazine 2-aza-8-oxohypoxanthine (AOH) (50) was isolated from AHX-treated rice, Arabidopsis, turfgrass, and 3064



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Scheme 6. Proposed Biosynthetic Pathways (A and B) to Thiadiazole Alkaloids 36a and 36b58

precursors of 57.67 It was suggested that 59 does not occur naturally, but was isolated as a degradation product of 57.67 2096D (59) showed no activity in PTP inhibition assays.67

Philmus and co-workers uncovered a slight modification to this pathway (Scheme 8),68 whereby GTP-derived 2,5-diamino-6(5-phospho-D-ribosylamino)pyrimidin-4-(3H)-one (60) undergoes deamination and reductive ring-opening of the ribose moiety, followed by dephosphorylation and annulation with glycine to forge the 1,2,4-triazine.68 The unnamed 1,2,4-triazin-3,6-dione 61 was isolated from the seeds of Butea monosperma,69 a herb used in certain naturopathic contraceptive remedies. The seed extract was found to prevent pregnancy in female rats, confirming its contraceptive activity, although the biological activity of pure 61 was not reported.69 The triazinone 62 was isolated in 2014 from Portulaca oleracea, one of the most widely used medicinal plants in certain Mediterranean, Central European, and Asian countries.70 Triazinone 62 was found to have moderate cytotoxicity against the A549 and K562 cell lines with IC50 values of 21.8 and 66.9 μM, respectively; however, no cytotoxic activity was observed against MCF-7 and MDA-MB-435 cells.70 Noelaquinone (63), a hexacyclic quinone containing a 1,2,4triazine moiety, was isolated from Xestospongia sp., a marine

Although the proposed biosynthesis of toxoflavin (53) from guanosine triphosphate was detailed in the aforementioned review,66 it is relevant to mention that recent investigation by 3065



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Scheme 7. (A) Proposed Biosynthesis of AHX (49) and AOH (50); (B) Biomimetic Synthesis of AHX (49) from AICA (51)61,62,65

Scheme 8. Biosynthesis of Toxoflavin (53)68

sponge collected from Derawan Island, Indonesia.71 Despite its close structural relationship with the potent kinase inhibitors xestoquinone, halenaquinone, and the viridian class of furanosteroids, the biological activity of 63 has yet to be explored.72 The tricyclic pyrimido[1,2-d]-1,2,4-triazine cinachyramine (64) was isolated from the marine sponge Cinachyrella sp., collected from Okinawa, Japan, in 2006.73 The circular dichroism spectrum of cinachyramine trifluoroacetate salt displayed Cotton effects (ECD [MeOH] λext 302 nm [Δε −0.19], 287 nm [Δε +0.09]); however, the absolute

configuration of 64 was undetermined.73 The trifluoroacetate salt of 64 was shown to exhibit weak activity against HeLa S3 cells, with an IC50 of 6.8 μg mL−1.73 In 2008, an unnamed natural product assigned as the 1,2,4-triazinane 65 was isolated from the seeds of the leguminous tree Detarium senegalense; however, this structure likely needs revision.74 Triazinane 65 exhibited potent inhibition of Escherichia coli, Proteus mirabillis, and Pseudomonas aeruginosa, but affected neither Staphylococcus aureus nor Klebsiella pneumonia.74 The oxadiazolotriazine CDMHK (66) was isolated from Myxobacterium sp. HK1 3066



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collected from Korean soil in 2005.75 CDMHK (66) was shown to inhibit the growth of human cancer cell lines A549, Sk-OV-3, AK-MEL-2, XF498, and HCT15 with ED50 values of 0.62, 0.36, 0.76, 0.70, and 0.60 μg mL−1, respectively.75

Clavibacter michiganensis, Mycobacterium B5, Escherichia coli, Pseudomonas syringae, and Xanthomonas malvacearum, with MIC values ranging from 5 to 50 mg mL−1.81 Fluviol E was found to cause 40% in vivo growth inhibition of Ehrlich carcinoma at 0.2 mg kg−1 (the highest tolerated dose), but caused toxicity to mice at this dose.81 Natural fluviol C showed superior antitumor properties, causing 64% in vivo growth inhibition of Ehrlich carcinoma, with significantly lower toxicity (highest tolerated dose of 20 mg kg−1).81 Fluviol A (70) exhibited the strongest antitumor activity, resulting in 83% in vivo growth inhibition, with the least toxicity to mice (highest tolerated dose of 50 mg kg−1).81

The violet pigment nostocine A (67) contains a pyrazolotriazine unit (confirmed by X-ray crystallographic analysis) that is an extracellular metabolite produced by the freshwater cyanobacterium Nostoc spongiaeforme TISTR 8169 in response to oxidative stress.76 The pigment 67 was isolated in 1996 from the cyanobacterium collected from a Thai paddy field.77 Nostocine A (67) inhibits the growth of several cyanobacteria, Nostoc commune, Anabaena variabilis, and Anabaena cylindrica, with MIC values of 20, 30, and 30 μM, respectively, and also possesses algicidal activity against Chlamydomonas reinhardtii, Chlorella pyrenoidosa, Chlorella fusca, Dunaliella tertiolecta, and Dunaliella salina with MIC values of 30, 30, 5, 20, and 15 μM, respectively.76 Nostocine A (67) was also found to exhibit herbicidal activities against Catharanthus roseus, Daucus carota, and Armoracia rusticana with MIC values of 1−2 μg mL−1 and antibacterial activity against both Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli, Proteus vulgaris, and Serratia marcescens) bacteria, with MIC values of 6, 8, 12, and 7 μg mL−1, respectively.76,78 Additionally, 67 was found to completely inhibit the growth of human cancer cell lines ACHN, Calu-1, MKN-1, SK-HEP-1, and MRC-5 at 1.0 μg mL−1, with cytotoxic potency comparable to 5-fluorouracil. However, 67 demonstrated acute toxicity when administered to mice, precluding its potential use in cancer chemotherapy.76,78 The pyrazolotriazine pseudoiodinine was isolated in 1972 from Pseudomonas f luorencens var. pseudoiodinum and assigned the structure 68;79 however, synthetic studies by Kelly and coworkers revised the structure of pseudoiodinine to 69.80 These synthetic studies also confirmed the structure of fluviol A (70) (a degradation product of pseudoiodinine) and nostocine A (67).80 Fluviols A (70), B (71), C, D (72), and E (73) are brightly colored pyrazolotriazine pigments isolated in 1997 from the same microorganism as pseudoiodinine (69).81 The structural reassignment of pseudoiodinine from 68 to 69 in turn meant that the structure proposed for fluviol C (69) was incorrect, and the true structure of fluviol C remains unknown. D-DFT/PCM-calculated absorptions for the structures proposed for fluviols C and E (69 and 73, respectively) did not corroborate the UV−visible spectra reported for the natural products.82 However, a comparison of the physical properties and the UV−visible spectra of natural fluviol E with synthetic pseudoiodinine (69) suggest they are identical, despite the absence of NMR data for natural fluviol E.82 Natural fluviol E was found to be a broad-spectrum antibiotic, with moderate activity against both the Gram-positive and Gram-negative bacteria Staphylococcus aureus, Bacillus cereus, Bacillus subtilis,

Halimedin (74) was isolated from the marine alga Halimeda xishaensis in 1998. No biological studies on 74 were undertaken.83 The 1,3,5-triazine motif was assigned based on several diagnostic bands in the IR spectrum (3156, 1616, 1581, 1503, and 1461 cm−1) and the pattern of the proton decoupled 13 C NMR spectrum, which showed three singlets in the aromatic region (δC 167.1, 137.9, and 171.7 ppm), and was subsequently confirmed by X-ray crystallographic analysis.83 Halimedin (74) was purported to be the first natural product to contain a 1,3,5-triazine heterocycle; however, Ujváry suggested that 74 was an artifact derived from the widely used herbicide cyanazine (75).84 Cyanazine (75) has been associated with groundwater and surface water contamination, and it was proposed subsequently that 74 is a “seminatural” product, resulting from the biotransformation of 75 by Halimeda xishaensis.84 However, experimental evidence to support this was lacking due to the inavailability of the algae; thus the true origin of 74 remains unclear. In 2009, nocarsin A (76) was isolated from Nocardia alba sp. nov (strain YIM 30243T) collected from a soil sample in Hekou, Yunnan, People’s Republic of China.85 NMR experiments including 1H, 13C, and HMBC spectra were used to assign the structure of 76 as a pyrrolopyrrole-fused triazindione.85 No biological studies were reported for this structurally unprecedented natural product. Terrestric acid (77) was isolated in 2011 from Salsola collina, collected from Shandong Province, mainland China.86 S. collina is used in Traditional Chinese Medicine for the treatment of hypertension, headache, and vertigo.86 Terrestric acid (77) exhibited antifungal activity in vitro against Candida albicans (YO109 and SC5314), Cryptococcus neoformans, and Trichophyton rubrum, with minimum 80% inhibitory concentrations (MIC 80) of 8, 32, 16, and 64 g mL−1 respectively.86 The absolute configuration of 77 was not determined. Psychotripine (78), a trimeric pyrroloindoline derivative with an unprecedented hendecacyclic ring system bearing a hexahydro-1,3,5triazine unit, was isolated in 2011 from the leaves of Psychotria 3067



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Scheme 9. Proposed Biosynthesis of Psychotripine (78)87

pilifera collected from Mengna, Yunnan Province, People’s Republic of China.87 Psychotripine (78) was evaluated for cytotoxicity against the five human cancer cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480, but it did not show any significant activity (IC50 > 40 μM).87 A proposed biosynthesis of 78 is detailed in Scheme 9.87 Psychotripine (78) is proposed to be derived from the pyrroloindoline calycosidine (79), a natural product present in the bark and twigs of Psychotria rostrata.88 Oxidation of 79 to a bisimine intermediate followed by two intramolecular aminations would forge the 1,3,5-triazine and hence psychotripine (78).

