Naturally Occurring Lumazines | Journal of Natural Products

Review pubs.acs.org/jnp

Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

Naturally Occurring Lumazines Benjamin J. Daniels,† Freda F. Li,† Daniel P. Furkert,†,‡ and Margaret A. Brimble*,†,‡ †

School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand

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‡

ABSTRACT: Natural products containing a lumazine motif were first isolated from natural sources in 1940. These natural products are relatively rare, with fewer than 100 lumazines known to occur in Nature. This review discusses the isolation of lumazines, their biological activity, and their biosynthesis, where known.

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INTRODUCTION Pteridines (1) are nitrogen-containing heterocycles consisting of a pyrimidine ring fused to a pyrazine.1 Naturally occurring pteridines fall into two structural categories: pterins (2), with a C-2 amino group and a carbonyl group at the C-4 position, and lumazines (3), with carbonyl groups at both the C-2 and C-4 positions.1 Although tautomerism is expected for both pterins (2) and lumazines (3) as a result of intramolecular proton transfer, it has been demonstrated by spectroscopic and crystallographic studies that, in the most prominent tautomeric species of natural pteridines, the ring nitrogen adopts the thermodynamically more stable lactam configuration, as represented by structures 2 and 3.2−4

dicarboxylic acid, followed by thermal decarboxylation to generate the product 3.8,9 Later, in 1901 and 1906, synthesis of the pteridine ring system 1 was also reported by Gabriel and Colman,10 and Isay,11 respectively. Parallel with these synthetic efforts, the discovery of natural pteridine compounds began in 1889, when Sir Frederick Hopkins reported the isolation of the yellow pigments xanthopterin (5) and leucopterin (6) from the wings of the common brimstone butterfly (Gonepterix rhamni) and the cabbage butterfly (Pieris rapae), respectively.12 The structures of pterins 5 and 6 were not confirmed until 1940; since then, much work has been directed toward the isolation of new natural pteridines and the investigation of their biological roles.1−3,13 Most naturally occurring pteridines belong to the pterin family, and some of these pterins possess important biological properties including antitumor, antimicrobial, and antiviral activity, as well as being cofactors in enzymatic reactions.14,15 Thus far, reviews of the reactivity, synthesis, isolation, and bioactivity of pteridines have focused on natural pterins and their analogues rather than lumazines.1−3,14−16 Lumazines are less widely distributed in Nature than the better known pterins, and knowledge of their biological functions remains limited. This review aims to summarize all naturally occurring lumazines, including lumazine peptides and some complex derivatives reported more recently. The relevant biosynthetic processes of these natural lumazines are discussed, along with an overview of their biological activities, if known. Synthetic approaches to the natural lumazines and derivatives are not included in this review, as the utility of synthetic methods to construct pterins, which have been reviewed previously,1 can also be applied to the chemical synthesis of related lumazines.

Chemically synthesized pteridines appeared long before they were isolated from Nature. In 1857, Wöhler and Hlasiwetz reported the formation of novel fluorescent compounds upon heating uric acid in water, and it was not until 100 years later that some of these products were recognized as lumazine derivatives.2,5−7 In 1894, Kühling described the first intentional synthesis of lumazine (3) in which benzo[g]pteridine, also known as alloxozine (4), was oxidized to lumazine-6,7© XXXX American Chemical Society and American Society of Pharmacognosy

Received: April 17, 2019

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DOI: 10.1021/acs.jnatprod.9b00351 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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Scheme 1. Biosynthesis of (A) Pterins and (B) Lumazines

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biomarker for the authentication of manuka honey.31−33 Note ̅ that 6,7-dimethyllumazine (9) had been synthesized prior to its isolation and utilized as an effective fluorescent probe for adenine position opposite an abasic site in DNA duplexes.34 No further biological testing has been reported for lumazines 8 and 9.

SIMPLE LUMAZINES Since the first synthesis of lumazine (3) was reported in 1894, several improved procedures for its preparation have been developed by different authors.17−20 Compound 3 was first named lumazine in 1937 by Kuhn and Cook to reflect its intense bluish-green fluorescence even in very dilute aqueous solution.21 Lumazine (3) itself as a natural product was first isolated from the European red wood ant Formica polyctena in 1967.22 Since then, it has also been observed in the seeds and leaves of the Indian mustard Brassica juncea.23 Although no biological activity for lumazine (3) was reported at the time of its isolation, the fluorescent properties of lumazine (3) and the biological activity resulting from its photochemical properties have attracted continued interest of chemists for decades.4,24−26 Lumazine (3) was found to be bactericidal to Methanobacterium thermoautotrophisum strain Marburg, and the use of lumazine (3) as a selective inhibitor for methanogenesis to improve the hydrogen production in microbial electrolysis cells was also recently reported.27,28 1-Methyllumazine (7) was isolated from the lithistid sponges Corallistes f ulvodesmus and C. undulatus in 1989 and 1993, respectively.29,30 No biological testing was conducted on this natural lumazine. Lepteridine (8) was isolated from New Zealand ma̅ nuka honey (derived from the nectar of Leptospermum scoparium) by Brimble et al., who also confirmed its structure by total synthesis.31 Speer et al. reported the replication of this isolation, along with 6,7-dimethyllumazine (9); the structures of both compounds were assigned using Xhoney is well ray crystallography.32 New Zealand manuka ̅ known for its antibacterial activity and, as a result of its high cost and limited availability, is often the subject of honey fraud.33 Lepteridine (8) exhibits fluorescence that is only detectable in manuka honey samples and has been put forward as a unique ̅

