Natural Products Containing a NitrogenâNitrogen Bond - Journal of

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Natural Products Containing a Nitrogen−Nitrogen Bond Lachlan M. Blair and Jonathan Sperry* School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand ABSTRACT: As of early 2013, over 200 natural products are known to contain a nitrogen−nitrogen (N−N) bond. This report categorizes these compounds by structural class and details their isolation and biological activity.

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INTRODUCTION Natural products that contain a nitrogen−nitrogen (N−N) bond constitute a fascinating group of compounds with a vast degree of structural diversity. LaRue’s 19771 review in the Journal of Natural Products’ predecessor journal Lloydia summarized the isolation and biological activity of these compounds, but in the years since many new members from several different structural classes have emerged. Indeed, a comprehensive examination of the natural product literature (up to early 2013) has unearthed over 200 natural products containing an N−N bond, and this review details the isolation and biological activity of these compounds. In order to be as comprehensive and clear as possible, the natural products have been segregated by structural class and compounds covered in the 1977 review have been included where appropriate.

components of the UV and IR spectra assigned to the N−N moiety to confirm its presence in the natural product. The toxicity of 1 and related azoxyglycosides is due to the aglycone methylazoxymethanol (2), which forms upon hydrolysis of the sugar moiety in vivo and occurs naturally in Cycas circinalis L.3,4 Various glycoside derivatives have been isolated from species of Cycas, Macrozamia, Encephelartos, and Zamia and covered in detail previously,1,4b most notably cycasin (3), which was first isolated from Cycas revoluta Thunb alongside macrozamin (1) in 1955.5 Elaiomycin (4) was first isolated from Streptomyces hepaticus in 19546 and again some 60 years later, together with elaiomycins D−H (5−9), from Streptomyces sp. HKI0708.7 Elaiomycin is thought to originate biosynthetically from C-2 of acetate, along with L-serine and n-octylamine.7,8 More recently, elaiomycins K (10) and L (11) were isolated from Streptomyces sp. Tü 6399, a species closely related to the producer of elaiomycins B and C (discussed in the Hydrazides section).9 The elaiomycins possess a remarkable array of biological activity; elaiomycin (4) is both hepatotoxic and carcinogenic to rodents,10 but also demonstrates antibiotic activity along with its analogues;6,7,9 elaiomycin (4) and elaiomycins G (8) and H (9) are tuberculostatics;6,7 elaiomycin H (9) is active against Aspergillus species and is the most cytotoxic of the elaiomycins against human tumor cell lines.7 Elaiomycin E (6) exhibits the strongest antiproliferative effects, likely related to the presence of the 3-hydroxy group, the configuration of which could not be established on account of insufficient material.7 Elaiomycin L (11) weakly inhibits acetylcholinesterase, an enzyme also

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NATURAL PRODUCTS CONTAINING AN N−N BOND Azoxy Compounds. Macrozamin (1) is the toxic constituent of Macrozamia spiralis, a cycad endemic to Australia, and was the first reported example of a natural product to possess an N−N bond.2,3 During the structure elucidation, the production of nitrogen gas upon hydrolysis of 1 served as a reliable indicator that the natural product contains contiguously linked nitrogen atoms. Further evidence favoring the presence of the N−N bond was obtained when upon treatment of the hexa-acetate of 1 with dry hydrogen chloride, hydrazine dihydrochloride was formed. The nitrogen atoms in 1 possess no basic properties and the presence of the azoxy group was finally confirmed upon UV and IR analysis (∼1540 cm−1). Although these studies were conducted in early 1950’s, today’s isolation chemists still rely on the characteristic © XXXX American Chemical Society and American Society of Pharmacognosy

Received: February 8, 2013

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dx.doi.org/10.1021/np400124n | J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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affected by elaiomycins B and C (discussed in the Hydrazides section).9 LL-BH872α (12) was isolated as an unstable yellow oil from Streptomyces hinnulinis in 1969 and was named after the batch number assigned to the bacterial culture held at Lederle Laboratories.11 It was found that 12 decomposed spontaneously despite storage under nitrogen at −15 °C.11 The resulting product was assigned the putative structure 13, which was isolated and assigned as geralcin E in 2013.12 The authors propose that the transformation of 12 to 13 is presumed to arise by shift of the N-oxide oxygen in 12 followed by intramolecular cyclization and subsequent cleavage in a retro aldol-type condensation.11 Although 12 was referred to by the authors as having potent antifungal properties, no elaboration or data from assays was published, and to the best of our knowledge no follow-up biological studies were pursued.11 In 1986, the unstable azoxy compound 14 was isolated from Streptomyces viridifaciens MG456-hF10 and named valanimycin based upon its putative biosynthesis from valine and alanine. The azoxy compound 14 was found to exhibit antibacterial activity against both Gram-positive and Gram-negative species, along with cytotoxicity against certain cancer cells.13 The characterization of 14 was thwarted by its instability, and hence the structure elucidation was carried out on the more stable ammonia adduct 15. The biosynthesis of valanimycin (14) has been the subject of extensive research by Parry and coworkers.14 Two nematicidal azoxy compounds were isolated from the culture broth of Streptomyces sp. KP-197 in 1987 and named jietacins A (16) and B (17).15 Apparently unique to azoxy compounds, 16 and 17 were found to exhibit potent antiparasitic activity, specifically against the pinewood nematode Bursaphelenchus lignicolus.15 A pair of azoxy antibiotics maniwamycins A (18) and B (19) were isolated from Streptomyces prasinopilus KC-7367.16 The maniwamycins were screened for antibiotic activity, which revealed strong antifungal

