Review
pubs.acs.org/jnp
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.
■
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
■
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
© 2013 American Chemical Society and
American Society of Pharmacognosy
Received: February 8, 2013
Published: April 11, 2013
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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
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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 bio796
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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 (<0.01%) of 3- and 4methylcinnoline (180 and 181).172
synthetic 185 exhibited no antibacterial activity.178b The
proposed explanation for this contrast is that biological studies
were purportedly carried out with extracts.178b Penipanoid A
(186) was first isolated in 2011 from Penicillium paneum SD-44,
a marine sediment-derived fungus collected from the South
China Sea.179 Penipanoid exhibits significant activity against the
SMMC-7721 cell line in cytotoxicity assays, but showed no
antimicrobial activity against a range of bacteria and fungi.179
Azamerone (182) was isolated from a marine-derived species
of Streptomyces in 2006 and represents the only natural product
known to possess a phthalazinone ring.173 The biosynthesis of
182 has been investigated, which has led to validation of its
biosynthetic relationship to the napyradiomycin meroterpenoids, which include some examples of diazo natural products
(not shown), and provides insight into the formation of N−N
bonds in nature.174 6-Azidotetrazolo[5,1-a]phthalazine (183)
was isolated in 1985 from Gymnodinium breve, a toxic red-tide
dinoflagellate. The only known naturally occurring tetrazole
natural product, 183 contains a remarkable five contiguous
nitrogen atoms.175
Triazines and Derivatives. The unnamed triazine 187 was
isolated in 1988 from the seeds of Butea monosperma (Lam.)
Kuntze, a constituent of certain naturopathic contraceptive
remedies.99 The antifertility activity of the seed extract was
assayed with female rats, confirming significant inhibition of
pregnancy.99 The activity of pure 187 was not reported.
Noelaquinone (188) is a hexacyclic quinone containing a 1,2,4triazine moiety and was isolated in 1998 from the marine
sponge Xestospongia sp. collected from Derawan Island,
Indonesia.180 Despite its close relationship with certain
bioactive quinones and furanosteroids, no investigation into
the biological activity of 188 has been reported.181 In 2006 the
unusual tricyclic alkaloid cinachyramine (189) was isolated
from Cinachyrella sp., a marine sponge collected in Okinawa,
Japan. 182 Biological assays were carried out with the
trifluoroacetate salt of 189, revealing that the compound
exhibits weak activity against HeLa-S3 cells.182 In 2008, the
seeds of Detarium senegalense yielded a natural product assigned
as the 1,2,4-triazinane 190, the structure of which likely needs
revision.183 Triazinane 190 exhibited potent inhibition of
Proteus mirabillis, Ps. aeruginosa, and E. coli, but did not affect
Klebsiella pneumonia nor Staph. aureus.183 CDMHK (191) was
isolated in 2005 from Myxobacterium sp. HK1 collected from
Korean soil and was shown to inhibit the growth of various
human cancer cell lines.184
Both the occurrence and biological properties of the naturally
occurring 7-azapterdines were collated by Nagamatsu in
2001,185 and as such, we encourage readers to seek further
information from this review. It is relevant to mention that 2methylfervenulone (192) was recently isolated from Streptomyces sp. IM 2096 alongside co-metabolites 193−195.186 2Methylfervenulone (192) is a broad spectrum antibiotic and
also inhibits several protein tyrosine phosphatases (PTPs), a
family of proteins commonly targeted in various disease
therapies.186,187 Interconvertible diastereomers 193 and 194
are precursors of 192 and do not effect inhibition of PTPs.186
Likewise, 195 was inactive in the PTP inhibition assays and is
Triazoles and Derivatives. Although there appears to be
no examples of natural products bearing a 1,2,3-triazole, there
are examples of natural 1,2,4-triazoles. The first example of such
is the ribofuranosyl triazolone 184, which was previously
known by synthesis and isolated in 2000 from an Actinomadura
species.176 Triazole 184 exhibits broad spectrum phytotoxicity
through inhibition of adenylosuccinate synthetase and offers
promise in the development of new herbicides.176 Essramycin
(185) is the first example of a triazolopyrimidine isolated from
nature, specifically from the marine-derived Streptomyces sp.
isolate Merv8102 growing in the Egyptian Mediterranean
Sea.177 In the original report, 185 was claimed to exhibit
antibacterial activity.177 Later studies confirmed the unique
structure of 185 by synthesis;178 however it was found that
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postulated to be a degradation product of 2-methylfervenulone
(192).186
N−N Linked Heterocycles. Previously known by synthesis, fabioline (196) (1,1′-bipiperidine) was discovered in
nature following its isolation from Cassia grandis L.