The oxo-lumazine natural products containing carbonyl groups at the 6- and/or 7-positions of the lumazine core are known. The 7-oxolumazine violapterin (10) was first isolated as a blue fluorescent compound from the honey bee Apis mellifera in 1963,35 and since then it has been found in three different species (Locris sp., Leptocoris apicalis, and Pyrrhocoris apterus) of Hemiptera, the ant Formica polyctena, the oriental hornet Vespa orientalis, and the silkworm Bombyx mori.36,37 Its 8-methyl derivative, luciopterin (11), was isolated as a blue fluorescent lumazine from the Japanese firefly Luciola cruciata in 1968, along with another fluorescent compound, 12.38 Light was emitted by L. cruciata at a shorter wavelength (λmax 544 μm) than that of other firefly species (including Photinus, Photuris, Pyrohphorus, Diphotus, and Lecontea), which typically emit light with a λmax of 552−582 μm.38 Whether or not luciopterin (11) is the source of this unusual bioluminescence was not initially determined; subsequent work identified an isotope of the bioluminescent enzyme luciferase that was demonstrated to be responsible for the dim glow in L. cruciata by reacting with its substrate luciferin 12.39 6-Oxolumazine (13), its dihydro derivative 14, and B



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dioxolumazine 15 were also found in the honey bee A. mellifera.40 The syntheses of 6-oxolumazine (13), violapterin (10), and luciopterin (11) were reported before their isolation, and the structural assignment of these lumazines was therefore confirmed by comparison of the spectroscopic data with those of their synthetic samples.41,42 Additionally, 6-oxolumazine (13) was found to be a strong competitive inhibitor of the enzyme xanthine oxidase, which plays an important role in the catabolism of purines in some species, including humans.43

together with their corresponding pterin derivatives from natural sources, suggesting a biosynthetic relationship between lumazines and their respective pterin family. The biosynthesis of pterins is known to begin with guanosine triphosphate (GTP, 17) (Scheme 1A).1,2 The imidazole ring of GTP (17) is opened to produce formyl pyrimidine 18, which gives imine 19 after decarbonylation. α-Hydroxyimine 19 then undergoes an Amadori rearrangement to afford ketone 20, which readily cyclizes to give dihydropterin 21. The various pterin derivatives 22 found in Nature are derived from dihydropterin 21 via different metabolic pathways. The pterins thus produced (22) are converted into lumazines via the action of pterin deaminases (Scheme 1B).45 These amidohydrolase enzymes catalyze the hydrolytic deamination of pterins 22 at the C-2 position to produce ammonia and the corresponding lumazines 23, which generally adopt the more stable tautomeric structure, 24.45,46 Pterin deaminases have been isolated from a range of sources, and their deamination activity was initially found to be limited to pterins, in which substitution at the C-6 position is relatively unimportant; however, C-7 substitution often negates the ability of the pterin to serve as a substrate.45−47 The lumazines found in Nature are thus generally 6-substituted derivatives. Subsequent work has shown that tolerance of substituents at C-6 and C-7 positions, as well as the lack of aromaticity of the pyrazine ring of pterins, varies depending on the biological source from which the enzyme is isolated.45

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6-SUBSTITUTED LUMAZINES Lumazine-6-carboxylic acid (25) was first isolated as a blue fluorescent compound from the European red wood ant Formica polyctena and has since been observed in seawater and spinach (Spinacea oleracea).22,48−50 Lumazine acid 25 arises from the microbial degradation of folic acid (26) (Scheme 2), in which process several lumazine-containing metabolites are formed.51 Folic acid (26) degrades either by loss of glutamate to give acid 27 or by the action of pterin deaminase to give lumazine 28.

Violapterin (10) is often found together with the corresponding pterin compound isoxanthopterin (16) during isolation from different species.35−37 Additionally, 6-oxolumazine (13) was observed as a major metabolite following the addition of xanthopterin (5) to a culture of soil bacteria.44 Similar to these oxo-lumazines, many natural lumazines have been isolated

Scheme 2. Enzymatic Degradation of Folic Acid (26) to Lumazine Acid 25

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D. discoideum cells.64 No other biological properties were reported for chiral lumazines 34−38.