properties with an absence of antibacterial activity, with maniwamycin B (19) being the less potent of the two.16 During studies on microbially produced antifungal agents, azoxybacilin (20) was isolated from the culture broth of Bacillus cereus (Frankland and Frankland NR2991).17 Azoxybacilin exhibits broad spectrum antifungal activity in methionine-free environments via inhibition of gene expression of sulfite reductase.18 Azoxyalkene (21) is an unstable azoxy compound isolated in 2003 from Actinomadura sp. (strain A7), an actinomycete growing in apricot roots.19 Preliminary biological assays revealed that 21 exhibits weak antifungal activity against Rhodotorula sp., but is inactive against the fungus Aspergillus niger and the bacteria Escherichia coli and Micrococcus luteus.19 B



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synthetic production of lactones 29 and 30 (collectively named DC8118) by Streptomyces sp. DO-118 has been described in a Japanese patent.22 These azoxy compounds were reported to possess both antibiotic and antitumor activity.22

In 1974, calvatic acid (31) was isolated from the mushroom Calvatia lilacina and recognized as the compound responsible for the antimicrobial properties of the fungus.23 This highly unusual molecule contains a cyano group, a unique feature among azoxy natural products. The biological activity of 31 has since been explored in a host of biological studies, firmly establishing its antibiotic profile and also revealing its antineoplastic activity.24 In 1978, 4,4′-azoxydibenzoic acid (32) and its hydroxymethyl analogue 33 were both isolated from Entomophthora virulenta, an entomopathogenic zygomycete.25 Interestingly, the benzyl alcohol 33 is a potent insecticide, yet the diacid 32 is not.25 Three unusual eightmembered heterocycles containing an azoxy-like moiety were isolated from the diatom Asterionella sp. and named asterionellins A−C (34−36).26 Lyophyllin (37) was isolated in 1984, named after the mushroom from which it was isolated, Lyophyllum connatum.27 Nitrosamines. Streptozotocin (38) was the first reported nitrosamine, isolated in 1959 from Streptomyces achromogenes var. 128 collected from soil in Kansas.28 Streptozotocin occurs as a mixture of anomers29 and possesses antibacterial activity against various species through its conversion to the highly toxic diazomethane in bacteria.30 Streptozotocin is also active against cancer cells and has been implemented in chemotherapy regimens, particularly in the treatment of gastrointestinal cancers and metastatic pancreatic cancer.30a,31 However, like other alkylnitrosoureas the effectiveness of 38 is marred by resistance development, myelosuppression, and therapy-related secondary malignancies.30a Furthermore, streptozotocin is acutely toxic to pancreatic β-cells, which has led to its common use in the induction of insulin-dependent diabetes mellitus in animal models.30a 4-Methylnitrosaminobenzaldehyde (39) is a metabolic product of the basidomycete Clitocybe suaveolens, isolated in

The bispyridine azoxy alkaloid pyrinadine A (22) was first isolated from the Okinawan marine sponge Cribrochalina sp. (SS-1115) in 2006.20 Soon after, pyrinadines B−G (23−28) were isolated from the same species, alongside pyrinadine A (22).21 The pyrinadines each possess varying degrees of cytotoxic activity against L1210 murine leukemia and KB human epidermoid carcinoma cells in vitro.20,21 The bioC



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Triacsins A (42) and B (43) were isolated from Streptomyces sp. SK-1894 collected in Japan,39 and triacsins C (44) and D (45) (also known as WS-1228A/B) were isolated previously from Streptomyces aureofaciens.40 The triacsins inhibit longchain acyl-CoA synthetase; however A (42) and C (44) are significantly more potent than B (43) and D (45).41 The triacsins also inhibit the growth of Vero, HeLa, and Raji animal cells, while triacsins C (44) and D (45) possess antimalarial and vasodilatory properties.41b,42

Nitrosohydroxylamines. In 1966, alanosine (46) was isolated from Streptomyces alanosinicus (ATCC 15710).43 Alanosine was immediately recognized as having a broad spectrum of biological activity, with antibiotic activity against Candida albicans, Mycobacterium marinum, and Saccharomyces cerevisiae,44 along with antiviral activity against polio and sheep and cow pox in vitro using human epithelial cells and neurovaccinia in vivo using infected rabbits.43 Furthermore, 46 was shown to exhibit immunosuppressive effects in mice, rats, and rabbits and to inhibit tooth germ morphogenesis and reproduction in insects.44 Most notable are the antitumor effects of 46, which have led this nitrosohydroxylamine to be investigated in ongoing clinical trials as a potential chemotherapy drug.44 One year later, fragin (47) was isolated from Pseudomonas f ragi.45 Fragin was found to inhibit the growth of lettuce, the growth of the fungus Aspergillus niger, and the growth of the alga Chlorella.46 Furthermore, the nitrosohydroxylamine had antimicrobial activity against Bacillus subtilis PCI 219, E. coli, Penicillium crysogenum Q176, and Sacchromyces cerevisiae.46 Fragin (47) also exhibits antitumor activity against Yoshida sarcoma cells and inhibited the plaque formation of vaccinia virus in vitro.46 In 1972, dopastin (48) was isolated from Pseudomonas no. BAC-125.47 Dopastin was found to exhibit antihypertensive effects in rats and inhibits dopamine β-hydroxylase.47 Dopastin (48) was subsequently shown to inhibit the germination of barley,47 and later studies demonstrated that dopastin also inhibits mushroom tyrosinase.48 Nitrosofungin (49) was isolated from a bacterial culture of Alcaligenes (UC9152) and Streptomyces plicatus (UC 8272) (Alcaligenes is the producing organism, S. plicatus enhances the production of 49) in 1983.49 Within the same year, the same