against Herpes simplex virus with approximately 50% survival rate after 28 days, with a dose of 400 mg kg−1, compared to 0% survival in the control group.97

Oxadiazines, Dioxanes, Dithianes, Oxadithianes, and Derivatives. Alboinon (82) was isolated from the ascidian Dendrodoa grossularia in 1997 and was found to contain a unique 4-dimethylamino-1,3,5-oxadiazin-2-one heterocycle, which was assigned using a combination of mass spectrometry fragmentation and NMR experiments.98 Mass spectrometry fragmentation indicated a carboxyindole unit [m/z 144 (C9H6NO), 116 (C8H6N), and 89 (C7H5)] and a cyano-indole fragment [m/z 142 (C9H6N2)], while a δ-lactone was indicated by the splitting off of CO2 from the molecular ion [m/z 212 (C12H12N4)] and a band at 1750 cm−1 in the IR spectrum.98 The proton-decoupled 13C NMR spectrum displayed one singlet at δC 153.7 ppm (C-2′) and two multiplets at δC 164.6 (C-4′) and 167.3 (C-6′) ppm.98 The HMBC spectrum showed long-range coupling between the signal at δC 164.6 ppm (C-4′) and the N,N-dimethylamino group and between the signal at δC 167.3 ppm (C-6′) and the indole H-2, suggesting a 4dimethylamino-1,3,5-oxadiazin-2-one motif.98 Synthesis of N2-(trimethylsilyl)ethoxymethyl protected 82, and comparison of the 1H and 13C NMR data with the natural product confirmed the structure of alboninon (82).98 No biological studies have been reported for this natural product. Alboinon (82) is likely derived from the 2dimethylaminoimidazole natural product 83 (also present in D. grossularia) by a Baeyer−Villiger-type ring expansion (Scheme 10A). 2-Dimethylaminoimidazole 83 can itself be assembled from 2-(3-indolyl)glycine (84) or indolylglyoxylic acid (85) (Scheme 10B).98 In 1994, extracts of the perennial shrub Fissistigma oldhamii, collected in Taihung, Taiwan, yielded the 1,3,5-dihydrooxadiazine alkaloid fissoldhimine (86).99 The structure of 86 was determined by X-ray crystallographic analysis.99 F. oldhamii is used in traditional medicine in southern mainland China and Taiwan for the treatment of sciatica and arthritis, as well as for antitumor and anti-inflammatory purposes.99 Despite the medicinal properties of its source, biological studies on pure 86 were not performed. A biosynthesis of 86 has been proposed (Scheme 11A).99 Decarboxylation of ornithine (87) to putrescine (88) followed by oxidative deamination afforded

5-Azacytidine (80) is produced by fermentation of the sporeforming bacterium Streptoverticillium ladakanus.89,90 This triazinone nucleoside exhibited anticancer activity in vivo against T-4 lymphoma, causing a 100% reduction in tumor size after 14 days with a daily dose of 200 mg kg−1 and against the multidrug-resistant leukemia cell line L-1210, effecting a significantly prolonged survival time at doses of 1.25−5.0 mg kg−1.90 5-Azacytidine (80) also exhibited growth inhibition of the human carcinoma KB cell line (IC50 of 0.23 μg mL−1) and Escherichia coli cells (MIC of 0.01 μg mL−1) in vitro.90 It was suggested that 80 interferes with nucleic acid metabolism prior to incorporation of cytidine and uridine since these pyrimidines were found to reverse the antimicrobial activity of 80.90 The antitumor properties of 80 culminated in its approval by the U.S. FDA in 2004 for treatment of all subtypes of myelodysplastic syndromes.91 The biological activity and clinical use of 80 have been included in numerous reviews and, as such, will not be discussed in detail herein.92−96 The 1,3,5-triazinane-2,4dione nucleoside analogue U-44590 (81) was isolated from a fermentation broth of Streptomyces platensis var. clarensis in 1974.97 U-44590 (81) possesses in vitro antibacterial activity against Streptococcus hemolyticus, Klebsiella pneumoniae, Salmonella sp., Serratia marcescens, Pasteurella multocida, Haemophilus sp., Proteus morgana, and Proteus rettgeri (inhibition of 2.0−125 μg m−1).97 U-44590 (81) displayed in vivo antiviral activity 3068



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butyraldehyde (94) followed by cyclodehydration would forge the dihydro-1,3,5-oxadiazine and hence fissoldhimine (86). Interestingly, the authors proposed that the true structure of the natural product could be 93 since butyraldehyde (94) present in butanol used during the isolation process could have triggered the final aminoacetylization step, affording the structure assigned to fissoldhimine (86).99 An alternative biosynthetic pathway to urea 93 was proposed by Twin and co-workers (Scheme 11B).100 N-Carbamoyl transfer of 90′ (from carbamoyl phosphate 91) would afford urea 95, which would exist as a tautomeric mixture with iminium ion 95′ under acidic conditions. Heterodimerization of 95 and 95′ could then occur through a Mannich-type process via intermediate 96, to give cyclic urea 93. Alternatively, an inverse electron demand hetero-Diels−Alder reaction between 95 and 95′ would afford 1,3-oxazinan-2-imine 97, which on rearrangement could yield urea 93. Although this proposed cascade outlined in Scheme 11B was validated synthetically, the desired exo diastereomer was the minor product [maximum 35:65 (exo:endo)].100 Alchornedine (98) was isolated in 2014 from the leaves of the gnarled tree Alchornea glandulosa, collected at the Parque Ecológico Perequê in the Atlantic rain forest region of São Paulo state, Brazil.101 Alchornedine was assigned the 1,2,4-

Scheme 10. (A) Biomimetic Synthesis of Alboinon (82); (B) Proposed Biosynthetic Precursors to 8398

4-aminobutanal (89), which underwent spontaneous cyclization to give a tautomeric mixture of 90 and 90′. Dimerization of 90 and 90′ followed by carbamoyl transfer (from carbamoyl phosphate 91) and cyclization would then provide intermediate diazinone 92, which, in turn, could undergo an additional carbamoyl transfer to afford urea 93. Electrophilic attack of

Scheme 11. Proposed Biosyntheses (A and B) of Fissoldhimine (86)99,100

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(112) (isolated as a 2:1 mixture).106 Sarcodonin (100), sarcodonin α (105), sarcodonin γ (107), episarcodonin (108), and a mixture of the sarcoviolins (111 and 112) exhibited cytotoxicity against breast, lung, and CNS cell lines, with 100, 107, and 108 showing inhibitory activity against the CNS cell line SF-268, with 96%, 93%, and 95% of cells killed, respectively, at 50 μM.106 Sarcodonin δ (113) was first isolated from the fruiting bodies of the bitter-tasting mushroom Sarcodon scabrosus, collected from Ailao Mountain, Yunnan Province, People’s Republic of China, in 2005,107 and was again isolated in 2006 from the inedible mushroom Hydnellum geogerium along with hydnellins A (114) and B (115) from H. suaveolens.108 The fruiting bodies of both fungi were collected on Mount Fuji, Japan.108 Sarcodonin δ (113) and hydnellin A (114) exhibited moderate antioxidant activity with IC50 values of 25.0 and 29.1 μM, respectively.108 Phellodonin (104) was isolated in 2010 from the edible mushroom Phellodon niger, collected from Wuging, Yunnan Province, People’s Republic of China.109 The dioxazine framework of the sarcodonins are proposed to arise biosynthetically by the [4+2]-cycloaddition between an ortho-quinone 116 and the C2β−N1β double bond of oxidized pyrazine derivative 117 (Scheme 13),105 a hypothesis supported by Baran’s aforementioned biomimetic synthetic studies. cis-4,6-Dimethyl-1,3,5-dithiazine (118) was isolated in 1999 from the pods of the flowering tree Acacia latescens, collected near Darwin, Australia, and its structure was confirmed by synthesis.110 Many species of Acacia trees have been used by the Aborigines of Australia’s Northern Territory for medicinal purposes. Despite this, no biological studies were reported for 118.110 The 1,2,3-dithiazin-4-one scorodophlone A (119) was isolated in 2006 from the seeds of the tropical tree Scorodophloeus zenkeri collected in the forest of Yokadouma in southern Cameroon, Africa. 111 The IR and NMR spectroscopic data enabled the structural assignment of scorodophlone A (119). The IR spectrum indicated the presence of N−H (3553 cm−1), carbonyl (1631 cm−1), sulfone (1302 and 1104 cm−1), and S−S (488 and 455 cm−1) moieties.111 The 1H NMR displayed a typical AMX spin system, together with a singlet at δH 3.18 ppm characteristic of a methylsulfonyl group, while the 13C NMR spectrum showed an amide carbonyl peak at δC 174.7 ppm.111 The absolute configuration of optically active 119 was not determined, and no biological data were reported despite the use of bark, seeds, and wood of S. zenkeri in folk medicine for the treatment of several diseases.111 Krempene A (120) was isolated in 2006 from the marine soft coral Cladiella krempfi, collected from the inner reef of Hainan Island in the South China Sea.112 Krempene A (120) contains an unprecedented 1,3,4oxadithiane ring fused to the tetracyclic steroidal framework.112 No biological studies were reported.