(Leguminosae), a plant native to Central America with
ethnomedicinal applications.188 Schischkiniin (197) is a
structurally remarkable alkaloid isolated from seeds of the
thistle Centaurea schischkinii in 2005. This natural product
possesses a rare 1,1′-bisindole moiety embedded within a 14membered macrocycle that is proposed to arise from
dehydration of two Trp-Gly diketopiperazines followed by
[2+2]-cycloaddition.189 Schischkiniin (197) displayed significant antioxidant activity in DPPH assays and also exhibited
general cytotoxicity in a brine shrimp lethality assay and
moderate in vitro activity against colon cancer cells.189 The
unnamed ergot alkaloids 198−200 were isolated in 2003 from
12 Penicillium strains.190 These N−N linked bisindoles are the
homodimers of epoxyagroclavine-1, agroclavine-1, and their
corresponding heterodimer, respectively.190
Indolosesquiterpenes dixiamycin A (201) and its atropisomer dixiamycin B (202) were isolated in 2012 from
marine-derived Streptomyces sp. SCSIO 02999 collected from
sediment in the South China Sea, alongside their corresponding
monomer (xiamycin A).191 Dixiamycins A and B were
independently isolated in the same year by a research group
investigating indolosesquiterpene biosynthesis with genetic
modification.192 Both 201 and 202 exhibited weak inhibition
against a panel of four human tumor cell lines and displayed
antibacterial activity against four species.191 Interestingly, the
dimers were more active than their corresponding monomer,
and dixiamycin A was more active against Staph. aureus and B.
thuringiensis than dixiamycin B.191
The N−N linked β-carboline dimer 203 (previously known
by synthesis) was isolated in 1995 from Didemnum sp., an
ascidian growing on Sykes Reef.193 Dimer 203 was isolated
alongside traces of β-carboline and associated N−C linked
dimers.194
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(20) Kariya, Y.; Kubota, T.; Fromont, J.; Kobayashi, J. Tetrahedron
Lett. 2006, 47, 997−998.
(21) Kariya, Y.; Kubota, T.; Fromont, J.; Kobayashi, J. Bioorg. Med.
Chem. 2006, 14, 8415−8419.
(22) Nakano, H.; Hara, M.; Katsuyama, T.; Uozaki, Y.; Gomi, K. U.S.
patent 9309110, 1993. Chem. Abstr. 1993, 119, 158353.
(23) Gasco, A.; Serafino, A.; Mortarini, V.; Menziani, E. Tetrahedron
Lett. 1974, 15, 3431−3432.
(24) (a) Calvino, R.; Fruttero, R.; Gasco, A. J. Antibiot. 1986, 39,
864−868. (b) Gadoni, E.; Miglietta, A.; Olivero, A.; Gabriel, L.
Biochem. Pharmacol. 1989, 38, 1121−1124. (c) Gadoni, E.; Gabriel, L.;
Olivero, A.; Bocca, C.; Miglietta, A. Cell Biochem. Funct. 1995, 13,
231−238. (d) Antonini, G.; Pitari, G.; Caccuri, A. M.; Ricci, G.;
Boschi, D.; Fruttero, R.; Gasco, A.; Ascenzi, P. Eur. J. Biochem. 1997,
245, 663−667.
(25) Claydon, N. J. Invertebr. Pathol. 1978, 32, 319−324.
(26) (a) Wang, R. The investigation of biologically active secondary
metabolites produced by diatoms. Ph.D. Dissertation, University of
Rhode Island, 1992. (b) Shimizu, Y. Chem. Rev. 1993, 93, 1685−1698.
(27) Fugmann, B.; Steglich, W. Angew. Chem., Int. Ed. 1984, 96, 71−
72.
(28) Vavra, J. J.; DeBoer, C.; Dietz, A.; Hanka, L. J.; Sokolski, W. T.
Antibiot. Annu. 1959−1960, 7, 230−235.
(29) Herr, R. R.; Jahnke, J. K.; Argoudelis, A. D. J. Am. Chem. Soc.
1967, 89, 4808−4809.
(30) (a) Bolzan, A. D.; Bianchi, M. S. Mutat. Res, Rev. Mutat. Res.
2002, 512, 121−134. (b) Jacobson, G. R.; Poy, F. Infect. Immun. 1990,
58, 543−549.
(31) Delaunoit, T.; Ducreux, M.; Boige, V.; Dromain, C.; Sabourin, J.
C.; Duvillard, P.; Schlumberger, M.; de Baere, T.; Rougier, P.; Ruffie,
P.; Elias, D.; Lasser, P.; Baudin, E. Eur. J. Cancer 2004, 40, 515−520.