1961.32 Since its initial report, 39 has been the subject of studies on carcinogenic N-nitroso compounds but was found to be noncarcinogenic.33 Dimethylnitrosamine (40) was first isolated from the fruit of Solanum incantum in 1969; however the simple compound was already known from previous synthetic studies and its mutagenicity well established.34 Dimethylnitrosamine is used in a variety of industrial applications, and its presence in drinking water is a topic of growing concern.35 Also, 40 is carcinogenic, a potent hepatotoxin, and an immunosuppressant.36 It is worth noting that various other carcinogenic nitrosamines have been detected as trace contaminants in drinking water, foods, and particularly tobacco preparations, which have been detailed thoroughly elsewhere.37

Brachystemidine G (41) was isolated in 2007 from the roots of Brachystemma calycinum, a plant with widespread use in traditional medicine.38 Brachystemidine G (41) is essentially a nitrosoamide but exists as its N-hydroxydiazenyl tautomer. The configuration of 41 could not be elucidated due to insufficient material.38 Brachystemidine G inhibited the proliferation of Band T-lymphocytes from Balb/c mice.38 D



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previous to the isolation of N-nitroglycine (55) from nature reported that the synthesized compound is strongly phytotoxic.56 In 1975, β-nitraminoalanine (56) and its decarboxylated derivative N-nitroethylenediamine (57) were isolated from the mushroom Agaricus silvaticus, bearing similar Nnitrated amino acid structures to N-nitroglycine (55).57 The nitroamines 55−57 are suspected mutagens and may also act as precursors to the formation of diazoalkanes in vivo, raising concern over the consumption of the producing mushrooms.58 Nitroamines 56 and 57 were later isolated from Agaricus subrutilescens in 1981, along with two new derivatives, 58 and 59.59 Further discussion regarding N-nitro compounds can be found in an excellent review by Parry and co-workers.60 natural product was independently isolated from Micromonospora chalcea, named propanosine (K-76) and depicted as 50.50 Nitrosofungin inhibits a variety of fungi, including Valsa ceratosperma, a pathogen responsible for Valsa canker in apple trees.49,50 Neither of the research teams who identified the compound were able to elucidate the absolute configuration. The compound is also known as U-66-026 within a patent filed on its production.51

Nitrosoxacins A−C (51−53) were isolated in 1993 from Streptomyces strain AA4091, which was collected from Japanese soil.52 The nitrosoxacins each inhibit 5-lipoxygenase.52 In 1997 poecillanosine (54) was isolated from Poecillastra sp. aff. tenuilaminaris, a marine sponge collected off the west coast of Tokyo.53 Poecillanosine (54) is a free radical scavenger, inhibiting the lipid peroxidation of rat brain homogenate and is also cytotoxic against P388 murine leukemia cells.53

Azo Compounds. In 1982 azoformamide 60 and its azoxy derivative 61 were isolated from the puffball Lycoperdon pyriforme (Scheme 1).61 The related alkaloid rubroflavin (62) was isolated by Gill and Steglich in 1987 from Calvatia rubrof lava (North American puffball).62 All three compounds were again isolated in 1997 from a related puffball, C. craniformis, alongside novel phenol derivatives 63, 64, and craniformin (65).63 The methylated derivatives 60 and 61 were again isolated in 1999, alongside a new dichloro derivative, 66, from L. pyriforme, and their nematicidal activity was investigated.64 Finally, rubroflavin (62) was again isolated in 2001 alongside related pigments leucorubroflavin (67), oxyrubroflavin (68), and deoxyrubroflavin (69) (Scheme 1).65 While these puffball-derived natural products span several structural classes presented in this review, we have elected to amalgamate them here for clarity purposes. Their interesting properties have been extensively discussed elsewhere,63,65,66 and we therefore encourage readers to seek further information from these reports. It is relevant to note that these compounds are closely related to the previously discussed calvatic acid (31). The symmetrical azo compound trans-2,2′-4,4′-tetramethyl6,6′-dinitroazobenzene (70) was isolated in 2004 from the leaves of Aconitum sungpanese growing in China.67 No biological activity was reported for the compound, despite the use of the plant in traditional medicine preparations.67

Nitroamines. N-Nitroglycine (55) was isolated in 1968, marking the discovery of an additional class of N−N linked natural products at the time.54 This nitroamine was produced by Streptomyces noursei 8045-MC3 collected in Tokyo, Japan. At low concentrations, 55 inhibits the growth of E. coli, Xanthomonas oryzae, and Pseudomonas tabaci.54 N-Nitroglycine (55) is also toxic to mice, and further studies suggest this may be secondary to its inhibitory action on succinate dehydrogenase, an enzyme involved in the Krebs cycle.54,55 Finally, studies E