dihydrooxadiazine structure 98, the absolute stereochemistry of which was undetermined. A. glandulosa, commonly referred to as “tapiá”, “tamanqueiro”, or “amor-seco”, is native to South America and is used in traditional medicine to treat inflammatory disorders.101 Alchornedine (98) exhibited antiparasitic activity against Trypanosoma cruzi, the protozoan responsible for Chagas disease, with an IC50 of 93 μg mL−1.101 Moreover, 98 exhibited 2.4-fold greater efficacy (IC50 of 27 μg mL−1) against intracellular amastigotes compared to benznidazole, the current treatment for Chagas disease, making it a valuable scaffold for further drug development against this neglected tropical disease.101 Alchornedine (98) was proposed to be derived from pteroginine (99), also present in the leaves of A. glandulosa, by the oxidation−cyclization sequence outlined in Scheme 12.101 Scheme 12. Alchornedine (98) and its Proposed Biosynthesis from Pteroginine (99)101

Sarcodonin (100) was the first member of a unique series of benzodioxazine natural products to be isolated from the fruiting bodies of the fungus Sarcodon leucopus, collected on the slopes of Mount Etna near Catania, Italy.102 The unprecedented and seemingly unstable N,N-dioxide-containing benzodioxazine framework proposed for the structure of sarcodonin (100) (and its derivatives) prompted a detailed analysis and sweeping structural revision of the sarcodonin natural product family to the benzodioxane aminal framework (as depicted for 101) by Baran and co-workers in 2011.103 This structural revision followed the serendipitous synthesis of the benzodioxane aminal 102, the structure of which was determined by X-ray crystallography and the spectroscopic data of which closely resembled those reported for the sarcodonins.103 However, the originally proposed benzodioxazine framework was verified in 2013 upon isolation of sarcodonin ε (103) from Sarcodon scabrosus104 and X-ray crystallographic analysis of its dimethyl derivative confirming the presence of the benzodioxazine.104 The biomimetic total synthesis of phellodonin (104) and sarcodonin ε (103) by Baran and co-workers in 2013 confirmed unequivocally the N,N-dioxide-containing benzodioxazine framework of the sarcodonin natural product family.105 Sarcodonin (100) exhibited weak cytotoxicity against the KB (ED50 10.0 μg mL−1) and P388 (ED50 27.0 μg mL−1) tumor cell lines.102 In 2004, eight new sarcodonin derivatives were isolated from the same source: scardodonins α, β, γ (105−107), episarcodonin, episarcodonin α and episarcodonin β (108−110) (the N-oxide epimers of 100, 105, and 106), along with sarcoviolin α (111) and its epimer episarcoviolin α

Oxadiazepines, Oxathiazepines, Trioxepanes, and Dioxadiazepines. The 3-imino-1,2,4-oxadiazepine deaminocanavanine (121) was isolated from the legume Caragana spinosa in 1970 and again from the jack bean Canavalia 3070



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Scheme 13. Sarcodonin Natural Product Family and the Key Cycloaddition in their Proposed Biosynthesis105

stereochemistry of the sulfur−oxygen bond was assigned as α based on the 13C NMR shifts of the N-acetyl derivative of 128.118 In 1989, debromoeudistomin K (129) was isolated from the same source, along with 123, 126, and 128. All of the aforementioned eudistomins exhibited antiviral activity against HSV-1 in vitro, with 123 and 124 displaying potent inhibition in the 5−10 ng/disk range.116,118−120 Eudistomin K (126) displayed antitumor activity against L1210, A549, HCT-8, and P388 cell lines both in vitro and in vivo, with an IC50 of 0.01 μg mL−1 against P388 in vitro and T/C = 137% at 100 mg kg−1 in vivo.120 In 1998, another eudistomin containing a 1,2,4oxathiazepine motif was isolated from E. olivaceum and was named eudistomin V (130).121 Eudistomins V and E (130 and 124) exhibited comparable antimicrobial activity against Micrococcus luteus (41 mm vs 46 mm inhibition zones at 20 μg, respectively) and cytotoxic activities against L1210 cells (both with 100% inhibition at 5 μg).121 Periplosides A (131) and C (132) were first isolated in 1987 from the root bark of Periploca sepium Bge. (Asclepiadaceae) and were assigned the spiro-1,3,5-trioxepane structures 131 and 132, respectively.122 Periplocosides A−E, J, and K were isolated

ensiformis in 1972.113,114 The spontaneous formation of 121 from aqueous or alcoholic solutions of canavanine (122) is well established,115 and thus, in the latter isolation report, the authors proposed that 121 is an artifact of canavanine (122) isolation (an amino acid known to be abundant in certain legumes including C. spinosa and C. ensiformis).113 Thus, the true origin of 121, natural or otherwise, remains unclear.113

Eudistomins C, E, F, K, and L (123−127) were isolated in 1984 from the Caribbean marine tunicate Eudistoma olivaceum116 and were shown subsequently to possess an unprecedented 1,2,4-oxathiazepine motif. In 1987, the stereochemistry of the N−O bond was reassigned from 2β (cis-fused) to 2α (trans-fused) as depicted for 123−127.117 In 1988, eudistomin K sulfoxide (128) was isolated from the ascidian Ritterella sigillinoides collected in New Zealand.118 The 3071



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from the same source the following year,123−125 while periperoxides A−E were isolated from P. sepium and P. forrestii in 2008.126 The periplocosides and periperoxides were all originally assigned as endoperoxides, but in 2011 their structures were all reassigned to spiro-1,3,5-trioxepanes. Consequently the names of the natural products were changed from periplocosides A, B, C, D, E, F, J, and K to periplosides C, M, N, D, A, F, J, and K (132−135, 131, and 136−138) and from periperoxides A, B, C, D, and E to periplosides E, G, I, L, and H (139−143), respectively.127 In 2017, periplosides C (132), F (136), M (133), and N (134) along with nine new 1,3,5-trioxepane-containing steroidal glycosides were isolated, also from the root bark of P. sepium, and were named periplosides O−V (144−151) and 3-O-formylperiploside A (152).128 Following this isolation, the authors conducted a chemical transformation and X-ray crystal diffraction analysis of 132 and 136, which led to reassignment of the stereochemistry of the spiro center from S to R in 132−134 and 136,128 which has been applied to the entire periploside family herein, as depicted for 131−152. Periplosides E (139), G (140), H (143), I (141), and L (142) displayed immunosuppressive activity through inhibition of T lymphocyte proliferation in vitro with IC50 values ranging from 0.29 to 1.97 μM.126 The spiro-orthoester moiety was found to be critical for this observed immunosuppressive activity through structure− activity relationship studies.127 Additionally, periploside C (132) showed significant antitumor activity against Sarcoma 180 ascites in mice (growth ratio of 53% at a dose of 10 mg/ kg/day) and significant preventative effects on concanavalin Ainduced mice hepatitis (1−20% necrosis at a dose of 10 mg kg−1 compared to ∼40% necrosis in the control group).123,129 Cripowellin A (153) contains a tetrahydropyranotrioxepane and was isolated from the bulbs of the ornamental perennial plant Crinum × powellii in 1997.130 The structure of 153 was assigned using X-ray crystallography.130 The natural product 153 was reported to have insecticidal activity.130,131 Cripowellin A (153) was again isolated in 2016 from the swamp lily Crinum erubescens and was found to exhibit potent antiplasmodial activity against the chloroquine/mefloquine-resistant Dd2 strain of Plasmodium falciparum (IC50 30 nM), as well as potent antiproliferative activity against the human ovarian cancer cell line A2780 (IC50 11.1 nM).132 Geralcin D (154) was isolated in 2013 from Streptomyces sp. LMA-545 and was found to possess an unprecedented dioxadiazepine motif.133 This dioxadiazepine motif was assigned using IR and detailed NMR experiments. Characteristic bands in the IR spectrum at 1657 and 1448 cm−1 indicated the presence of an amide CO and an N−O motif, respectively.133 The chemical shifts for C-8 (δC 83.0 ppm) and C-9 (δC 90.5 ppm) indicated neighboring oxygen atoms, while 1H−13C HMBC and 1H−15N HMBC data indicated connectivities from both C-9 and C-11 to C-10 and from C-11

to both C-10 and N−B.133 Geralcin D (154) was examined for cytotoxic and antimicrobial properties, but failed to show any appreciable activity at 100 μM.133 Polysulfides. The 1,2,3-trithiolane 155, the 1,2,3,4tetrathiane 156, and the 1,2,5-trithiepanes 157−159 were isolated in 2007 from two Cytophaga strains (BIO137 and BIO138) isolated from biofilms collected in the North Sea.134 3072



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both Tutukaka and Leigh Harbour, New Zealand.139,140 A 1,2,3-trithiane ring was confirmed by the sequential loss of three 32S in the low- and high-resolution EI mass spectrum.139 Both enantiomers of 164 showed modest cytotoxicity against P388 murine leukemia cells (IC50 21.6 μM), as well as antibacterial activity against Candida albicans and Gram-positive Bacillus subtilis (4 mm zone of inhibition at 120 μg/disk), but not against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa.139,140 Trithiane (+)-164 did not inhibit the cell cycle checkpoint enzyme cdc2/cyclin B kinase (at 100 μM) or induce thiol-generated DNA strand scission and was inactive at the National Cancer Institute (panel average GI50 32 μM, TGI 63 μM, LC50 100 μM) and against Mycobacterium tuberculosis H37Rv (10% inhibition at 12.5 μg mL−1).140 In 2000, the 1,2,3-trithiane cassipoureamide B (165) was isolated from the stem wood of Cassipourea guianensis collected in Belén, Pará, Brazil.141 The UV spectrum of 165 exhibited a maximum at 267 nm, indicative of a 1,2,3-trithiane ring.141 No biological studies were reported for this natural product.