(32) Herrmann, H. Naturwissenschaften 1960, 47, 162.
(33) Luan, F.; Zhang, R.; Zhao, C.; Yao, X.; Liu, M.; Hu, Z.; Fan, B.
Chem. Res. Toxicol. 2005, 18, 198−203.
(34) (a) Du Plessis, L. S.; Nunn, R. J.; Roadh, W. A. Nature 1969,
222, 1198−1199. (b) Malling, H. V. Mutat. Res., Fundam. Mol. Mech.
Mutagen. 1966, 3, 537−540.
(35) Newcombe, G.; Morran, J.; Culbert, J. Water (Melbourne) 2012,
39, 76−82.
(36) Haggerty, H. G.; Holsapple, M. P. Toxicology 1990, 63, 1−23
and references therein.
(37) (a) Andra, S. S.; Makris, K. C. Environ. Int. 2011, 37, 412−417.
(b) Sharma, V.; Singh, M. Int. Res. J. Pharm. 2012, 3, 60−65.
(38) Lu, Q.; Zhang, L.; He, G. R.; Liang, H. X.; Du, G. H.; Cheng, Y.
X. Chem. Biodiversity 2007, 4, 2948−2952.
(39) Omura, S.; Tomoda, H.; Xu, Q.; Takahashi, Y.; Iwai, Y. J.
Antibiot. 1986, 39, 1211−1218.
(40) Yoshida, K.; Okamoto, M.; Umehara, K.; Iwami, M.; Kohsaka,
M.; Aoki, H.; Imanaka, H. J. Antibiot. 1982, 35, 151−156.
(41) (a) Tomoda, H.; Igarashi, K.; Omura, S. Biochim. Biophys. Acta
1987, 921, 595−598. (b) Tomoda, H.; Igarashi, K.; Cyong, J. C.;
Omura, S. J. Biol. Chem. 1991, 266, 4214−4219.
(42) Ui, H.; Ishiyama, A.; Sekiguchi, H.; Namatame, M.; Nishihara,
A.; Takahashi, Y.; Shiomi, K.; Otoguro, K.; Omura, S. J. Antibiot. 2007,
60, 220−222.
(43) Murthy, Y. K. S.; Thiemann, J. E.; Coronelli, C.; Sensi, P. Nature
1966, 211, 1198−1199.
(44) Jalal, M. A. F.; Hossain, M. B.; van der Helm, D. Acta Crystallogr.
C 1986, 42, 733−738 and references therein.
(45) Tamura, S.; Murayama, A.; Hata, K. Agric. Biol. Chem. 1967, 31,
758−759.
(46) Murayama, A.; Hata, K.; Tamura, S. Agric. Biol. Chem. 1969, 33,
1599−1605.
(47) Iinuma, H.; Takeuchi, T.; Kondo, S.; Matsuzaki, M.; Umezawa,
H.; Ohno, M. J. Antibiot. 1972, 25, 497−500.
(48) Shiino, M.; Watanabe, Y.; Umezawa, K. Bioorg. Med. Chem.
2001, 9, 1233−1240.
(49) Dolak, L. A.; Castle, T. M.; Hannon, B. R.; Argoudelis, A. D.;
Reusser, F. J. Antibiot. 1983, 36, 1425−1430.
■
CONCLUSIONS
This report describes the isolation and biological activity of
over 200 natural products that contain a nitrogen−nitrogen
bond. These natural products are dispersed over several
structural classes, isolated from many different sources (both
marine and terrestrial) and possess a diverse array of biological
activities. We hope this report will stimulate further research
into this interesting class of natural products.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.sperry@auckland.ac.nz.
Notes
The authors declare no competing financial interest.
■
REFERENCES
(1) LaRue, T. A. Lloydia 1977, 40, 307−321.
(2) Langley, B. W.; Lythgoe, B.; Riggs, N. V. J. Chem. Soc. 1951,
2309−2316.
(3) Riggs, N. V. Aust. J. Chem. 1954, 7, 123−124.
(4) (a) Kobayashi, A.; Matsumoto, H. Arch. Biochem. Biophys. 1965,
110, 373−380. (b) Hoffmann, G. R.; Morgan, R. W. Environ. Mutagen.
1984, 6, 103−116.
(5) Nishida, K.; Kobayashi, A.; Nagahama, T. Bull. Agric. Chem. Soc.
1955, 19, 77−84.
(6) Haskell, T. H.; Ryder, A.; Bartz, Q. R. Antibiot. Chemother. 1954,
4, 141−144.