Both compounds 27 and 28 then degrade to lumazine amine 29, which forms lumazine acid 25 as the end product through loss of p-aminobenzoic acid and oxidation. 6-Hydroxymethyllumazine (30) was first isolated from spinach (Spinacea oleracea) in 1965, and its structure was confirmed by chemical synthesis.52 Concurrent work also isolated lumazine acid 25 and lumazine sulfate 31 from spinach, in addition to lumazine 30.50 Spinach extracts containing these compounds were found to catalyze photosynthetic phosphorylation in spinach photochloroplasts, suggesting these lumazines (25, 30, and 31) may act as redox substances to stimulate the energy conversion process in the plant.53−55 Sepialumazine (32) was isolated as a minor yellow pigment from lemon mutants of the silkworm Bombyx mori in 1950.56 Sepialumazine (32) was found to be converted to lumazines 25 and 30 under various reduction and oxidation conditions, and the structure 32 was eventually assigned in 1966 by comparing its spectroscopic data to those of the known sepiapterin (33).57 The configuration at the C-2′ position of lumazine 32 has not been clarified by the authors. Subsequent studies isolated the enzyme sepiapterin deaminase from silkworm wild-type B. mori and the Kyuki mutant, which was demonstrated to catalyze the conversion of sepiapterin (33) to sepialumazine (32).58,59 No biological activity was reported for lumazine 32.

A collection of 6-acyl lumazines 39−46 were also isolated from the Japanese fireworm Odontosyllis undecimdonta by Inoue et al., in addition to lumazines 35 and 36.66−68 Based on various spectroscopic studies on these lumazine metabolites, the structures of the side chains at the C-6 position were determined to be propionyl for lumazines 39−41, acetyl for 42, βmethoxypropionyl for 43 and 44, and β-hydroxypropionyl for 45 and 46.66−68 The authors synthesized the three major metabolites 39−41 to confirm their structural assignments.66−68 Three cyclic enol phosphate lumazine derivatives (47−49) were also isolated by the authors from the same polychaete.69 Investigations into the chemistry of O. undecimdonta were prompted by its bioluminescent properties.70,71 The worm appears annually over a three-week period during September and October in Toyama Bay. Groups of the worms congregate near the surface of the ocean after sunset and give off a bluishgreen luminescence for 30 min. The source of the bioluminescence was later suggested to be a unique luciferase from the fireworm species, although whether or not these lumazine metabolites 39−49 serve as a luciferin substrate is yet to be established.70,71 No biological tests were conducted on lumazines 39−49.

The optically active lumazine leucettidine (34) was first isolated from the sponge Leucetta microraphis in 1981.60 The structure was originally assigned as 3-methyllumazine 35, but was later revised to 1-methyllumazine 34 by Pfleiderer, who synthesized both structures in racemic form.61,62 The stereochemistry of 34 was assigned by comparison of the optical rotation with other structurally similar compounds.61,62 Following the synthesis and structural revision of leucettidine (34) by Pfleiderer, Inoue et al. reported the isolation of lumazine 35 and its 1,3-dimethyl derivative 36 from the polychaete worm Odontosyllis undecimdonta in Toyama Bay, Japan.63 The authors undertook the asymmetric synthesis of lumazines 35 and 36 and confirmed the absolute S-configuration at the C-1′ position in these lumazines.63 Leucettidine (34) has also been isolated from the sponge Corallistes undulatus, found in New Caledonian coral reefs, along with dihydroxylumazine 37.30 The 1′S,2′Rconfiguration of dihydroxylumazine 37 was determined by diacetylation of the compound and comparison of its spectroscopic data with those of a semisynthetic sample.30 Dictyolumazine (38) was observed in the media of starved Dictyostelium discoideum and identified by comparison to a semisynthetic chiral standard using chiral HPLC.64,65 Dictyolumazine (38) was demonstrated to be responsible for the extracellular fluorescence linked with the aggregation ability of

The isolation of duramidines A−D (50−53) from the Australian marine ascidian Leptoclinides durus was reported in 2012.72 In addition to a lumazine moiety, these alkaloids contain a three-carbon side chain esterified at C-1′ with a methoxy cinnamic acid and are either hydroxylated or sulfated at C-2′.72 The structures of duramidines A−D (50−53) were assigned through detailed analysis of their spectroscopic data, although D



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no synthesis of these lumazines was reported.72 The authors did not deduce the absolute configuration for structures 50−53, in which the propyl side chain at C-1′ was assigned a threo relative configuration.72 Lumazines 50−53 were tested for cytotoxicity against breast and prostate cancer cell lines as well as a series of microbes, but no activity was observed.72