Trithiepanes 158 and 159 were tested for antimicrobial activity, but were reported to be inactive.134

1,2,3-Trithiane-5-carboxylic acid (160) was isolated from cooked white asparagus in 1977, although it was originally proposed to form from asparagustic acid (161) during the cooking process.135,136 However, a few years later, 160 was isolated from raw asparagus shoots (Asparagus off icinalis) cultivated at Hokkaido University, Japan, thus verifying its presence in the vegetable.136 A biosynthetic route to 160 from cysteine (162) was proposed (Scheme 14), but in isotopic labeling experiments [U−14C]cysteine was not transformed to asparagustic acid (161); thus it remains unclear as to whether 160 is derived from cysteine.135

The 1,2,3-trithiepin 166 was isolated from steam-distilled hop oil in 1982.142 Lenthionine (1,2,3,5,6-pentathiepane; 167) was isolated in 1966 from shiitake (Lentinus edodes) mushrooms, and its structure was confirmed by synthesis.143 Despite being isolated in 1966, research into the biosynthesis of lenthionine has been for the most part dormant since the 1970s, when it was established that 167 is formed from the peptide lentinic acid by the enzymes cysteine sulfoxide lyase and a glutamyl transpeptidase.144−146 Further details surrounding the biosynthesis of 167 from lentinic acid remain unclear. 1,2,4-Trithiolane, 1,2,4,6-tetrathiepane, and 1,2,3,4,5,6-hexathiepane (168, 169, and 170) were isolated from the same source in 1967.147 Both lenthionine (167) and 1,2,4,6-tetrathiepane (169) were examined for antibacterial and antifungal activities; however 169 showed only weak activity (lowest MIC 50 μg mL−1 against Piricularia oryzae), while 167 exhibited moderate antibacterial activity against Bacillus subtilis and Proteus vulgaris (both with MIC 50 μg mL−1) and potent antifungal activity against Pyricularia oryzae, Glomerella cingulata, Trichophyton mentagrophytes, Candida albicans, Saccharomyces cerevisiae, Cryptococcus neoformans, and Trichophyton rubrum (MIC 12.5, 12.5, 3.12, 6.25, 6.25, 6.25, and 3.12 μg mL−1, respectively).143 Lenthionine (167) inhibited platelet aggregation induced by both arachidonic acid (1.5 mM) and U-46619 (1 μM) (IC50 161 and 183 μg mL−1, respectively).148 Despite its biologically active properties, 167 is more commonly known for the unique aroma it imparts on the edible shiitake mushroom.143 The volatile cyclic polysulfides 168, 169, and 171−173 were also isolated from shiitake (Lentinus edodes) mushrooms in 1986, along with lenthionine (167).149 1,2,4-Trithiolane (168) was again isolated in 2012 from the bacterium Streptomyces f ilamentosus along with polysulfides 170, 174, and 175 from Streptomyces bottropensis.150 Trithianes 176 and 177, in addition to tetrathiepane 178, were isolated in 1985 from the leaves of the neem tree (Azadirachta indica).151 A crude steam distillate of the leaves of A. indica exhibited in vitro antifungal activity

Scheme 14. Proposed Biosynthesis of 1,2,3-Trithiane-5carboxylic Acid (160)135

5-Methylthio-1,2,3-trithiane (163) was isolated in 1980 from the alga Chara globularis and was found to be at least partially responsible for the observed allelopathic effect of the alga on phytoplankton, by effecting complete inhibition of photosynthesis in Nitzschia palea, at 3 μM.137,138 Another 1,2,3-trithiane, (+)-164, was isolated in 1989 from the cherry-colored ascidian Aplidium sp. D collected from Kaikoura in New Zealand, and its enantiomer (−)-164 was isolated separately in 2001 from the delicate pink-stalked ascidian Hypsistoza fasmeriana, collected at 3073



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against Trichophyton mentagrophytes, although the biological activity of the isolated polysulfides 176−178 was not reported.151 Dialkyl trithiolanes 179 and 180, 3-methyl-1,2,4trithiane (181), and 3,6-dimethyl-1,2,4,5-tetrathiane (182) were isolated in 1996 from the durian fruit, Durio zibethinus, collected from Purworedjo, near Yogyakarta, Indonesia.152 The authors did not elucidate the absolute or relative stereochemistry of these alkyl polysulfides 179−182. In 1976, polysulfides 168 and 169, lenthionine (167), its sulfone analogue 183, and the sulfoxides 184 and 185 were isolated from the red alga Chondria californica collected at Isla San Jose in the Gulf of California.153 Trithiolaniacin (186) was isolated from the wet roots of Petiveria alliacea in 1974 and was assigned the cis-3,5-diphenyl-1,2,4-trithiolane structure 186.154

found to exhibit chirality on the NMR time scale, although it did not show optical activity.159 Lissoclinotoxin B (212) was isolated in 1994, also from L. perforatum.158 Lissoclinotoxin A (211) displayed both antifungal activity against Candida albicans (MIC 40 μg mL−1) and Trichosporon mentagrophytes (MIC 20 μg mL−1) and in vitro antibacterial activity against a variety of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Streptococcus faecalis, Citrobacter spp., Klebsiella spp., Escherichia coli, Enterobacter spp., Salmonella sp., Proteus sp.) with MIC values in the range of 0.1−0.6 μg mL−1.157,158 Lissoclinotoxin A (211) also showed modest cytotoxicity against L1210 leukemia cells (IC50 1 μg mL−1) and strong antimalarial activity against Plasmodium falciparum, although it proved to be toxic to mice during in vivo studies (LD50 < 50 mg kg−1).157,158 Varacin (213) is a benzopentathiepin isolated in 1991 from the lavender-colored ascidian Lissoclinum vareau, collected in the Fiji islands.160 Varacin (213) and the benzotrithianes varacins A−C (214−216) were isolated in 1995 from the ascidian Polycitor sp. collected near Valentin Bay, on the northwestern shore of the Sea of Japan.161 Some benzopentathiepins have been reported to decompose into sulfur and the corresponding benzotrithianes in solution.162 The same type of occurences, in that varacin (213) (or varacin acetate) and varacin A (214) (or varacin A acetate) can interconvert (varacin ↔ varacin A + S8), have been observed in chloroform, methanol, and pyridine solutions.161 However, the fact that varacin A acetate did not oxidize into varacin B or C acetates at room temperature in methanol solution after standing for one year indicates that both 215 and 216 are natural products.161 Varacin (213), its acetate, and varacin A− C acetates exhibited potent antifungal activities against Candida albicans (20 mm/0.1 μg for varacin and 20 mm/10 μg for the synthetic acetates) and antibacterial activities against Bacillus subtilus (20 mm/0.1 μg for varacin and 20 mm/1.0 μg for the synthetic acetates).161 Varacin C (216) causes DNA cleavage under acidic conditions, explaining the observed potent cytotoxicity of 216 against a series of cancer cell lines (HT29, PC-3, MDA231, UMUC3, and PACA2, IC50 in the range of 2.4−11.9 nM), as well as the aforementioned antifungal and antibacterial activities.163 Varacin (213) also exhibits potent antifungal activity against Candida albicans (14 mm inhibition zone at 2 μg/disk) and cytotoxicity 100 times more potent that 5-fluorouracil against human colon cancer HCT 116 cells (IC90 of 0.05 μg mL−1), as well as potent cytotoxicity against human prostate (PC-3, IC50 0.6 nM), lung (PACA2, IC50 1.8 nM), and breast (MCF-7, IC50 1.69 nM) cancer cell lines.160,164 Additionally, 213 causes thiol-mediated DNA cleavage, a process that was accelerated in acidic media.164 The structure of varacin (213) was confirmed by synthesis in 1993.165 The dibenzo-1,2,5-trithiepin lissoclinotoxin F (217) was isolated from a didemnid ascidian collected from Sabtang Reef, Batanes Islands, in the Philippines in 2003,166 and again in 2005 from Lissoclinum cf. badium collected from Monado in Indonesia.167 Lissoclinotoxin F (217) showed cytotoxicity against the Chinese hamster V79 and HL-60 cell lines (IC50 0.28 and 0.23 μM, respectively), as well as the human breast carcinoma MDA-MB-468 cell line (IC50 4.2 μg mL−1), with 3-fold greater cytotoxicity toward a PTEN−-deficient cell line.166,168 In 1994, five unnamed trithianes and pentathiepins (218−222) were isolated from ascidians collected in Micronesia.169 A trisubstituted benzopentathiepin (218) and a benzotrithiolane (220) were isolated from Lissoclinum japonicum from Palau and again in 2005 from Lissoclinum cf. badium,167 and their primary amine

In 1993, 23 cyclic polysulfides were isolated as diastereomeric mixtures from the intact cells of the sulfur-metabolizing hyperthermophilic archaea Thermococcus tadjuricus and Thermanaerovibrio acidaminovorans.155 These included a series of trithiolanes (187−196), three disubstituted 1,2,4,5-tetrathianes (197−199), a series of 1,2,3,5,6-pentathiepanes (200−206), a pentathiane (207), and two hexathiepanes (208 and 209). The characterization of all these cyclic polysulfides relied on highresolution EI mass spectrometry fragmentation experiments, whereby fragment ions indicated loss of R-CH-S and sequential loss of 32Sn.155 Sulfur-metabolizing archaea of the genus Thermococcus metabolize sulfur (S0) in a form of anaerobic respiration, in which elemental sulfur acts as a terminal electron acceptor to form Sn2− and ATP.155,156 Aldehydes derived from deamination and decarboxylation of an amino acid (e.g., leucine or alanine) then react with intracellular polysulfides such as S52− in a nonenzymatic fashion, forming substituted cyclic polysulfides (the formation of hexathiepanes 208 and 209, outlined in Scheme 15B).155 Lissoclinotoxin A was first isolated in 1991 from the white perforated marine tunicate Lissoclinum perforatum (Verril 1871), collected off the coast of Dinard, France, and was originally assigned as the benzotrithiane 210,157 but was later revised to the pentathiepin 211.158 Lissoclinotoxin A (211) was isolated again in 1994 from Lissoclinum sp. (91-02-028) collected from the Great Barrier Reef in Australia and was 3074