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Scheme 1

to the consensus that Agaricus mushrooms are safe for human consumption.71 Anthglutin (74) was first isolated in 1977, from a culture of Penicillium oxalicum SANK 10477.73 It is a strong competitive and specific inhibitor of γ-glutamyl transpeptidase.73 The arylhydrazide xanthodermine (75) was isolated in 1985 from extracts of the mushroom Agaricus xanthodermia, alongside leucoagaricone (114) and agaricone (132).74 Xanthodermine (75) was later reported to inhibit growth in melanoma cancer cells.75 Roullier and co-workers isolated the novel arylhydrazide 76 in 2009 from Lichina pygmaea, a cyanobacterial lichen collected on the west coast of France.76 A year later the same team again isolated 76 alongside a novel compound named pygmeine (77) (the ortho analogue of the previously isolated xanthodermine (75) from L. pygmaea).75 In the same year, Yim and co-workers described the isolation of ramalin (77) from the Antarctic lichen Ramalina terebrata.77 Although the configuration of ramalin was not reported, it is likely that the glutamyl moiety is derived from L-glutamic acid, rendering it identical to pygmeine (77). L-Glutamic acid 5[(2,4-dimethoxyphenyl)hydrazide] (76) was found to exhibit antioxidant activities.75 Pygmeine (77) exhibits some activity against B16 melanoma cancer cells, with a potency 4-fold weaker than xanthodermine (75), suggesting that the parahydroxy group is correlated to biological activity.75 Ramalin (77) was subsequently shown to possess significant antioxidant activity in vivo with remarkably low cytotoxicity, along with antibacterial activity against B. subtilis.77b,c In 1966, spinamycin (78) was isolated from Streptomyces albospinus78 and was subsequently found to exhibit activity against certain fungi and also against rat tumor cells.78 However, the biological activity of 78 has not appeared to garner further interest since its initial report. The antibiotic XK90 (79) was isolated in 1976 from Streptomyces MK-90 collected in Japan.79 Following its isolation, the broad spectrum of antibacterial activity against Gram-positive and Gramnegative species displayed by antibiotic 79 was elucidated, although no activity was observed following in vivo administration in mice.79 In 2001, the isolation of stephanosporin (80) from Stephanospora caroticolor, a gasteromycete known as the carrot truffle due to its bright orange appearance, was reported.80 Dinohydrazides A (81) and B (82) were isolated in 2010 from an unidentified symbiotic dinoflagellate

Diazo Compounds. A relatively small number of diazo compounds occur naturally, ranging from simple modified αamino acids such as duazomycin (71) to the complex antibiotic lomaiviticin A (72). The majority of these natural products have pronounced biological activity, presumably due to the favorable loss of molecular nitrogen, leading to a reactive species that can interact with a range of biomolecules. Diazo compounds will not be discussed in detail herein, and readers are directed to an extensive review on naturally occurring diazo compounds by Nawrat and Moody.68

Hydrazides. The first example of a naturally occurring hydrazide was agaritine (73), isolated from the button mushroom Agaricus bisporus in 1961.69 Early biological studies suggested that 73 was mutagenic and toxic to mice,70 raising concern over consumption of commercially available mushrooms.71 Furthermore, studies have shown that enzymatic hydrolysis of 73 yields 4-hydroxymethylphenylhydrazine (126) and L-glutamate.72 Numerous biological studies have since been carried out, many contradicting the earlier findings and leading F



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Negamycin (83) was isolated in 1970 from three strains of Streptomyces closely related to S. purpeof uscus (strains M890C2, MA91-M1, and MA104-M1) in Japan. Negamycin is a potent antibacterial both in vitro and in vivo against a range of Gram-positive and Gram-negative bacteria via inhibition of bacterial protein synthesis,82 and its mechanism of action has been the subject of various studies.83 Negamycin has also been identified as a potentially viable therapy in the treatment of Duchenne muscular dystrophy and other diseases associated with nonsense mutations, due to its readthrough-promoting activity.84 Leucylnegamycin (84) was isolated from Streptomyces strain M890-C2 during its early growth phase and identified as a biosynthetic precursor to 83.85 Leucyl derivative 84 was also active against various species of bacteria, albeit 2−16 times less active than negamycin (83).86 In 1978, 3-epi-deoxynegamycin (85) and its corresponding leucyl derivative 86 were isolated from Streptomyces goshikiensis No. MD967-A2.87 Interestingly, the placement of the leucyl group in 86 differs from that of leucylnegamycin (84). Both 85 and 86 were screened for antibacterial activity, with 85 possessing roughly half the activity of negamycin (83) against Gram-positive bacteria and very weak activity against Gram-negative strains.87 The leucyl derivative 86 displayed only weak activity against one organism in the assay, Pseudomonas fluorescens.87

on Xeospongia sp., a marine sponge growing in Japanese waters.81 Both dinohydrazides exhibit moderate growth inhibition of human umbilical vein endothelial cells and mammalian cancer cells (HL60 leukemia and B16 melanoma).81