Lumazines 58 and 59 were found to exhibit green and violet fluorescence, respectively.77,78 In 2012, a novel ribityl lumazine (60), together with lumazines 58 and 59, was observed in the supernatant of cultured Salmonella typhimurium and found to activate human mucosal-associated invariant T-cells (MAIT cells) isolated from peripheral blood.79 MAIT cells were observed to respond only to microbes known to synthesize riboflavin (55); therefore the authors suggested that ribityl lumazines 58−60 are all metabolites of the biosynthesis of riboflavin and that they induce an immune response to microbial infection.79 Several lumazines containing a ribityl substituent at N-8 have been isolated from microorganisms. In 1969, indolyl lumazine 61 was isolated from Achromobacter petrophilum by McNutt and Takeda, and the structure was confirmed by chemical synthesis.80 The authors also suggested a possible biosynthetic relationship of lumazine 61 with tryptophan due to the 3-indoyl rather than 2-indoyl linkage to its 6-position.80 Putidolumazine (62) was subsequently isolated from Pseudomonas putida in 1970.81 This lumazine (62) has been later utilized as a specific ligand for the affinity chromatography purification of riboflavin synthase.82 A recent paper reported the synthesis of lumazine 62 and revealed its inhibition activity against Escherichia coli riboflavin synthase.83 Following its first isolation, putidolumazine (62) was also isolated from Pseudomonas ovalis by Goto et al., along with 8-ribityl lumazine derivatives 59, 61, 63, and 64.84,85 In 1973, lumazine 64 was again isolated by the same authors from Photobacterium phosphoreum and given the name photolumazine C (64).86,87 Photolumazines A (65, racemic) and B (66) were found from the same source, and their structures were confirmed by total synthesis.87 All three lumazines 64−66 and putidolumazine (62) were found to inhibit Eremothesium ashbyii riboflavin synthase.87

Asteropterin (54) was isolated from the sponge Asteropus simplex, collected off Shikine Island, Japan.73 The isolation was guided by screening sponge isolates for inhibitors of cathepsin B, which is a type of lysosomal protein-degrading enzyme known to contribute to tumor invasion.73 Asteropterin (54) was found to inhibit cathepsin B activity (IC50 = 1.4 μg/mL), and further studies suggested that the linkage between the lumazine and histamine moiety of lumazine 54 is necessary for its activity, as neither lumazine, histamine alone, nor a mixture of the two components was active against cathepsin B.73

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N8-RIBITYL LUMAZINES Many natural lumazines are substituted at C-6 due to their metabolic relationship with natural pterins, but a structurally distinct group of lumazines with a ribityl substitutuent at N-8 exists. No pterins containing 8-ribityl groups have been identified as yet; hence it is possible that the biosynthesis of ribityl lumazines does not involve the action of pterin deaminases. Such 8-ribityl lumazines are known to arise during the biosynthesis of riboflavin (55) (Scheme 3).74 The riboflavin pathway starts from GTP (17), which is converted to ribosyl uracil 56 over three biosynthetic steps. Uracil 56 undergoes a condensation reaction with hydroxy ketone 57 to generate 8ribityl lumazine 58, catalyzed by the enzyme lumazine synthase. Riboflavin (55) is formed from two molar equivalents of lumazine 58 via the action of riboflavin synthase, in which process uracil 56 is produced and recycled into the pathway. Riboflavin biosynthesis occurs in plants, fungi, and most microorganisms but not in humans.74 The enzymes lumazine synthase and riboflavin synthase have been studied extensively with the aim of developing antibiotic drugs from inhibitors of these enzymes.74,75 8-Ribityl lumazines 58 and 59 were first isolated from the mycelium of the fungus Eremothecium ashbyii, along with riboflavin (55) in 1956.76 The structure of lumazine 58 was assigned by comparing its spectroscopic data with that of the known 6,7,8-trimethyllumazine.76,77 Lumazine 59 was also isolated from the European red wood ant Formica polyctena.22

Russupteridine-yellow I (67) and IV (68) were first isolated from Russula mushrooms, along with riboflavin (55), ribityl uracil 56, lumazine 58, and photolumazine C (64).88 Russupteridine-yellow I (67) was isolated from different species of Russula including R. emetica, R. sardonia, R. paludosa, R. obscura, and R. badia, while russupteridine-yellow IV (68) was observed only in R. sardonia.88 The structures of russupteridines 67 and 68 were confirmed by total synthesis, and no biological study was conducted on any of these lumazines.89

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LUMAZINE PEPTIDES Lumazines 69 and 70 were isolated from the freshwater leech Limnatus nilotica in 2005 by Pfleiderer et al. and are the earliest natural lumazines found to contain an amide bond.90 The identities of lumazines 69 and 70 were confirmed by total synthesis, but no biological testing on these compounds was reported.90 E