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Scheme 15. (A) Cyclic Polysulfides 187−209 Isolated from Thermococcus tadjuricus and Thermanaerovibrio acidaminovorans; (B) Proposed Biosynthesis of Cyclic Polysulfides 208 and 209 during Anaerobic Fermentation by Sulfur-Metabolizing Archea155,156

aureus (13.1 and 15.8 mm inhibition zone at 50 μg/disk, respectively) and Escherichia coli (15.7 and 11.6 mm inhibition zone at 50 μg/disk, respectively).170 L. cf. badium from Monado, Indonesia, again yielded a series of polysulfur alkaloids in 2009, including the benzotrithiane lissoclibadin 13 (226) and the benzopentathiepin lissoclibadin 14 (227), both of which displayed moderate cytotoxicity against the Chinese hamster V79 (IC50 0.14 and 0.25 μM, respectively) and murine leukemia L1210 (IC50 0.70 and 0.64 μM, respectively) cell lines.171 Although 226 showed optical activity ([α]D −6.1 (c 0.2, MeOH)), the absolute configuration of this compound was undetermined.171 Lissoclibadins 4 (224) and 14 (227) displayed cytotoxicity against the HCT-15 (IC50 17.2 and 4.2 μM, respectively) and HeLa-S3 (IC50 17.8 and 5.9 μM, respectively) human cancer cell lines.172 Brzostowska and Greer provided a valid explanation for the enhanced bioactivity observed for pentathiepins bearing a primary amine [such as varacin (213) and lissoclinotoxin A (211)] compared to those bearing a dimethylamine. The primary amine initiates an intramolecular nucleophilic ring opening of the pentathiepin ring followed by desulfurization, generating the two thiazine sulfides 228 and 229 and the reactive sulfur species S3 (Scheme 16A).173 In contrast, tertiary amines add reversibly to S1 since the nitrogen cannot lose its positive charge by deprotonation, precluding the catalysis step. This hypothesis was tested subsequently using a trapping experiment. Decomposition of pentathiepin 230 by an amine nucleophile and trapping of the reactive S3 species with norbornene led to the formation of trithiolane 231 and benzotrithiolane 232 (Scheme 16B).173 This experimental evidence lent support to the hypothesis of the authors that S3 unit transfer to biological targets could be associated with a

derivatives 219 and 221 were isolated as an inseparable mixture (2:3) from a different Lissoclinum species from Pohnpei, while the varacin derivative 222 was isolated from an Eudistoma sp. also collected from Pohnpei.169 All five natural products showed potent and selective inhibition of protein kinase C over protein kinase A (IC 50 0.3−3.0 and >25 μg mL −1 , respectively).169 The benzopentathiepin 218 and the benzotrithiolane 220 also exhibited moderate antimicrobial against Mucor hiemalis, Ruegeria atlantica, Saccharomyces cerevisiae, Staphylococcus aureus, and Escherichia coli, with inhibition zones in the ranges 14.2−30.0 mm and 10.3−32.4 mm, respectively, at 50 μg/disk.167 Both the benzopentathiepin 218 and the benzotrithiolane 220 also exhibited cytotoxic activity against Chinese hamster V79 cells (IC50 0.15 and 0.19 μM, respectively).168 In 2005, the dibenzo-1,2,5-trithiepin lissoclibadin 2 (223) was isolated from Lissoclinum cf. badium collected from Monado, Indonesia.167 Lissoclibadin 2 (223) showed moderate antimicrobial activity against Ruegeria atlantica (28.2 mm inhibition zone at 50 μg/disk) and exhibited cytotoxicity against the HL-60 human leukemia cell line and Chinese hamster V79 cells (IC50 0.08 and 0.21 μM, respectively), as well as potent inhibitory activity against human colon (DLD-1 and HCT116), breast (MDA-MB-231), renal (ACHN), and large-cell lung (NCI-H460) cancer cell lines with IC 50 values of 0.10, 0.14, 0.20, 0.24, and 0.27 μM, respectively.167,168 Lissoclibadin 2 (223) was also stable in rat plasma for >30 min and showed no apparent toxicity to mice (single intravenous dose, 50 mg kg−1), making it a potential lead compound for further development as a cancer chemotherapy agent.168 In 2006, the related dibenzo-1,2,5-trithiepins lissoclibadins 4 (224) and 5 (225) were isolated from the same source collected at the same site and were also shown to possess moderate antimicrobial activity against Staphylococcus 3075



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their structural resemblance to known bioactive molecules or their isolation from constituents of traditional medicines. Although several unprecedented biosynthetic processes are suggested to operate during the assembly of these heterocycles, research that validates these proposals is lacking, which is sure to stimulate further study in this area.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +64 (0) 9 923 8269. E-mail: [email protected]. ORCID

Jonathan Sperry: 0000-0001-7288-3939 Notes

The authors declare no competing financial interest.

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REFERENCES

(1) (a) Hanson, J. R. Natural Products: The Secondary Metabolites; The Royal Society of Chemistry: Cambridge, 2003. (b) Dictionary of Natural Products http://dnp.chemnetbase.com. (c) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R. Nat. Prod. Rep. 2016, 33, 382−431. (2) For overviews of natural products containing a heterocycle with one heteroatom, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309− 3362. (b) Marmsater, F. P.; West, F. G. Chem. - Eur. J. 2002, 8, 4347− 4353. (c) Sheikh, N. S. Nat. Prod. Rep. 2014, 31, 1088−1100. (d) Lorente, A.; Lamariano-Merketegi, J.; Albericio, F.; Á lvarez, M. Chem. Rev. 2013, 113, 4567−4610. (e) Gallimore, A. R. Nat. Prod. Rep. 2009, 26, 266−280. (f) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435− 446. (g) Gribble, G. W. Indole Ring Synthesis: From Natural Products to Drug Discovery; Wiley: Chichester, UK, 2016. (h) Schneider, M. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10, pp 155−299. (i) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953−2989. (j) Laschat, S.; Dickner, T. Synthesis 2000, 2000, 1781− 1813. (3) For overviews of natural products containing a heterocycle with two heteroatoms, see: (a) Wijtmans, R.; Vink, M. K.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. Synthesis 2004, 2004, 641−662. (b) Laursen, J. B.; Nielsen, J. Chem. Rev. 2004, 104, 1663− 1686. (c) Ashihara, H.; Sano, H.; Crozier, A. Phytochemistry 2008, 69, 841−856. (d) Lee, S.; LaCour, T. G.; Fuchs, P. L. Chem. Rev. 2009, 109, 2275−2314. (e) Jin, Z. Nat. Prod. Rep. 2013, 30, 869−915. (f) Borthwick, A. D. Chem. Rev. 2012, 112, 3641−3716. (g) Pilkington, L. I.; Barker, D. Nat. Prod. Rep. 2015, 32, 1369−1388. (4) Anzai, K.; Nagatsu, J.; Suzuki, S. J. Antibiot. 1961, 14, 340−342. (5) Grunberger, D.; Grunberger, G. In Antibiotics: Mechanism of Action of Antieukaryotic and Antiviral Compounds; Hahn, F. E., Ed.; Springer-Verlag: Berlin, Heidelberg, 1979; Vol. 5, Part 2, pp 110−123. (6) Gong, Q.-L.; Hu, X.-G.; Fang, G.-Y.; Li, X.-H. J. Mol. Model. 2012, 18, 493−500. (7) Gogia, S.; Puranik, M. J. Biomol. Struct. Dyn. 2014, 32, 27−35. (8) Dourado, M.; Sarmento, A. B.; Pereira, S. V.; Alves, V.; Silva, T.; Pinto, A. M.; Rosa, M. S. Pathophysiology 2007, 14, 3−10 and references therein. (9) Parks, R. E.; Agarwal, K. C. In Antineoplastic and Immunosuppressive Agents II; Sartorelli, A. C.; Johns, D. G., Eds.; Springer-Verlag: Berlin, Heidelberg, 1975; pp 458−467. (10) Keough, D. T.; Skinner-Adams, T.; Jones, M. K.; Ng, A.; Brereton, I. M.; Guddat, L. W.; de Jersey, J. J. Med. Chem. 2006, 49, 7479−7486. (11) Ridzlan, F. R.; Bahaman, A. R.; Khairani-Bejo, S.; Mutalib, A. R. Trop. Biomed. 2010, 27, 632−638. (12) Hirasawa, K.; Isono, K. J. Antibiot. 1978, 31, 628−629. (13) Elstner, E. F.; Suhadolnik, R. J. J. Biol. Chem. 1971, 246, 6973− 6981. (14) Imamura, N.; Murata, M.; Yao, T.; Oiwa, R.; Tanaka, H.; Omura, S. J. Antibiot. 1985, 38, 1110−1111.