The unique phosphorus-containing hydrazide FR-900137 (87) was first isolated from Streptomyces unzenensis sp. nov. collected from Japanese soil in 1980.88 FR-900137 exhibited pronounced antibacterial activity on E. coli and B. subtilis and moderate activity on Staph. aureus and Proteus,88 via inhibition of cell wall biosynthesis.89 A pair of phosphorus-containing hydrazides isolated in 1983 from Streptomyces lavendofoliae No. 630 were named fosfazinomycins A (88) and B (89).90 Hydrazidomycins A−C (90−92) were isolated from Streptomyces aratus obtained from Yunnan Province in southwestern China.91 By chance, an entirely independent group reported the isolation of elaiomycins B (93) and C (92) G



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from Streptomyces sp. BK 190 only weeks prior to the aforementioned report, adopting the name of elaiomycin (4), which was also isolated from the same extract.92 As indicated, hydrazidomycin C and elaiomycin C (92) are identical. However, the assignment of the double bond in hydrazidomycin B (91) differs from that of elaiomycin B (93), suggesting they are in fact different. Elaiomycins 92 and 93 both displayed slight activity against Staph. lentus DSM 6672 (growth inhibition of 23% and 24%, respectively), a degree of enzyme inhibition against acetylcholinesterase and phosphodiesterase, but no cytotoxicity toward cancer cell lines HepG2 and HT29. The hydrazidomycins were specifically screened for antineoplastic activity, with hydrazidomycin A (90) exhibiting the strongest activity followed by hydrazidomycin B (91). Hydrazidomycin C (92) was not found to exhibit cytotoxicity against any of the selected cancer cell lines, and the authors concluded that the degree of unsaturation in the aliphatic chain was tied with the cytotoxic activity of these natural hydrazides, an observation that is consistent with the findings for elaiomycin C (92), but contrary to the findings of elaiomycin B (93) (which may be indicative of the structural disparity between these two compounds).91 The naturally occurring hydrazides geralcins A (94) and B (95) both contain an α,β-unsaturated γ-lactone moiety.93 Geralcins A (94) and B (95) were isolated in 2012 from Streptomyces sp. LMA-545 growing in soil collected from La Réunion Island, France. Neither of the geralcins exhibited antibacterial activity in the screening conducted. However, geralcin B exhibited antineoplastic activity against the breast cancer cell line MDA231.93 In 2013, the structurally diverse geralcins C (96), D (97), and E (13) were isolated from Streptomyces sp. LMA-545 alongside geralcins A (94) and B (95). Interestingly, geralcin E (13) was first observed in 1969 as a degradation product of LL-BH872α (12).11 Neither geralcin D (97) nor E (13) exhibited significant bioactivity, yet geralcin C (96) possesses activity against cancer cells and inhibited the E. coli DnaG primase.12 Montamine (98) was isolated in 2006 from the seeds of Centaurea montana, and to the best of our knowledge is the only example of an N,N′dialkyl-N,N′-diacyl hydrazide.94 Montamine is a dimer of the known natural product moschamine, also present in C. montana. Montamine (98) displays moderate antioxidant properties, activity on par with the positive control

podophyllotoxin in the brine shrimp lethality assays, and exhibits cytotoxicity against CaCo-2 colon cancer cells.94 Linatine (99) was isolated from the seeds of Linum usitatissimum, a variety of flax.95 The presence of 99 led to vitamin B deficiencies in poultry reared on feed containing this particular flaxseed, owing to the vitamin B6 antagonistic properties of 99, which were overcome following treatment of the feed with pyridoxine. It is noteworthy that N-amino-Dproline (discussed later, 127) was also isolated from flaxseed.96

Indenecarbazates caribbazoins A (100) and B (101) were isolated in 1990 from the marine sponge Cliona caribboea.97 H



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esculenta in 1967.104 It is believed that several high molecular weight adducts and glycosylated derivatives of gyromitrin (107) also exist in the flesh of the mushroom.105 The mushroom G. esculenta and its relatives, commonly known as false morel, had been long suspected of poisonings known as “Gyromitra syndrome”, the effects of which range from gastrointestinal symptoms to coma and fatality.105 The toxicity of false morel was confirmed with the discovery of 107 and derivatives.105 The gyromitrins are converted to N-methyl-N-formylhydrazine and ultimately N-methylhydrazine in vivo, giving rise to the fungi’s toxicity.105

However, the unprecedented structural characteristics along with inconsistent quantities of 100 and 101 in sample batches led the authors to caution that they may be linked to pollutants rather than naturally occurring.97 Both 100 and 101 exhibit mild hypotensive activity in rats.97

Leucoagaricone (114) was isolated from Agaricus xanthoderma in 1985, alongside xanthodermine (75) and agaricone (132).74 In 1991, hydrazone NG-061 (115) was isolated from a fermentation broth of Penicillium minioluteum F-4627 collected in Japan, during a search for naturally occurring nerve growth factor mimics and potentiators.106 NG-061 induced neurite outgrowth in PC12 cells at low concentrations (1−10 μg/mL), thus establishing the hydrazone as an effective nerve growth potentiator.106 Two phenylhydrazones named farylhydrazones A (116) and B (117) were isolated in 2011 from Isaria farinosa, an entomopathogenic fungus.107 Given the promising biological activity of the culture extracts, 116 and 117 were subject to various assays; however no antimicrobial or cytotoxic effects were observed107 and unrelated compounds were found to be responsible for this activity.107