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Scheme 3. (A) Biosynthesis of Riboflavin (55) and (B) the Related Metabolites 59 and 60

Penicillium sp.91 Based on a detailed spectroscopic analysis, penilumamide A (71) was assigned as a lumazine peptide with a 1,3-dimethyllumazine acid moiety coupled to methionine sulfoxide, which is in turn linked to an anthranilate group.91 The absolute S-configuration of the amino acid was determined

To date, all natural lumazine peptides have been isolated from various marine-derived fungi. In 2010, penilumamide A (71) was isolated from the fermentation broth of the fungal strain F



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by Marfey’s method.91 The authors also reported a 5:1 ratio of Sto R-configurations at the sulfoxide based on 13C NMR analysis.91 The same lumazine 71 was later isolated in 2014 from a gorgonian-derived Aspergillus sp. fungus, along with three closely related lumazine peptides, penilumamides B−D (72− 74).92 Penilumamides A−C (71−73) differ only in the oxidation state at the sulfur atom of the methionine residue, whereas penilumamide D (74) contains an alanine residue coupled to the anthranilamide. A total synthesis of penilumamides B−D (72−74) was reported in 2017.93 Aspergilumamide A (75), which contains a glutamine residue linked to the anthranilate group, was isolated from a mangrove-derived fungus Aspergillus sp., along with penilumamide A (71).94 The biosynthetic pathway of these lumazine peptides (71−75) was proposed to start from lumazine-6-carboxylic acid (25), formed via folic acid catabolism, followed by stepwise addition of the amino acid (methionine or glutamine) and anthranilic acid.94 The biological activity of penilumamides 71−74 and aspergilumamide A (75) was investigated upon their respective isolations. All were tested against multiple strains of Grampositive and Gram-negative bacteria and displayed no activity.91,92,94 Additionally, penilumamide A (71) did not influence Ca2+ levels in a test for the cellular Ca2+ signaling in neuroendocrine cells.91 Penilumamides B−D (72−74) displayed no acetylcholinesterase inhibitory activity.92 Aspergilumamide A (75) was examined for toxicity against a range of human tumor cell lines, but no activity was observed.94

DNA oligomers in a combined mode: via intercalation by the lumazine moiety and groove binding by the peptide backbone.95

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FUSED LUMAZINES Several fused lumazines, bearing a thieno[3,2-g]lumazine skeleton, have been isolated from leeches. Hirudonucleodisulfides A (78) and B (79) were isolated from Whitmania pigra in 2008; the structure of 78 was assigned using X-ray crystallography.97 The structure of hirudonucleodisulfide B (79) was assigned through comparison of the spectroscopic data to those of structure 78; hence the stereochemistry of the secondary alcohol in the side chain of lumazine 79 was not clarified by the authors.97 Hirudonucleodisulfides A (78) and B (79) were tested for their antianoxic activity in PC12 cells injured by treatment with sodium hydrosulfite, and both lumazines exhibited moderate activity (78, EC50 = 27.01 μg/ mL; 79, EC50 = 19.54 μg/mL) compared with the positive drug nimodipine (EC50 = 1.29 μg/mL).97 Hirudinoidines A−C (80− 82) were isolated from Hirudo nipponica in 2008.98,99 The structures 80−82 were assigned on the basis of extensive spectroscopic analysis, and the structure of hirudinoidine A (80) was confirmed by X-ray crystallography.98 In 2013, another two fused lumazines, whitmanines A (83) and B (84), were isolated from the leech W. pigra.100 The authors suggested that a unique biosynthetic pathway for lumazines might exist in leeches, as all lumazine structures isolated from the different species of leeches were shown to share a common fused lumazine skeleton.100 Although both H. nipponica and W. pigra have been used in traditional Chinese medicine to promote blood circulation by dissipating blood stasis, fused lumazines 78−84 have not been tested for this activity.

Terrelumamides A (76) and B (77) were isolated from Aspergillus terreus in 2015.95 The isolation of terrelumamide A (76) from A. terreus was replicated in 2016, although the authors referred to lumazine 76 as a novel compound, penilumamide E.96 Both peptides 76 and 77 contain threonine and serine moieties coupled to the anthranilate group, and the lumazine moiety is methylated only at position 1, which is unusual among lumazine natural products. Terrelumamides A (76) and B (77) again exhibited no cytotoxic or antimicrobial activity.95 The authors assayed lumazines 76 and 77 against several enzymes including sortase A, isocitrate lyase, and Na+/K+-ATPase, but no activity (IC50 > 100 μM) was observed.95 Lumazines 76 and 77 were, however, found to increase the production of adiponectin during adipogenesis in human bone-marrow mesenchymal stem cells, suggesting an ability to modulate insulin sensitivity.95 Lumazines 76 and 77 were also assayed for DNA-binding activity, which could be monitored by their fluorescent behavior, and both lumazines were found to bind to double-stranded