Scheme 16. (A) Proposed Activation of Varacin (213) and Lissoclinotoxin A (211); (B) S3 Trapping Experiment with Model Pentathiepin 230173

novel mechanism of action in which naturally occurring pentathiepins exert potent biological activity.173

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CONCLUSIONS This review has collated all natural products that contain a heteroatom-rich ring system, namely, a five-, six-, or sevenmembered cyclic structure containing more than two heteroatoms. Of the 170 natural products described, the majority (145) can be classed as either a polysulfide (70) or containing nitrogen (75). The majority of these natural products have been isolated from terrestrial plants and marine sources, with fewer isolated from bacteria, fungi, and protists. The biological activities associated with these natural products are vast and diverse, with many compounds having potential applications in both the pharmaceutical and agrochemical industries. On the other hand, several of the natural products described herein have never been tested for bioactivity, despite 3076



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(15) Jones, R.; Ainsworth, C. J. Am. Chem. Soc. 1955, 77, 1538−1540. (16) Levin, A. P.; Hartman, P. E. J. Bacteriol. 1963, 86, 820−828. (17) Haines, D. R.; Leonard, N. J.; Wiemer, D. F. J. Org. Chem. 1982, 47, 474−482. (18) Schmitzer, P. R.; Graupner, P. R.; Chapin, E. L.; Fields, S. C.; Gilbert, J. R.; Gray, J. A.; Peacock, C. L.; Gerwick, B. C. J. Nat. Prod. 2000, 63, 777−781. (19) El-Gendy, M. M.; Shaaban, M.; Shaaban, K. A.; El-Bondkly, A. M.; Laatsch, H. J. Antibiot. 2008, 61, 149−157. (20) Tee, E. H.; Karoli, T.; Ramu, S.; Huang, J. X.; Butler, M. S.; Cooper, M. A. J. Nat. Prod. 2010, 73, 1940−1942. (21) Battaglia, U.; Moody, C. J. J. Nat. Prod. 2010, 73, 1938−1939. (22) Li, C.-S.; An, C.-Y.; Li, X.-M.; Gao, S.-S.; Cui, C.-M.; Sun, H.-F.; Wang, B.-G. J. Nat. Prod. 2011, 74, 1331−1334. (23) An, C.-Y.; Li, X.-M.; Li, C.-S.; Gao, S.-S.; Shang, Z.; Wang, B.-G. Helv. Chim. Acta 2013, 96, 682−687. (24) Hossain, M.; van der Helm, D.; Sanduja, R.; Alam, M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1985, 41, 1199−1202. (25) Rücker, G.; Manns, D.; Schenkel, E. P.; Hartmann, R.; Heinzmann, B. M. Arch. Pharm. 2003, 336, 205−207. (26) Ponomarenko, L. P.; Kalinovsky, A. I.; Martyyas, E. A.; Doudkin, R. V.; Gorovoy, P. G.; Stonik, V. A. Phytochem. Lett. 2012, 5, 118−122. (27) Carbone, M.; Li, Y.; Irace, C.; Mollo, E.; Castelluccio, F.; Di Pascale, A.; Cimino, G.; Santamaria, R.; Guo, Y.; Gavagnin, M. Org. Lett. 2011, 13, 2516−2519. (28) Brogan, J. T. Total Synthesis and Biological Evaluation of Alkaloid Natural Products (+)-7-Bromotrypargine and Phidianidines A and B and the Development of a Novel Class of Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1. Ph.D. Thesis, Vanderbilt University, Nashville, TN, 2013. (29) Brogan, J. T.; Stoops, S. L.; Lindsley, C. W. ACS Chem. Neurosci. 2012, 3, 658−664. (30) Vitale, R. M.; Gatti, M.; Carbone, M.; Barbieri, F.; Felicità, V.; Gavagnin, M.; Florio, T.; Amodeo, P. ACS Chem. Biol. 2013, 8, 2762− 2770. (31) Lin, H.-Y.; Snider, B. B. J. Org. Chem. 2012, 77, 4832−4836. (32) Buchanan, J. C.; Petersen, B. P.; Chamberland, S. Tetrahedron Lett. 2013, 54, 6002−6004. (33) Manzo, E.; Pagano, D.; Carbone, M.; Ciavatta, M. L.; Gavagnin, M. Arkivoc 2012, 220−228. (34) Takayama, H.; Katakawa, K.; Kitajima, M.; Seki, H.; Yamaguchi, K.; Aimi, N. Org. Lett. 2001, 3, 4165−4167. (35) Inubushi, Y.; Ishii, H.; Harayama, T.; Burnell, R. H.; Ayer, W. A.; Altenkirk, B. Tetrahedron Lett. 1967, 8, 1069−1072. (36) Heathcock, C. H.; Smith, K. M.; Blumenkopf, T. A. J. Am. Chem. Soc. 1986, 108, 5022−5024. (37) Takemoto, T.; Takagi, N.; Nakajima, T.; Arihara, S.; Koike, K. In An Ascaricidal Principle of Quisqualis fructus. The Chemical Structure of Quisqualic Acid; 16th Symposium on the Chemistry of Natural Products: Osaka, Japan, 1972. (38) Ranger, C. M.; Winter, R. E.; Singh, A. P.; Reding, M. E.; Frantz, J. M.; Locke, J. C.; Krause, C. R. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 1217−1221. (39) Jin, R.; Horning, M.; Mayer, M. L.; Gouaux, E. Biochemistry 2002, 41, 15635−15643. (40) Subasinghe, N.; Schulte, M.; Roon, R. J.; Koerner, J. F.; Johnson, R. L. J. Med. Chem. 1992, 35, 4602−4607. (41) London, E. D.; Coyle, J. T. Mol. Pharmacol. 1979, 15, 492−505. (42) Schoepp, D. D.; Johnson, B. G. J. Neurochem. 1988, 50, 1605− 1613. (43) Recasens, M.; Guiramand, J.; Nourigat, A.; Sassetti, I.; Devilliers, G. Neurochem. Int. 1988, 13, 463−467. (44) Shinozaki, H.; Izumi, S. Neuropharmacology 1974, 13, 665−672. (45) Muir, J. L.; Page, K. J.; Sirinathsinghji, D. J. S.; Robbins, T. W.; Everitt, B. J. Behav. Brain Res. 1993, 57, 123−131. (46) Robbins, T. W.; Everitt, B. J.; Marston, H. M.; Wilkinson, J.; Jones, G. H.; Page, K. J. Behav. Brain Res. 1989, 35, 221−240.

(47) Connor, D. J.; Langlais, P. J.; Thal, L. J. Brain Res. 1991, 555, 84−90. (48) Dunnet, S. B.; Whishaw, I. Q.; Jones, G. H.; Bunch, S. T. Neuroscience 1987, 20, 653−669. (49) Mallet, P. E.; Beninger, R. J.; Flesher, S. N.; Jhamandas, K.; Boegman, R. J. Brain Res. Bull. 1995, 36, 51−56. (50) Funayama, S.; Cordell, G. A. Alkaloids: A Treasury of Poisons and Medicines; Elsevier Science: London, UK, 2014. (51) Gmelin, R.; Strauss, G.; Hasenmaier, G. Z. Naturforsch., B: J. Chem. Sci. 1958, 13, 252−256. (52) Gmelin, R.; Strauss, G.; Hasenmaier, G. Hoppe-Seyler's Z. Physiol. Chem. 1959, 314, 28−32. (53) Heitz, S.; Durgeat, M.; Guyot, M.; Brassy, C.; Bachet, B. Tetrahedron Lett. 1980, 21, 1457−1458. (54) Hogan, I. T.; Sainsbury, M. Tetrahedron 1984, 40, 681−682. (55) Pham, C.-D.; Weber, H.; Hartmann, R.; Wray, V.; Lin, W.; Lai, D.; Proksch, P. Org. Lett. 2013, 15, 2230−2233. (56) Davison, E. K.; Sperry, J. Org. Chem. Front. 2016, 3, 38−42. (57) Abas, S. A.; Hossain, M. B.; van der Helm, D.; Schmitz, F. J.; Laney, M.; Cabuslay, R.; Schatzman, R. C. J. Org. Chem. 1996, 61, 2709−2712. (58) Chen, M.; Lin, S.; Li, L.; Zhu, C.; Wang, X.; Wang, Y.; Jiang, B.; Wang, S.; Li, Y.; Jiang, J.; Shi, J. Org. Lett. 2012, 14, 5668−5671. (59) Yang, Z.; Huang, N.; Xu, B.; Huang, W.; Xie, T.; Cheng, F.; Zou, K. Molecules 2016, 21, 232−244. (60) Choi, J.-H.; Fushimi, K.; Abe, N.; Tanaka, H.; Maeda, S.; Morita, A.; Hara, M.; Motohashi, R.; Matsunaga, J.; Eguchi, Y. ChemBioChem 2010, 11, 1373−1377. (61) Choi, J.-H.; Ohnishi, T.; Yamakawa, Y.; Takeda, S.; Sekiguchi, S.; Maruyama, W.; Yamashita, K.; Suzuki, T.; Morita, A.; Ikka, T.; Motohashi, R.; Kiriiwa, Y.; Tobina, H.; Asai, T.; Tokuyama, S.; Hirai, H.; Yasuda, N.; Noguchi, K.; Asakawa, T.; Sugiyama, S.; Kan, T.; Kawagishi, H. Angew. Chem. 2014, 126, 1578−1581. (62) Choi, J.-H.; Kikuchi, A.; Pumkaeo, P.; Hirai, H.; Tokuyama, S.; Kawagishi, H. Biosci., Biotechnol., Biochem. 2016, 80, 2045−2050. (63) Tobina, H.; Choi, J.-H.; Asai, T.; Kiriiwa, Y.; Asakawa, T.; Kan, T.; Morita, A.; Kawagishi, H. Field Crops Res. 2014, 162, 6−11. (64) Suzuki, T.; Yamamoto, N.; Choi, J. H.; Takano, T.; Sasaki, Y.; Terashima, Y.; Ito, A.; Dohra, H.; Hirai, H.; Nakamura, Y.; Yano, K.; Kawagishi, H. Sci. Rep. 2016, 6, 39087. (65) Ikeuchi, K.; Fujii, R.; Sugiyama, S.; Asakawa, T.; Inai, M.; Hamashima, Y.; Choi, J.-H.; Suzuki, T.; Kawagishi, H.; Kan, T. Org. Biomol. Chem. 2014, 12, 3813−3815. (66) Nagamatsu, T. Recent Res. Devel. Org. Bioorg. Chem. 2001, 4, 97−121. (67) Wang, H.; Lim, K. L.; Yeo, S. L.; Xu, X.; Sim, M. M.; Ting, A. E.; Wang, Y.; Yee, S.; Tan, Y. H.; Pallen, C. J. J. Nat. Prod. 2000, 63, 1641−1646. (68) Philmus, B.; Shaffer, B. T.; Kidarsa, T. A.; Yan, Q.; Raaijmakers, J. M.; Begley, T. P.; Loper, J. E. ChemBioChem 2015, 16, 1782−1790. (69) Porwal, M.; Mehta, B.; Gupta, D. Natl. Acad. Sci. Lett. 1988, 2, 81−84. (70) Tian, J.-L.; Liang, X.; Gao, P.-Y.; Li, D.-Q.; Sun, Q.; Li, L.-Z.; Song, S.-J. J. Asian Nat. Prod. Res. 2014, 16, 259−264. (71) Zhu, Y.; Yoshida, W. Y.; Kelly-Borges, M.; Scheuer, P. J. Heterocycles 1998, 49, 355−360. (72) Cao, L.; Maciejewski, J. P.; Elzner, S.; Amantini, D.; Wipf, P. Org. Biomol. Chem. 2012, 10, 5811−5814. (73) Shimogawa, H.; Kuribayashi, S.; Teruya, T.; Suenaga, K.; Kigoshi, H. Tetrahedron Lett. 2006, 47, 1409−1411. (74) Okwu, D. E.; Uchegbu, R. Res. J. Biotechnol. 2008, 3, 335−339. (75) Lee, H.-K.; Lee, I.-H.; Yim, J.-S.; Kim, Y.-H.; Lee, S.-H.; Lee, K.; Koo, Y.-Mo; Kim, S.-J.; Jeong, B.-C. J. Microbiol. Biotechnol. 2005, 15, 734−739. (76) Hirata, K.; Yoshitomi, S.; Dwi, S.; Iwabe, O.; Mahakhant, A.; Polchai, J.; Miyamoto, K. J. Biosci. Bioeng. 2003, 95, 512−517. (77) Hirata, K.; Nakagami, H.; Takashina, J.; Mahmud, T.; Kobayashi, M.; In, Y.; Ishida, T.; Miyamoto, K. Heterocycles 1996, 7, 1513−1519. 3077