(7) Ding, L.; Ndejouong, B. L. S. T.; Maier, A.; Fiebig, H. H.;
Hertweck, C. J. Nat. Prod. 2012, 75, 1729−1734.
(8) (a) Parry, R. J.; Rao, H. S. P.; Mueller, J. J. Am. Chem. Soc. 1982,
104, 339−340. (b) Parry, R. J.; Mueller, J. V. J. Am. Chem. Soc. 1984,
106, 5764−5765.
(9) Manderscheid, N.; Helaly, S. E.; Kulik, A.; Wiese, J.; Imhoff, J. F.;
Fiedler, H. P.; Süssmuth, R. D. J. Antibiot. 2013, 66, 85−88.
(10) Schoental, R. Nature 1969, 221, 765.
(11) McGahren, W. J.; Kunstmann, M. P. J. Am. Chem. Soc. 1969, 91,
2808−2810.
(12) Le Goff, G.; Martin, M. T.; Iorga, B. I.; Adelin, E.; Servy, C.;
Cortial, S.; Ouazzani, J. J. Nat. Prod. 2013, 76, 142−149.
(13) (a) Yamato, M.; Iinuma, H.; Naganawa, H.; Yamagishi, Y.;
Hamada, M.; Masuda, T.; Umezawa, H. J. Antibiot. 1986, 39, 184−191.
(b) Yamato, M.; Umezawa, H.; Sakata, N.; Moriya, Y.; Hori, M. J.
Antibiot. 1987, 40, 558−560.
(14) (a) Garg, R. P.; Parry, R. J. Microbiology 2010, 156, 472−483.
(b) Garg, R. P.; Alemany, L. B.; Moran, S.; Parry, R. J. J. Am. Chem.
Soc. 2009, 131, 9608−9609 and references therein.
(15) Omura, S.; Otoguro, K.; Imamura, N.; Kuga, H.; Takahashi, Y.;
Masuma, R.; Tanaka, Y.; Tanaka, H.; Xue-Hui, S.; En-Tai, Y. J.
Antibiot. 1987, 40, 623−629.
(16) Nakayama, M.; Takahashi, Y.; Itoh, H.; Kamiya, K.; Shiratsuchi,
M.; Otani, G. J. Antibiot. 1989, 42, 1535−1540.
(17) Fujiu, M.; Sawairi, S.; Shimada, H.; Takaya, H.; Aoki, Y.; Okuda,
T.; Yokose, K. J. Antibiot. 1994, 47, 833−835.
(18) Aoki, Y.; Yamamoto, M.; Hosseini-Mazinani, S. M.; Koshikawa,
N.; Sugimoto, K.; Arisawa, M. Antimicrob. Agents Chemother. 1996, 40,
127−132.
(19) Bianchi, G.; Dallavalle, S.; Merlini, L.; Nasini, G.; Quaroni, S.
Planta Med. 2003, 69, 574−576.
809
dx.doi.org/10.1021/np400124n | J. Nat. Prod. 2013, 76, 794−812
Journal of Natural Products
Review
(50) Abe, Y.; Kadokura, J.; Shimazu, A.; Seto, H.; Otake, N. Agric.
Biol. Chem. 1983, 47, 2703−2705.
(51) Hannon, B. R.; Reusser, F.; Dolak, L. A.; Argoudelis, A. D.;
Castle, T. M. U.S. Patent, 4540661, 1985. Chem. Abstr. 1986, 104,
4633.
(52) Nishio, M.; Hasegawa, M.; Suzuki, K.; Sawada, Y.; Hook, D. J.;
Oki, T. J. Antibiot. 1993, 46, 193−195.
(53) Natori, T.; Kataoka, Y.; Kato, S.; Kawai, H.; Fusetani, N.
Tetrahedron Lett. 1997, 38, 8349−8350.
(54) Miyazaki, Y.; Kono, Y.; Shimazu, A.; Takeuchi, S.; Yonehara, H.
J. Antibiot. 1968, 21, 279−282.
(55) Alston, T. A.; Seitz, S. P.; Porter, D. J.; Bright, H. J. Biochem.
Biophys. Res. Commun. 1980, 97, 294−300.
(56) Borer, K.; Hardy, R. J.; Lindsay, W. S.; Spratt, D. A. J. Exp. Bot.
1966, 17, 378−389.
(57) Chilton, W. S.; Hsu, C. P. Phytochemistry 1975, 14, 2291−2292.
(58) Nilsson, L.; Noori, G.; Bergman, R.; Kesler, E.; Sterner, O.;
Wickberg, B. Acta Chem. Scand. B 1983, 37, 929−933.
(59) Hatanaka, S. Trans. Mycol. Soc. Jpn. 1981, 22, 213−217.