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COMPLEX NATURAL LUMAZINES Lumazines possessing increasingly complex and interesting structures have been found in Nature. The dimeric lumazine 85 was isolated by Inoue et al. in 1996 from the marine swimming polychaete Odontosyllis undecimdonta, which was found to contain considerable amounts of 6-acyl lumazines and related compounds.101 Lumazine 85 was assigned as the dimeric structure of 1,3-dimethyl-6-acyllumazine based on various spectroscopic studies, and the authors also reported the asymmetric synthesis of lumazine 85 to determine the absolute S-configuration at its C-2′ position.101 No biological studies were conducted on lumazine dimer 85. The pigments responsible for the red coloration of the eyes of the fruit fly Drosophila melanogaster were first isolated (as a mixture of five components) in 1940.102 Their structures were G



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1978.103,104 The structure of one of the minor components, the lumazine-containing aurodrosopterin (87), was elucidated and confirmed by total synthesis in 1993.105 Both drosopterin (86) and aurodrosopterin (87) were isolated as racemic mixtures, and the structures of the two complex pteridines differ only in their substituent at the C-2 position. Whether H-6a and H-6b of structures 86 and 87 share a cis or trans relationship has not been established, although it has been suggested that the cis-6a,b ring system, in which a more planar shape would be expected to be adopted, might be more thermodynamically stable.106 The biosynthesis of drosopterin (86) and aurodrosopterin (87) (Scheme 4) is proposed to begin with the conversion of GTP (17) into pteridine precursor 21.107 Conversion of 21 into 6pyruvoyltetrahydropterin (PTP, 88) via oxidation and phosphate cleavage is facilitated by the enzyme PTP synthase. Cleavage of the pyruvate side chain of PTP (88) by an unidentified enzyme gives dihydropterin 89, which then undergoes hydrolysis in the presence of dihydropterin deaminase to give dihydrolumazine 90. Concurrently, PTP (88) is converted into pyrimidodiazepine (PDA, 91) via the action of PDA synthase. Drosopterin (86) is then generated from a reaction between dihydropterin 89 and PDA (91).

not immediately elucidated; that of the major component, drosopterin (86), was proposed in 1972 and later revised to the correct structure by the synthesis of its methylated derivative in

Scheme 4. Biosynthesis of Drosopterin (86) and Aurodrosopterin (87)

H



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were detected only in those gastropods dwelling in the Ganyudo area of Suruga Bay, while B. japonica cultivated outside this area did not exhibit any toxicity.112 These lumazines were discovered subsequently to arise in B. japonica through a bacterium, Corynforme sp., isolated from the gut of B. japonica, although no further biosynthetic information was reported.113 The highly decorated structures and biological significance of toxins 95−97 have attracted much attention in the field of synthetic chemistry.114−122 The racemic total syntheses of surugatoxin (95) and neosurugatoxin (96) were reported in 1994.120,121 A concise stereoselective synthesis of the aglycone core of neosurugatoxin (96) and prosurugatoxin (97) was accomplished in 2015.122 The surugatoxins 95−97 have not been isolated from any other source, nor have they been observed since.

Similarly, the reaction between PDA (91) and dihydrolumazine 90 gives aurodrosopterin (87). No further biological studies have been conducted on these animal pigments 86 and 87. Pseudoanchynazines A−C (92−94) were isolated from sponges of Clathria species collected off the coast of Rio Negro, Argentina.108 All three of these more complex natural products contain a tryptophan core attached via an ester linkage to a propanolic dimethyl lumazine and a second propyl lumazine group attached to the indole ring. The R enantiomer of lumazine alcohol 36 was also isolated from the sponge.108 Acidic alcoholysis of pseudoanchynazine A (92) also gave (R)-36, indicating an R-configuration at C-11′ of the natural product.108 The authors suggest that this stereochemistry is present in pseudoanchynazines B (93) and C (94); no further stereochemical information was elucidated. 108 Of the three pseudoanchynazines, only pseudoanchynazine A (92) was found to possess mild antimicrobial activity against Escherichia coli at 50 μg per disk.108

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CONCLUSIONS This review has collated all known lumazine natural products that contain carbonyl substituents at both the C-2 and C-4 positions of the pteridine ring system (1). Many natural lumazines exist as 6-substituted derivatives from the metabolic degradation of the related pterins; lumazines with ribityl substitution at the N-8 position arise from an alternative biogenic pathway. Natural lumazines have been isolated as animal and plant pigments and were observed in bacteria and fungi from marine sources more frequently than the better known pterin family. All naturally occurring lumazines described in this review and their closely related pterin compounds are listed in Table 1. In general, the fluorescent nature of these lumazine natural products renders them active in photochemistry and useful as fluorescent markers due to their unique occurrence in biological samples and DNA binding properties. Fused lumazines and more complex derivatives with interesting and sometimes very specific bioactivities have been isolated from Nature, although the biosynthetic pathways for most of these natural products remain unexplored. A considerable amount of the natural lumazines reported herein have yet to be tested for bioactivity, despite their isolation from natural sources employed as traditional medicines or their structural relation to known bioactive pterins. Novel lumazine natural products and new derivatives of known compounds are likely to continue to be isolated and explored, and we hope this review will stimulate further research into this class of natural products.