Review

(114) Toepfer, R.; Miersch, J.; Bothe, H. R. Biochem. Physiol. Pflanz. 1970, 161, 231−242. (115) Kitagawa, M.; Tsukamoto, J. J. Biochem. 1937, 26, 373−385. (116) Rinehart, K. L.; Kobayashi, J.; Harbour, G. C.; Hughes, R. G., Jr; Mizsak, S. A.; Scahill, T. A. J. Am. Chem. Soc. 1984, 106, 1524− 1526. (117) Blunt, J. W.; Lake, R. J.; Munro, M. H.; Toyokuni, T. Tetrahedron Lett. 1987, 28, 1825−1826. (118) Lake, R. J.; Brennan, M. M.; Blunt, J. W.; Munro, M. H.; Pannell, L. K. Tetrahedron Lett. 1988, 29, 2255−2256. (119) Rinehart, K. L.; Kobayashi, J.; Harbour, G. C.; Gilmore, J.; Mascal, M.; Holt, T. G.; Shield, L. S.; Lafargue, F. J. Am. Chem. Soc. 1987, 109, 3378−3387. (120) Lake, R.; Blunt, J.; Munro, M. Aust. J. Chem. 1989, 42, 1201− 1206. ́ 1998, 15, (121) Ibáñez-Calero, S. L.; Rinehart, K. L. Rev. Boliv. Quim. 39−51. (122) Oshima, Y.; Hirota, T.; Hikino, H. Heterocycles 1987, 26, 2093−2098. (123) Itokawa, H.; Xu, J.; Takeya, K.; Watanabe, K.; Shoji, J. Chem. Pharm. Bull. 1988, 36, 982−987. (124) Itokawa, H.; Xu, J.; Takeya, K. Chem. Pharm. Bull. 1988, 36, 2084−2089. (125) Itokawa, H.; Xu, J.; Takeya, K. Chem. Pharm. Bull. 1988, 36, 4441−4446. (126) Feng, J.; Zhang, R.; Zhou, Y.; Chen, Z.; Tang, W.; Liu, Q.; Zuo, J.; Zhao, W. Phytochemistry 2008, 69, 2716−2723. (127) Wang, L.-Y.; Chen, Z.-H.; Zhou, Y.-P.; Tang, W.; Zuo, J.; Zhao, W.-M. Phytochemistry 2011, 72, 2230−2236. (128) Wang, L.-Y. Y.; Qin, J.-J.; Chen, Z.-H.; Zhou, Y.; Tang, W.; Zuo, J.-P.; Zhao, W.-M. J. Nat. Prod. 2017, 80, 1102−1109. (129) Wan, J.; Zhu, Y.-N.; Feng, J.-Q.; Chen, H.-J.; Zhang, R.-J.; Ni, J.; Chen, Z.-H.; Hou, L.-F.; Liu, Q.-F.; Zhang, J.; Yang, L.; Tang, W.; Yang, Y.-F.; Nan, F.-J.; Zhao, W.-M.; Zuo, J.-P. Int. Immunopharmacol. 2008, 8, 1248−1256. (130) Velten, R.; Erdelen, C.; Gehling, M.; Göhrt, A.; Gondol, D.; Lenz, J.; Lockhoff, O.; Wachendorff, U.; Wendisch, D. Tetrahedron Lett. 1998, 39, 1737−1740. (131) Gehling, M.; Goehrt, A.; Gondol, D.; Lenz, J.; Lockhoff, O.; Moeschler, H. F.; Velten, R.; Wendisch, D.; Andersch, W.; Erdelen, C.; Harder, A.; Mencke, N.; Turberg, A.; Wachendorff-Neumann, U. (Bayer A.-G., Germany). German Patent 19610279, 1977. (132) Presley, C. C.; Krai, P.; Dalal, S.; Su, Q.; Cassera, M.; Goetz, M.; Kingston, D. G. I. Bioorg. Med. Chem. 2016, 24, 5418−5422. (133) Le Goff, G.; Martin, M.; Iorga, B. I.; Adelin, E.; Servy, C.; Cortial, S.; Ouazzani, J. J. Nat. Prod. 2013, 76, 142−149. (134) Sobik, P.; Grunenberg, J.; Böröczky, K.; Laatsch, H.; WagnerDöbler, I.; Schulz, S. J. Org. Chem. 2007, 72, 3776−3782. (135) Tressl, R.; Holzer, M.; Apetz, M. J. Agric. Food Chem. 1977, 25, 455−459. (136) Kasai, T.; Sakamura, S. Agric. Biol. Chem. 1982, 46, 821−822. (137) Anthoni, U.; Christophersen, C.; Øg, J.; Wium-Andersen, S.; Jacobsen, N. Phytochemistry 1980, 19, 1228−1229. (138) Wium-Andersen, S.; Anthoni, U.; Christophersen, C.; Houen, G. Oikos 1982, 39, 187−190. (139) Copp, B. R.; Blunt, J. W.; Munro, M. H.; Pannell, L. K. Tetrahedron Lett. 1989, 30, 3703−3706. (140) Pearce, A. N.; Babcock, R. C.; Battershill, C. N.; Lambert, G.; Copp, B. R. J. Org. Chem. 2001, 66, 8257−8259. (141) Ichimaru, M.; Kato, A.; Hashimoto, Y. J. Nat. Prod. 2000, 63, 1675−1676. (142) Elvidge, J. A.; Jones, S. P.; Peppard, T. L. J. Chem. Soc., Perkin Trans. 1 1982, 1089−1094. (143) Morita, K.; Kobayashi, S. Tetrahedron Lett. 1966, 7, 573−577. (144) Yasumoto, K.; Iwami, K.; Mitsuda, H. Agric. Biol. Chem. 1971, 35, 2059−2069. (145) Yasumoto, K.; Iwami, K.; Mitsuda, H. Agric. Biol. Chem. 1971, 35, 2070−2080.