The unnamed amido-hydrazide derivative 102 was isolated in 1991 from the seed coats of Butea monosperma (Lam.) Kuntze,98 a constituent of certain ethnomedicinal preparations.99 The 11-membered macrocyclic hydrazide 103 was isolated in 1999 from Sargassum vachellianum, an alga growing in the South China Sea.100 The unnamed butyrolactam 104 was isolated in 2008 from an ear of Schizonepeta mulifida (L.) Briq., a plant commonly used in traditional Chinese medicine.101 MTT assays with liver tumor cells (SMMC-7721) indicate that 104 possesses antitumor activity.101 The dibutenoyl hydrazide 105 was isolated in 2009 from the root-bulb of Crinum def ixum Ker-Gawl (wild garlic), a plant spread widely throughout Asia with common use in various ethnomedicines.102 Hydrazide 105 was found to possess antigenotoxic activity using the Allium test.102 Desferrimaduraferrin (106) is a constituent of the siderophore named maduraferrin, an oligopeptide iron complex that was isolated from a strain of Actinomadura madurae in 1988.103

The naphthopyridazone alkaloid yoropyrazone (118) was isolated from Streptomyces sp. IFM 11307, collected from soil in Japan (Yoro Valley).108 In the presence of a TNF-related apoptosis-inducing ligand (TRAIL), yoropyrazone exhibits moderate TRAIL resistance-overcoming activity against human gastric AGS cells. 108 Katorazone (119) is an unprecedented 2-azaquinone-phenylhydrazone isolated from Streptomyces sp. IFM 11299 in 2012. 109 Similarly to yoropyrazone (118), katorazone (119) exhibits synergistic effects with TRAIL against human gastric AGS cells.109 The phosphorus-containing hydrazone 120 was isolated from the red tide dinoflagellate Gymnodinium breve in 1982 and was identified as an ichthyotoxin.110 Later studies also confirmed the acute toxicity of 120 in rodents.111 The bromotyrosine derivative psammaplin G (121) was isolated in 2003 from the

Hydrazones. Gyromitrin (107) and small concentrations of various derivatives (108−113) were isolated from Gyromitra I



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sponge Pseudoceratina purpurea collected in Papua New Guinea and is a potent inhibitor of DNA methyltransferase.112

Hydrazines. Unlike their synthetic counterparts, natural hydrazines are relatively sparse in number. There are differing views as to whether hydrazine (122) occurs naturally in tobacco and cigarette smoke or is a product of pyrolysis.113 The tumorigenic N,N-dimethylhydrazine (123) has also been isolated from tobacco leaf, and its presence is independent of the commonly used herbicide maleic hydrazide (MH-30).114 The hydrazone gyromitrin (107) found in Gyromitra esculenta breaks down both within the mushroom and in the body following consumption to N-formyl-N-methylhydrazine (124) and ultimately methylhydrazine (125).105 These naturally occurring hydrazines are highly toxic and are responsible for the toxicity of the mushroom (see section on gyromitrin).105 Similarly, the hydrazide agaritine (73) has been demonstrated to break down to 4-hydroxymethylphenylhydrazine (126) enzymatically.72 A review by Toth on the natural occurrence, synthetic production, and use of carcinogenic hydrazines includes a section on naturally occurring hydrazines such as these.115 N-Amino-D-proline (127) is found in flaxseed alongside the hydrazide linatine (99).96

natural products possess the piperazic acid moiety (e.g., piperazimycin A 131), with several possessing intriguing biological activities. Owing to a detailed recent review by Ley and co-workers,118 piperazic acids will not be discussed in further detail herein.

Azines. Agaricone (132) was isolated in 1985 from the mushroom Agaricus xanthoderma,74 alongside leucoagaricone (114) and xanthodermine (75). Agaricone (132) is formed through oxidation of the hydrazone leucoagaricone (114), which occurs rapidly upon external stress to the mushroom.74 The dimeric chromane limnazine (133) was isolated in 2002, from the aquatic Bacillus strain GW90a collected from wastewater storage in Germany.119 No biological activity was observed following assays with a series of bacteria, fungi, and algae.119 The isolation of the 1,2-diazepine (134) from the leaves of Ilex opaca (American Holly) was reported in 2004.120 While the extracts from the leaves possessed antibiotic properties, no specific biological activity of 134 was reported.120 The isolation of o-hydroxyacetophenone azine (135) (previously known by synthesis) was reported in 2005, following the extraction of various alkaloids from Chione venosa (sw.) urban var. venosa, a plant native to Grenada that produces the popular aphrodisiac “Bois Bandé”.121 However, the authors note that 135 may have formed as an artifact in the isolation process.121 Pyrazoles and Indazoles. The first report of a naturally occurring pyrazole derivative was the isolation of β-pyrazol-1ylalanine (136) from watermelon seeds (Citrullus vulgaris var. Tom Watson) in 1960, a compound now known to occur widely in the Cucurbitaceae family.122 The γ-glutamyl derivative 137 was isolated from cucumber seeds in 1963.123 Despite the