Surugatoxin (95) was isolated from the digestive gland of the carnivorous gastropod Babylonia japonica in 1972.109 The structure of surugatoxin (95), confirmed by X-ray crystallography, features tetrahydrolumazine and spiroxindole motifs, with a myo-inositol side chain.109 The investigation of natural products produced by B. japonica was prompted by an outbreak of poisonings in Suruga Bay, Japan.110 Visual disorders, mydriasis abdominal distention, dryness of the mouth, constipation, and vomiting were experienced after consumption of the gastropod. The active species was believed to be surugatoxin (95), which was found to act via ganglionic blocking of neuronal nicotinic acetylcholine receptors with nanomolar affinity.110 Neosurugatoxin (96) and prosurugatoxin (97) were subsequently isolated from the digestive gland of B. japonica.111,112 The ring enlargement in structures 96 and 97 was found to cause significantly higher toxicity to nicotinic acetylcholine receptors (96 and 97 are about 100 and 25 times more active than 95, respectively), suggesting that lumazines 96 and 97 were responsible for the poisonings.113 Alkaloids 95−97 I



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Table 1. Trivial and Systematic/Semisystematic Names of Naturally Occurring Lumazines and Related Pterins trivial name (compound number) pteridine (1) pterin (2) lumazine (3) xanthopterin (5) leucopterin (6) (7) lepteridine (8) (9) violapterin/isoxantholumazine (10) luciopterin (11) (13) (14) (15) isoxanthopterin (16) (21) (25) folic acid (26) (27) (28) (29) (30) (31) sepialumazine (32) sepiapterin (33) leucettidine (34) (35) (36) (37) dictyolumazine (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) duramidine A (50) duramidine B (51) duramidine C (52) duramidine D (53) asteropterin (54)

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trivial name (compound number)

systematic or semisystematic name pteridine 2-aminopteridin-4-one pteridine-2,4-dione 3,5-dihydro-6-oxopterin 5,8-dihydro-6,7-dioxopterin 1-methyllumazine 3,6,7-trimethyllumazine 6,7-dimethyllumazine 7-oxolumazine

(58) (59) (60) (61) putidolumazine (62) (63) photolumazine C (64) photolumazine A (65) photolumazine B (66) russupteridine-yellow I (67) russupteridine-yellow IV (68) (69)

8-methyl-7-oxolumazine 6-oxolumazine 7,8-dihydro-6-oxolumazine 5,8-dihydro-6,7-dioxolumazine 7-oxopterin (2R,3S)-(3-(7,8-dihydropterin-6-yl)-2,3-dihydroxyprop-1-yl)triphosphoric acid lumazine-6-carboxylic acid (4-(((pterin-6-yl)methyl)amino)benzoyl)glutamic acid 6-(N-(4-carboxyphenyl)aminomethyl)pterin (4-(((lumazin-6-yl)methyl)amino)benzoyl)glutamic acid 6-(N-(4-carboxyphenyl)aminomethyl)lumazine 6-hydroxymethyllumazine 6-sulfooxymethyllumazine 6-(2-hydroxypropanoyl)lumazine (S)-6-(2-hydroxypropanoyl)pterin 6-((S)-1-hydroxypropyl)-1-methyllumazine 6-((S)-1-hydroxypropyl)-3-methyllumazine 6-((S)-1-hydroxypropyl)-1,3-dimethyllumazine 6-((1R,2S)-1,2-dihydroxypropyl)-1-methyllumazine 6-((1R,2R)-1,2-dihydroxypropyl)lumazine 1,3-dimethyl-6-propanoyllumazine 3-methyl-6-propanoyllumazine 6-propanoyllumazine 6-acetyl-1,3-dimethyllumazine 6-(3-methoxypropanoyl)-1,3-dimethyllumazine 6-(3-methoxypropanoyl)-3-methyllumazine 6-(3-hydroxypropanoyl)-1,3-dimethyllumazine 6-(3-hydroxypropanoyl)-3-methyllumazine 6-(2-hydroxy-4-hydro-2-oxo-1,3,2-dioxaphosphinin6-yl)-1,3-dimethyllumazine 6-(2-hydroxy-4-hydro-2-oxo-1,3,2-dioxaphosphinin6-yl)-3-methyllumazine 6-(2-hydroxy-4-hydro-2-oxo-1,3,2-dioxaphosphinin6-yl)lumazine 6-(1-((Z)-3-(4-hydroxyphenyl)-2-methoxyacryloxy)-2-sulfooxyprop-1-yl)-1,3-dimethyllumazine 6-(1-((Z)-3-(4-hydroxyphenyl)-2-methoxyacryloxy)-2-hydroxyprop-1-yl)-1,3-dimethyllumazine 6-(1-((Z)-3-(4-hydroxyphenyl)-2-methoxyacryloxy)-2-sulfooxyprop-1-yl)-1-methyllumazine 6-(1-((Z)-3-(4-hydroxyphenyl)-2-methoxyacryloxy)-2-hydroxyprop-1-yl)-1-methyllumazine 6-(methyl-(2-(imidazol-5-yl)ethyl)amino)lumazine