(60) Parry, R.; Nishino, S.; Spain, J. Nat. Prod. Rep. 2011, 28, 152−
167.
(61) Okuda, T.; Nakayama, N.; Fujiwara, A. Trans. Mycol. Soc. Jpn.
1982, 23, 225−234.
(62) Gill, M.; Steglich, W. In Progress in the Chemistry of Organic
Natural Products; Springer: New York, 1987; Vol. 51, p 242.
(63) Takaishi, Y.; Murakami, Y.; Uda, M.; Ohashi, T.; Hamamura, N.;
Kido, M.; Kadota, S. Phytochemistry 1997, 45, 997−1001.
(64) Köpcke, B.; Mayer, A.; Anke, H.; Sterner, O. Nat. Prod. Lett.
1999, 13, 41−46.
(65) Fugmann, B.; Arnold, S.; Steglich, W.; Fleischhauer, J.; Repges,
C.; Koslowski, A.; Raabe, G. Eur. J. Org. Chem. 2001, 3097−3104.
(66) Gill, M. Nat. Prod. Rep. 2003, 20, 615−639.
(67) Wang, X.; Li, Z.; Yang, B. Fitoterapia 2004, 75, 789−791.
(68) Nawrat, C. C.; Moody, C. J. Nat. Prod. Rep. 2011, 28, 1426−
1444.
(69) Levenberg, B. J. Am. Chem. Soc. 1961, 83, 503−504.
(70) (a) Sterner, O.; Bergman, R.; Kesler, E.; Magnusson, G.;
Nilsson, L.; Wickberg, B.; Zimerson, E.; Zetterberg, G. Mutat. Res.
1982, 101, 269−281. (b) Toth, B.; Erickson, J. Toxicology 1977, 7,
31−36.
(71) Roupas, P.; Keogh, J.; Noakes, M.; Margetts, C.; Taylor, P. J.
Funct. Foods 2010, 2, 91−98.
(72) Toth, B.; Nagel, D.; Patil, K.; Erickson, J.; Antonson, K. Cancer
Res. 1978, 38, 177−180.
(73) Kinoshita, T.; Minato, S. Bull. Chem. Soc. Jpn. 1978, 51, 3282−
3285.
(74) Hilbig, V. S.; Andries, T.; Steglich, W.; Anke, T. Angew. Chem.,
Int. Ed. 1985, 97, 1063−1064.
(75) Roullier, C.; Chollet-Krugler, M.; van de Weghe, P.; Devehat, F.
L. L.; Boustie, J. Bioorg. Med. Chem. Lett. 2010, 20, 4582−4586.
(76) Roullier, C.; Chollet-Krugler, M.; Bernard, A.; Boustie, J. J.
Chromatogr. B 2009, 877, 2067−2073.
(77) (a) Paudel, B. Isolation and characterization of antibacterial and
antioxidant compounds from the Antarctic lichen, Ramalina terebrata.
Ph.D. Dissertation, Soonchunhyang University, South Korea, 2009.
(b) Paudel, B.; Bhattarai, H. D.; Lee, H. K.; Oh, H.; Shin, H. W.; Yim,
J. H. Z. Naturforsch C. 2010, 65, 34−38. (c) Paudel, B.; Bhattarai, H.
D.; Koh, H. Y.; Lee, S. G.; Han, S. J.; Lee, H. K.; Oh, H.; Shin, H. W.;
Yim, J. H. Phytomedicine 2011, 18, 1285−1290.
(78) Wang, E. L.; Hamada, M.; Okami, Y.; Umezawa, H. J. Antibiot.
Ser. A 1966, 19, 216−221.
(79) Takasawa, S.; Yamamoto, M.; Okachi, R.; Kawamoto, I.; Sato,
S.; Nara, T. J. Antibiot. 1976, 29, 1015−1018.
(80) Lang, M.; Spiteller, P.; Hellwig, V.; Steglich, W. Angew. Chem.,
Int. Ed. 2001, 40, 1704−1705.
(81) Maru, N.; Ohno, O.; Yamada, K.; Uemura, D. Chem. Lett. 2010,
39, 596−597.
(82) Hamada, M.; Takeuchi, T.; Kondo, S.; Ikeda, Y.; Naganawa, H.;
Maeda, K.; Okami, Y.; Umezawa, H. J. Antibiot. 1970, 23, 170−171.
(83) (a) Xie, Y.; Dix, A. V.; Tor, Y. Chem. Commun. 2010, 46, 5542−
5544. (b) Schroeder, S. J.; Blaha, G.; Moore, P. B. Antimicrob. Agents
Chemother. 2007, 51, 4462−4465 and references therein.