Ostrerine A (128) is a dimeric adenosyl-alkaloid linked via a central hydrazine moiety and was isolated in 2004 from Ostrea rivularis, a marine mollusk of Quanzhou.116 The pentacyclic indole alkaloid braznitidumine (129) was isolated in 2006 and contains an N−N bond embedded within an 11-membered macrocycle.117 Braznitidumine was isolated from the stem bark of Aspidosperma nitidum, a plant spread throughout the Americas from Mexico to Argentina that is commonly used in traditional medicines.117 Piperazic acids (130) are nonproteinogenic amino acids with a cyclic hydrazine skeleton. Many architecturally complex J



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from various edible mushrooms.131 With their data being consistent with that of Parameswaran et al. it seems probable the authors have also mistaken uracil for 140. The C-nucleoside antibiotic formycin A (142) was first isolated in 1964 from a culture filtrate of the actinomycete Nocardia interforma, following a search for bacterially produced antitumor compounds in Japan.132 The isolation of formycin B (143) (also known as laurusin) from N. interforma followed one year later,133 and the natural occurrence of oxoformycin B (144) (a metabolite of formycin B) was observed in 1968.134 It should also be noted that formycin B is converted to formycin A in N. interforma.134 Together, formycins A and B possess a vast degree of biological activity. Formycin A in particular exhibits antitumor effects, cytotoxic potential in tumor islet cells, and insulinotropic action in rats.135 Both 142 and 143 possess antiviral and antibacterial activity.135 Formycin B alone exhibits antiparasitic effects, owing to its inhibition of purine nucleoside phosphorylases.135 The C-nucleoside pyrazomycin (145) (also known as Pyrazofurin) was first isolated in 1969 from Streptomyces candidus fermentations,136 followed by its αanomer pyrazomycin B (146) in 1973, isolated from the identical strain of bacteria.137 Pyrazomycin (145) possesses marked antitumor and antiviral activity on account of being an orotidine 5′-monophosphate (OMP) decarboxylase inhibitor, which has garnered significant interest from the scientific community owing to its therapeutic value and potential for derivatization.138 On the other hand, pyrazomycin B (146) does not inhibit OMP decarboxylase.139

accurate predictions that 136 and 137 are derived from pyrazole (138), a report of the heterocycle’s natural occurrence did not arrive until 1975, following its isolation from cucumber seeds.122b The conversion of toxic pyrazole into the amino acid conjugates 136 and 137 is believed to be a host detoxification mechanism.124 In relatively recent studies, β-pyrazol-1-ylalanine (136) has been demonstrated to impart insulinotropic effects 125 and interact with rat N-methyl- D -aspartate (NMDA)-type glutamate receptors.126 The pyrazole-fused tripeptide 139 was isolated in 2008 from Burkholderia glumae, a bacterial pathogen on rice.127 Tripeptide 139 was found to exhibit antibacterial activity, notably against Erwinia amylovora, a bacterium that causes fire blight disease in apple and pear trees.127

The natural occurrence of pyrazole-3-carboxylic acid (140) and its methylated derivative (141) was first reported by Parameswaran and co-workers in 1997, in the fire sponge Tedania anhelans.128 In the following year, 4-methylpyrazole-3carboxylic acid (141) was reportedly isolated from the marine sponge Suberites vestigium.129 However, the assignments reported by both groups have been scrutinized, raising doubt that 140 and 141 are accurate structures.130 Thymine and uracil, both common primary metabolites, have been presented as more likely compounds to match the spectroscopic data.130 Interestingly, the natural occurrence of pyrazole-3-carboxylic acid (140) was again reported in 2006, purportedly isolated

Withasomnine (147) was first isolated in 1966 from the roots of Withania somnifera Dun., a plant used in traditional Indian medicine.140 Withasomnine exhibits spasymolytic and mild analgesic activity, CNS and circulatory system depression,141 and COX-1, COX-2, and LTB4 inhibition.142 The 4hydroxy derivative (148) was isolated much later, in 1994, from K



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the roots of Newbouldia laevis, alongside 147 and the novel dihydro analogues newbouldine (149) and 4-hydroxynewbouldine (150). Finally, the isolation of the 4-methoxy derivative (151) from N. laevis, alongside its dihydro analogue 4-methoxy newbouldine (152) and analogues 147−150, was reported in 1998.143 The pyrazole alkaloid 153 structurally related to the withasomnines was isolated in 2008 from the endophytic strain of Streptomyces sp. 5B.144

Although matlystatins D−F (154−156) belong to the family of piperazic acids, they deserve special mention here owing to their pyrazole moiety. The matlystatins were isolated in 1992 from Actinomadura atramentaria SANK 61488, an actinomycete collected from Western Australian soil.145 Despite matlystatins A and B (not shown) having antimicrobial activity and inhibiting type IV collagenases, matlystatins D−F do not exhibit a significant degree of biological activity.146 Nigellicine (157) was the first indazole-containing natural product reported, isolated in 1985 from the seeds of Nigella sativa (black cumin), a herbaceous plant common to European and Asian regions.147 Notably, 157 contains a heterocyclic mesomeric betaine moiety, rarely encountered in nature.148 Despite the various medicinal uses of the parent plant,147b no biological studies of 157 have been reported. A decade passed before the discovery of a second naturally occurring indazole, an analogue of 157 named nigellidine (158), also isolated from N. sativa.149 As in the case of 157, no biological studies have been undertaken with nigellidine (158). In 2008, the 4-sulfate derivative 159 was isolated from N. sativa seeds alongside 158.150 The authors proposed that 159 may be the true natural product, forming 158 via facile cleavage of the sulfate group during the isolation process.150 It is worth noting that sulfatecontaining alkaloids are rare in nature, and indeed 159 is the only known sulfated indazole natural product.150 In 2005, nigeglanine (160) was isolated from N. glandulifera, a relative of N. sativa similarly regarded for its medicinal value.151 The first member of the small family of natural pyrazolo[4,3e][1,2,4]triazines, pseudoiodinine, was isolated from Pseudomonas f luorescens var. pseudoiodinum in 1972 and assigned as structure 161.152 In 1996, the violet pigment named nostocine A (162) was isolated from the freshwater cyanobacterium