(70) penilumamide A (71) penilumamide B (72) penilumamide C (73) penilumamide D (74) aspergilumamide A (75) terrelumamide A/penilumamide E (76) terrelumamide B (77) hirudonucleodisulfide A (78) hirudonucleodisulfide B (79) hirudinoidine A (80) hirudinoidine B (81) hirudinoidine C (82) whitmanine A (83) whitmanine B (84) (85) drosopterin (86) aurodrosopterin (87) 6-pyruvoyltetrahydropterin (PTP, 88) (89) (90) pseudoanchynazine A (92) pseudoanchynazine B (93) pseudoanchynazine C (94) surugatoxin (95) neosurugatoxin (96) prosurugatoxin (97)

AUTHOR INFORMATION

systematic or semisystematic name 6,7-dimethyl-8-D-ribityllumazine 6-methyl-7-oxo-8-D-ribityllumazine 6-hydroxymethyl-8-D-ribityllumazine 6-(3-indolyl)-7-oxo-8-D-ribityllumazine 3-(7-oxo-8-D-ribityllumazin-6-yl)propanoic acid 6-(4-hydroxyphenyl)-7-oxo-8-D-ribityllumazine 7-oxo-8-D-ribityllumazine 6-(1,2-dihydroxyethyl)-7-oxo-8-D-ribityllumazine 6-hydroxymethyl-7-oxo-8-D-ribityllumazine 6-amino-7-(N-formylimino)-8-D-ribityllumazine 1,5-dihydro-2-oxo-4-D-ribitylimidazolo[4,5-g]lumazine 6-(N-(4-(4-hydroxybenzamido)butyl)carbamoyl)1,3-dimethyllumazine 6-(N-(5-(4-hydroxybenzamido)pentyl)carbamoyl)1,3-dimethyllumazine (S)-methyl-2-(2-((1,3-dimethyllumazine)-6-carbonylamino)-4-(methylsulfinyl)butanamido)benzoate methyl-2-((N-((1,3-dimethyllumazine)-6-carbonyl)L-methionyl)amino)benzoate (S)-methyl-2-(2-((1,3-dimethyllumazine)-6-carbonylamino)-4-(methylsulfonyl)butanamido)benzoate 2-((N-((1,3-dimethyllumazine)-6-carbonyl)-L-alanyl)amino)benzamide methyl-2-((N-((1,3-dimethyllumazine)-6-carbonyl)L-glutaminyl)amino)benzoate methyl-2-((N-((1-methyllumazine)-6-carbonyl)-Lthreonyl)amino)benzoate methyl-2-((N-((1-methyllumazine)-6-carbonyl)-Lserinyl)amino)benzoate 7-carboxy-6-(methylsulfyl)thieno[3,2-g]lumazine 7-(1,2-dihydroxyethyl)-6-(methylsulfyl)thieno[3,2g]lumazine 1,3-dimethyl-6-(methylsulfinyl)thieno[3,2-g]lumazine 1-methyl-6-(methylsulfinyl)thieno[3,2-g]lumazine 6-(methylsulfinyl)thieno[3,2-g]lumazine 7-(N-(carboxymethyl)carbamoyl)-1,3-dimethyl-6(methylsulfyl)thieno[3,2-g]lumazine 7-carboxy-1,3-dimethyl-6-(methylsulfinyl)thieno [3,2-g]lumazine (S)-2-methyl-1,5-bis(1,3-dimethyllumazin-6-yl)-1,5pentanedione

5,6,7,8-tetrahydro-6-(2-oxopropanoyl)pterin 7,8-dihydropterin 7,8-dihydrolumazine

Margaret A. Brimble: 0000-0002-7086-4096

Corresponding Author

*Tel: +64(9)9238259. Fax: +64(9)3737422. E-mail: m. [email protected].

Notes

ORCID

The authors declare no competing financial interest.

Daniel P. Furkert: 0000-0001-6286-9105 J



■

Review

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