(84) Taguchi, A.; Nishiguchi, S.; Shiozuka, M.; Nomoto, T.; Ina, M.;
Nojima, S.; Matsuda, R.; Nonomura, Y.; Kiso, Y.; Yamazaki, Y.;
Yakushiji, F.; Hayashi, Y. ACS Med. Chem. Lett. 2012, 3, 118−122.
(85) Kondo, S.; Yamamoto, H.; Maeda, K.; Umezawa, H. J. Antibiot.
1971, 24, 732−734.
(86) Raju, B.; Mortell, K.; Anandan, S.; O’Dowd, H.; Gao, H.;
Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.; Yuan, Z.; White, R.;
Trias, J.; Patel, D. V. Bioorg. Med. Chem. Lett. 2003, 13, 2413−2418.
(87) Kondo, S.; Yoshida, K.; Ikeda, T.; Iinuma, K.; Honma, Y.;
Hamada, M.; Umezawa, H. J. Antibiot. 1977, 30, 1137−1139.
(88) Kuroda, Y.; Goto, T.; Okamoto, M.; Yamashita, M.; Iguchi, E.;
Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1980, 33, 272−279.
(89) Imanaka, H. Actinomycetologica 2000, 14, 22−26.
(90) (a) Ogita, T.; Gunji, S.; Fukazawa, Y.; Terahara, A.; Kinoshita,
T.; Nagaki, H. Tetrahedron Lett. 1983, 24, 2283−2286. (b) Kang, I. J.;
Hong, S. I.; Kim, Y. J. Bull. Korean Chem. Soc. 1991, 12, 127−130.
(c) Kang, I. J.; Hong, S. I.; Kim, Y. J. Bull. Korean Chem. Soc. 1991, 12,
358−359.
(91) Ueberschaar, N.; Ndejouong, B. L. S. T.; Ding, L.; Maier, A.;
Fiebig, H. H.; Hertweck, C. Bioorg. Med. Chem. Lett. 2011, 21, 5839−
5841.
(92) Helaly, S. E.; Pesic, A.; Fiedler, H. P.; Süssmuth, R. D. Org. Lett.
2011, 13, 1052−1055.
(93) Le Goff, G.; Martin, M. T.; Servy, C.; Cortial, S.; Lopes, P.;
Bialecki, A.; Smadja, J.; Ouazzani, J. J. Nat. Prod. 2012, 75, 915−919.
(94) Shoeb, M.; MacManus, S. M.; Jaspars, M.; Trevidu, J.; Nahar, L.;
Kong-Thoo-Lin, P.; Sarker, S. D. Tetrahedron 2006, 62, 11172−11177.
(95) Klosterman, H. J.; Lamoureux, G. L.; Parsons, J. L. Biochemistry
1967, 6, 170−177.
(96) Nugent, P. J. Chemical synthesis and metabolism of linatine.
Ph.D. Dissertation, North Dakota State University, 1970.
(97) Lemke, T. L.; Sanduja, R.; Mroue, M. M.; Iyer, S.; Alam, M.;
Hossain, M. B.; van der Helm, D. J. Pharm. Sci. 1990, 79, 840−844.
(98) Sharma, S.; Batra, A.; Mehta, B. K. Indian J. Chem. 1991, 30B,
715−716.
(99) Porwal, M.; Mehta, B. K.; Gupta, D. N. Nat. Acad. Sci. Lett.
1988, 2, 81−84.
(100) Xu, S. H.; Cen, Y. Z.; Li, Y. L.; Xu, S. Y. Chin. Chem. Lett. 1999,
10, 401−402.
(101) Liu, J. T.; Yu, J. C.; Jiang, H. M.; Zhang, L. Y.; Zhao, X. J.; Fan,
S. D. Chin. J. Chem. 2008, 28, 1129−1132.
(102) Bordoloi, M.; Kotoky, R.; Mahanta, J. J.; Sarma, T. C.; Kanjilal,
P. B. Eur. J. Med. Chem. 2009, 44, 2754−2757.
(103) Keller-Schierlein, W.; Hagmann, L.; Zaehner, H.; Huhn, W.
Helv. Chim. Acta 1988, 71, 1528−1540.
(104) List, P. H.; Luft, P. Tetrahedron Lett. 1967, 20, 1893−1994.
(105) Michelot, D.; Toth, B. J. Appl. Toxicol. 1991, 11, 235−243.
(106) Ito, M.; Sakai, N.; Ito, K.; Mizobe, F.; Hanada, K.; Mizoue, K.;
Bhandari, R.; Eguchi, T.; Kakinuma, K. J. Antibiot. 1999, 52, 224−230.