Nostoc spongiaeforme TISTR 8169 growing in a Thai paddy field.153 It has been proposed that the pigment is released from the cyanobacterium in response to oxidative stress.154 Nostocine A inhibits the growth of several bacteria and possesses strong herbicidal and algicidal activities.154,155 Furthermore, 162 inhibits the growth of various human cancer cell lines at concentrations as low as 0.1 μg/mL and has a cytotoxicity comparable to 5-fluorouracil.155 Acute toxicity was observed following the administration of 162 to mice.154 Fluviols A−E (163−167) were isolated from strains of P. f luorescens var. pseudoiodinum.156 Synthetic studies by Kelly confirmed the structure of fluviol A (163) and revised the structure of pseudoiodinine from 161 to 165.157 This in turn means the structure proposed for fluviol C is incorrect, and its L



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isolated from a species of Vibrio marine bacteria growing on the surface of coral in the Red Sea.164 Indazole-3-carbaldehyde (174) exhibited antibacterial activity against Gram-positive bacteria and was also cytotoxic to mouse lymphocytic leukemia cells and Jurkat-T-cell leukemia, while 173 did not produce significant results in bioassays.165

true structure remains unknown. Despite the absence of NMR data for fluviols B−E, comparison of the physical properties of natural fluviol E and synthetic pseudoiodinine suggests they are identical.156,157 Furthermore, DFT analysis of the structures proposed for fluviols C (165) and E (167) do not match the UV−visible spectra of the natural products.158 Natural fluviol E inhibits the growth of various bacteria, with weaker activity against fungi,156 inhibited the growth of the ascetic form of Ehrlich carcinoma in vivo, and was also toxic to the mice used.156 Natural fluviol C proved to be an inferior antibacterial and was also less toxic to mice, with moderate antitumor activity.156 Fluviol A (163) was the least toxic, yet possessed the strongest antitumor activity.156

Pyridazines and Cinnolines. Pyridazomycin (175) was the first example of a natural product containing a pyridazine core, isolated in 1988 from Streptomyces violaceoniger sp. griseof uscus (strain Tü 2557), a bacterium collected from soil in Mexico.166 Studies showed that 175 exhibits significant antifungal activity, along with minor inhibitory effects against B. subtilis.166 The biosynthesis of pyridazomycin (175) has also been studied.167 Pyridazocidin (176) was isolated almost a decade after the discovery of 175 from a strain of Streptomyces sp., collected from loam soil in Honduras.168 Pyridazocidin exhibits significant phytotoxicity, which operates via reversible redox reaction linked to photosynthetic electron transport, a highly unique mode of action among natural products.168 Liguducimine A (177) was isolated from the rhizomes of Ligularia duciformis, a plant used as an herbal antitussive and expectorant.169 Akalone (168) was isolated in 1995 from the marine bacterium Agrobacterium aurantiacum N-81106,159 and hydroxyakalone (169) was isolated two years later from the same species when cultivated under different conditions.160 Both 168 and 169 inhibit xanthine oxidase, with hydroxyakalone being the stronger inhibitor.160

In 1997 the 1-pyrazoline citreoazopyrone (170) was isolated from a hybrid (strain KO 0011) of Penicillium citreo-viride B., which was derived from strains IFO 4692 and 6200.161 Citreoazopyrone inhibited the growth of hypocotyls of lettuce seedlings, but did not affect their germination.161 In 2001 the highly unusual pyrazolidine alkaloid garceine (171) was isolated from Lotus garcinii, a flowering plant belonging to the Fabaceae family.162 No biological studies with 171 were undertaken on account of insufficient material.162 The unnamed 2-pyrazoline 172 was isolated from the aerial parts of Euphorbia guyoniana in 2010.163 Recently, 3-substituted indazoles 173 and 174 were

Schizocommunin (178) was isolated from a culture of Schizophyllum commune, a basidiomycetous fungus that was collected from the bronchus of a patient suffering allergenic bronchopulmonary mycosis.170 Schizocommunin exhibits strong cytotoxicity against murine lymphoma cells.170 The symmetrical cinnoline 4849F (179) was isolated in 2007 from a M



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culture of Streptomyces sp. 4849.171 Although 4849F (179) showed no antibacterial activity, it did exhibit cytotoxicity against human breast cancer MCF-7 and human ovarian cancer A2780 cell lines and was also shown to be a competitive inhibitor of interleukin-4.171 A study conducted in 1990 analyzed the volatile constituents of Hibiscus esculentus L. (Okra) pods, finding trace amounts (

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