(78) Hirata, K.; Takashina, J.; Nakagami, H.; Ueyama, S.; Murakami, K.; Kanamori, T.; Miyamoto, K. Biosci., Biotechnol., Biochem. 1996, 60, 1905−1906. (79) Lindner, H. J.; Schaden, G. Chem. Ber. 1972, 105, 1949−1955. (80) Kelly, T. R.; Elliott, E. L.; Lebedev, R.; Pagalday, J. J. Am. Chem. Soc. 2006, 128, 5646−5647. (81) Smirnov, V. V.; Kiprianova, E. A.; Garagulya, A. D.; Esipov, S. E.; Dovjenko, S. A. FEMS Microbiol. Lett. 1997, 153, 357−361. (82) Galasso, V. Chem. Phys. Lett. 2009, 472, 237−242. (83) Su, J.-Y.; Xu, X.-H.; Zeng, L.-M.; Wang, M.-Y.; Lu, N.; Lu, Y.; Zhang, Q.-T. Phytochemistry 1998, 48, 583−584. (84) Ujváry, I. Pest Manage. Sci. 2000, 56, 703−705. (85) Ding, Z.-G.; Zhao, J.-Y.; Yang, P.-W.; Li, M.-G.; Huang, R.; Cui, X.-L.; Wen, M.-L. Magn. Reson. Chem. 2009, 47, 366−370. (86) Jin, Y.-S.; Du, J.-L.; Yang, Y.; Jin, L.; Song, Y.; Zhang, W.; Chen, H.-S. Chem. Nat. Compd. 2011, 47, 257−260. (87) Li, X.-N.; Zhang, Y.; Cai, X.-H.; Feng, T.; Liu, Y.-P.; Li, Y.; Ren, J.; Zhu, H.-J.; Luo, X.-D. Org. Lett. 2011, 13, 5896−5899. (88) Lajis, N. H.; Mahmud, Z.; Toia, R. Planta Med. 1993, 59, 383− 384. (89) Bergy, M. E.; Herr, R. R. Antimicrob. Agents Chemother. 1966, 6, 625−630. (90) Hanka, L. J.; Evans, J. S.; Mason, D. J.; Dietz, A. Antimicrob. Agents Chemother. 1966, 6, 619−624. (91) Kaminskas, E.; Farrell, A. T.; Wang, Y.-C.; Sridhara, R.; Pazdur, R. Oncologist 2005, 10, 176−182. (92) Abdulhaq, H.; Rossetti, J. M. Expert Opin. Invest. Drugs 2007, 16, 1967−1975. (93) Derissen, E. J.; Beijnen, J. H.; Schellens, J. H. Oncologist 2013, 18, 619−624. (94) Scott, L. J. Drugs 2016, 76, 889−900. (95) Wanquet, A.; Vey, N.; Prebet, T. Int. J. Hematol. Oncol. 2013, 2, 419−428. (96) Wong, E.; Seymour, J. F.; Kenealy, M.; Westerman, D.; Herbert, K.; Dickinson, M. Leuk. Lymphoma 2013, 54, 878−880. (97) Deboer, C.; Bannister, B. U.S. Patent 3,907,779, 1975. (98) Bergmann, T.; Schories, D.; Steffan, B. Tetrahedron 1997, 53, 2055−2060. (99) Wu, J.-B.; Cheng, Y.-D.; Kuo, S.-C.; Wu, T.-S.; Iitaka, Y.; Ebizuka, Y.; Sankawa, U. Chem. Pharm. Bull. 1994, 42, 2202−2204. (100) Twin, H.; Wen, W. W.; Powell, D. A.; Lough, A. J.; Batey, R. A. Tetrahedron Lett. 2007, 48, 1841−1844. (101) Barrosa, K. H.; Pinto, E. G.; Tempone, A. G.; Martins, E. G. A.; Lago, J. H. G. Planta Med. 2014, 80, 1310−1314. (102) Geraci, C.; Neri, P.; Paternò, C.; Rocco, C.; Tringali, C. J. Nat. Prod. 2000, 63, 347−351. (103) Lin, D. W.; Masuda, T.; Biskup, M. B.; Nelson, J. D.; Baran, P. S. J. Org. Chem. 2011, 76, 1013−1030. (104) Masubuti, H.; Endo, Y.; Araya, H.; Uekusa, H.; Fujimoto, Y. Org. Lett. 2013, 15, 2076−2079. (105) Usui, I.; Lin, D. W.; Masuda, T.; Baran, P. S. Org. Lett. 2013, 15, 2080−2083. (106) Calì, V.; Spatafora, C.; Tringali, C. Eur. J. Org. Chem. 2004, 2004, 592−599. (107) Ma, B.-J.; Liu, J.-K. Z. Naturforsch. B Chem. Sci. 2005, 60, 565− 568. (108) Hashimoto, T.; Quang, D. N.; Kuratsune, M.; Asakawa, Y. Chem. Pharm. Bull. 2006, 54, 912−914. (109) Fang, S.-T.; Zhang, L.; Li, Z.-H.; Li, B.; Liu, J.-K. Chem. Pharm. Bull. 2010, 58, 1176−1179. (110) Peerzada, N.; Neely, I.; Fenn, D. Sulfur Lett. 2000, 23, 185− 192. (111) Songue, J. L.; Azebaze, A. G. B.; Vardamides, J. C.; Ndom, J. C.; Blond, A.; Meyer, M.; Dongo, E.; Mpondo, T. N. Bull. Chem. Soc. Ethiop. 2006, 20, 173−176. (112) Huang, X.; Deng, Z.; Zhu, X.; van Ofwegen, L.; Proksch, P.; Lin, W. Helv. Chim. Acta 2006, 89, 2020−2026. (113) Rosenthal, G. Phytochemistry 1972, 11, 2827−2832. 3078



Review

(146) Iwami, K.; Yasumoto, K.; Mitsuda, H. Agric. Biol. Chem. 1975, 39, 1947−1955. (147) Morita, K.; Kobayashi, S. Chem. Pharm. Bull. 1967, 15, 988− 993. (148) Shimada, S.; Komamura, K.; Kumagai, H.; Sakurai, H. BioFactors 2004, 22, 177−179. (149) Chen, C. C.; Ho, C. T. J. Agric. Food Chem. 1986, 34, 830−833. (150) Citron, C. A.; Rabe, P.; Dickschat, J. S. J. Nat. Prod. 2012, 75, 1765−1776. (151) Pant, N.; Garg, H. S.; Madhusudanan, K. P.; Bhakuni, D. S. Fitoterapia 1986, 57, 302−304. (152) Näf, R.; Velluz, A. Flavour Fragrance J. 1996, 11, 295−303. (153) Wratten, S. J.; Faulkner, D. J. J. Org. Chem. 1976, 41, 2465− 2467. (154) Adesogan, E. K. J. Chem. Soc., Chem. Commun. 1974, 906−907. (155) Ritzau, M.; Keller, M.; Wessels, P.; Stetter, K. O.; Zeeck, A. Liebigs Ann. Chem. 1993, 1993, 871−876. (156) Hedderich, R.; Klimmek, O.; Kröger, A.; Dirmeier, R.; Keller, M.; Stetter, K. O. FEMS Microbiol. Rev. 1998, 22, 353−381. (157) Litaudon, M.; Guyot, M. Tetrahedron Lett. 1991, 32, 911−914. (158) Litaudon, M.; Trigalo, F.; Martin, M.; Frappier, F.; Guyot, M. Tetrahedron 1994, 50, 5323−5334. (159) Searle, P. A.; Molinski, T. F. J. Org. Chem. 1994, 59, 6600− 6605. (160) Davidson, B. S.; Molinski, T. F.; Barrows, L. R.; Ireland, C. M. J. Am. Chem. Soc. 1991, 113, 4709−4710. (161) Makarieva, T. N.; Stonik, V. A.; Dmitrenok, A. S.; Grebnev, B. B.; Isakov, V. V.; Rebachyk, N. M.; Rashkes, Y. W. J. Nat. Prod. 1995, 58, 254−258. (162) Chenard, B.; Harlow, R.; Johnson, A.; Vladuchick, S. J. Am. Chem. Soc. 1985, 107, 3871−3879. (163) Lee, A. H. F.; Chen, J.; Liu, D.; Leung, T. Y. C.; Chan, A. S. C.; Li, T. J. Am. Chem. Soc. 2002, 124, 13972−13973. (164) Lee, A. H. F.; Chan, A. S.; Li, T. Chem. Commun. 2002, 2112− 2113. (165) Ford, P. W.; Davidson, B. S. J. Org. Chem. 1993, 58, 4522− 4523. (166) Davis, R. A.; Sandoval, I. T.; Concepcion, G. P.; da Rocha, R. M.; Ireland, C. M. Tetrahedron 2003, 59, 2855−2859. (167) Liu, H.; Fujiwara, T.; Nishikawa, T.; Mishima, Y.; Nagai, H.; Shida, T.; Tachibana, K.; Kobayashi, H.; Mangindaan, R. E. P.; Namikoshi, M. Tetrahedron 2005, 61, 8611−8615. (168) Oda, T.; Kamoshita, K.; Maruyama, S.; Masuda, K.; Nishimoto, M.; Xu, J.; Ukai, K.; Mangindaan, R. E. P.; Namikoshi, M. Biol. Pharm. Bull. 2007, 30, 385−387. (169) Compagnone, R. S.; Faulkner, D. J.; Carté, B. K.; Chan, G.; Freyer, A.; Hemling, M. E.; Hofmann, G. A.; Mattern, M. R. Tetrahedron 1994, 50, 12785−12792. (170) Nakazawa, T.; Xu, J.; Nishikawa, T.; Oda, T.; Fujita, A.; Ukai, K.; Mangindaan, R. E. P.; Rotinsulu, H.; Kobayashi, H.; Namikoshi, M. J. Nat. Prod. 2007, 70, 439−442. (171) Wang, W.; Takahashi, O.; Oda, T.; Nakazawa, T.; Ukai, K.; Mangindaan, R. E. P.; Rotinsulu, H.; Wewengkang, D. S.; Kobayashi, H.; Tsukamoto, S.; Namikoshi, M. Tetrahedron 2009, 65, 9598−9603. (172) Tatsuta, T.; Hosono, M.; Rotinsulu, H.; Wewengkang, D. S.; Sumilat, D. A.; Namikoshi, M.; Yamazaki, H. J. Nat. Prod. 2017, 80, 449−502. (173) Brzostowska, E. M.; Greer, A. J. Am. Chem. Soc. 2003, 125, 396−404.

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