(107) Ma, C.; Li, Y.; Niu, S.; Zhang, H.; Liu, X.; Che, Y. J. Nat. Prod.
2011, 74, 32−37.
(108) Abdelfattah, M. S.; Toume, K.; Ishibashi, M. J. Antibiot. 2012,
65, 245−248.
(109) Abdelfattah, M. S.; Toume, K.; Arai, M. A.; Masu, H.; Ishibashi,
M. Tetrahedron Lett. 2012, 53, 3346−3348.
(110) Alam, M.; Sanduja, R.; Hossain, M. B.; van der Helm, D. J. Am.
Chem. Soc. 1982, 104, 5232−5234.
(111) (a) Singh, J. N.; Das Gupta, S.; Gupta, A. K.; Dube, S. N.;
Deshpande, S. B. Toxicol. Lett. 2002, 128, 177−183. (b) Husain, K.;
Singh, R.; Kaushik, M. P.; Gupta, A. K. Ecotoxicol. Environ. Saf. 1996,
35, 77−80.
(112) Piña, I. C.; Gautschi, J. T.; Wang, G. Y. S.; Sanders, M. L.;
Schmitz, F. J.; France, D.; Cornell-Kennon, S.; Sambucetti, L. C.;
Remiszewski, S. W.; Perez, L. B.; Bair, K. W.; Crews, P. J. Org. Chem.
2003, 68, 3866−3873.
810
dx.doi.org/10.1021/np400124n | J. Nat. Prod. 2013, 76, 794−812
Journal of Natural Products
Review
(144) Zhu, N.; Zhao, P.; Kang, Q.; Shen, Y. Tianran Chanwu Yanjiu
Yu Kaifa 2008, 20, 395−396.
(145) Ogita, T.; Sato, A.; Enokita, R.; Suzuki, K.; Ishii, M.; Negishi,
T.; Okazaki, T.; Tamaki, K.; Tanzawa, K. J. Antibiot. 1992, 45, 1723−
1732.
(146) Tanzawa, K.; Ishii, M.; Ogita, T.; Shimada, K. J. Antibiot. 1992,
45, 1733−1737.
(147) (a) Atta-ur-Rahman; Malik, S.; He, C.; Clardy, J. Tetrahedron
Lett. 1985, 26, 2759−2762. (b) Randhawa, M. A.; Alghamdi, M. S. Am.
J. Chin. Med. 2011, 39, 1075−1091.
(148) Schmidt, A.; Habeck, T.; Kinderman, M. K.; Nieger, M. J. Org.
Chem. 2003, 68, 5977−5982.
(149) Atta-ur-Rahman; Malik, S.; Hasan, S. S.; Choudhary, M. I.; Ni,
C. Z.; Clardy, J. Tetrahedron Lett. 1995, 36, 1993−1996.
(150) Ali, Z.; Ferreira, D.; Carvalho, P.; Avery, M. A.; Khan, I. A. J.
Nat. Prod. 2008, 71, 1111−1112.
(151) Liu, Y. M.; Yang, J. S.; Liu, Q. H. Chem. Pharm. Bull. 2004, 52,
454−455.
(152) Lindner, H. J.; Schaden, G. Chem. Ber. 1972, 105, 1949−1955.
(153) Hirata, K.; Nakagami, H.; Takashina, J.; Mahmud, T.;
Kobayashi, M.; In, Y.; Ishida, T.; Miyamoto, K. Heterocycles 1996,
43, 1513−1519.
(154) Hirata, K.; Yoshitomi, S.; Dwi, S.; Iwabe, O.; Mahakhant, A.;
Polchai, J.; Miyamoto, K. J. Biosci. Bioeng. 2003, 95, 512−517.
(155) Hirata, K.; Takashina, J.; Nakagami, H.; Ueyama, S.;
Murakami, K.; Kanamori, T.; Miyamoto, K. Biosci., Biotechnol.,
Biochem. 1996, 60, 1905−1906.
(156) Smirnov, V. V.; Kiprianova, E. A.; Garagulya, A. D.; Esipov, S.
E.; Dovjenko, S. A. FEMS Microbiol. Lett. 1997, 153, 357−361.
(157) Kelly, T. R.; Elliott, E. L.; Lebedev, R.; Pagalday, J. J. Am.
Chem. Soc. 2006, 128, 5646−5647.
(158) Galasso, V. Chem. Phys. Lett. 2009, 472, 237−242.
(159) Izumida, H.; Adachi, K.; Nishijima, M.; Endo, M.; Miki, E. J.
Mar. Biotechnol. 1995, 2, 115−118.
(160) Izumida, H.; Adachi, K.; Mihara, A.; Yasuzawa, T.; Sano, H. J.
Antibiot. 1997, 50, 916−918.
(161) Kosemura, S.; Yamamura, S. Tetrahedron Lett. 1997, 38, 3025−
3026.
(162) Ali, M. S.; Ahmad, F.; Ahmad, V. U. Turk. J. Chem. 2001, 25,
107−112.
(163) Boudiar, T.; Hichem, L.; Khalfallah, A.; Kabouche, A.;
Kabouche, Z.; Brouard, I.; Bermejo, J.; Bruneau, C. Nat. Prod.
Commun. 2010, 5, 35−37.
(164) Al-Zereini, W.; Yao, C. B. F. F.; Laatsch, H.; Anke, H. J.
Antibiot. 2010, 63, 297−301.
(165) Yao, C. B. F. F.; Zereini, W. A.; Fotso, S.; Anke, H.; Laatsch, H.
J. Antibiot. 2010, 63, 303−308.
(166) Grote, R.; Chen, Y.; Zeeck, A. J. Antibiot. 1988, 41, 595−601.
(167) Bockholt, H.; Beale, J. M.; Rohr, J. Angew. Chem. 1994, 106,
1733−1735.
(168) Gerwick, B. C. Weed Sci. 1997, 45, 654−657.
(169) Zhang, C. F.; Wang, Q.; Zhang, M. J. Asian Nat. Prod. Res.
2009, 11, 339−344.
(170) Hosoe, T.; Nozawa, K.; Kawahara, N.; Fukushima, K.;
Nishimura, K.; Miyaji, M.; Kawai, K. Mycopathologia 1999, 146, 9−12.
(171) Wang, K.; Guo, L.; Zou, Y.; Li, Y.; Wu, J. J. Antibiot. 2007, 60,
325−327.
(172) Ames, J. M.; MacLeod, G. Phytochemistry 1990, 29, 1201−
1207.
(173) Cho, J. Y.; Kwon, H. C.; Williams, P. G.; Jensen, P. R.; Fenical,
W. Org. Lett. 2006, 8, 2471−2747.
(174) Winter, J. M.; Jansma, A. L.; Handel, T. M.; Moore, B. S.
Angew. Chem., Int. Ed. 2009, 48, 767−770.
(175) Hossain, M. B.; van der Helm, D. Acta Crystallogr. C 1985, 41,
1199−1202.
(176) 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.
(113) (a) Liu, Y. Y.; Schmeltz, I.; Hoffmann, D. Anal. Chem. 1974,
46, 885−889. (b) Toth, B. Cancer Res. 1975, 35, 3693−3697.
(114) Schmeltz, I.; Abidi, S.; Hoffmann, D. Cancer Lett. 1977, 2,
125−132.
(115) Toth, B. In Vivo 2000, 14, 299−319.
(116) Ouyang, M. A. Nat. Prod. Res. 2006, 20, 79−83.
(117) Pereira, M. M.; Alcântara, A. F.; Piló-Veloso, D.; Raslan, D. S. J.
Braz. Chem. Soc. 2006, 17, 1274−1280.
(118) Oelke, A. J.; France, D. J.; Hofmann, T.; Wuitschik, G.; Ley, S.
V. Nat. Prod. Rep. 2011, 28, 1445−1471.
(119) Asolkar, R. N.; Kamat, V. P.; Wagner-Dobler, I.; Laatsch, H. J.
Nat. Prod. 2002, 65, 1664−1666.
(120) Sorensson, M. M.; Gallo, A. A.; Guillory, C. C. J. Undergrad.
Chem. Res. 2004, 3, 151.
(121) Lendl, A.; Werner, I.; Glasl, S.; Kletter, C.; Mucaji, P.; Presser,
A.; Reznicek, G.; Jurenitsch, J.; Taylor, D. W. Phytochemistry 2005, 66,
2381−2387.
(122) (a) Fowden, L.; Foe, F. F.; Ridd, J. H.; White, R. F. M. Proc.
Chem. Soc. 1959, 131−132. (b) LaRue, T. A.; Child, J. J. Phytochemistry
1975, 14, 2512−2513.
(123) Sunnill, P. M.; Fowden, L. Biochem. J. 1963, 86, 388−391.
(124) Brown, E. G.; Diffin, F. M. Phytochemistry 1990, 29, 469−478.
(125) Nmila, R.; Gross, R.; Rchid, H.; Roye, M.; Manteghetti, M.;
Petit, P.; Tijane, M.; Ribes, G.; Sauvaire, Y. Planta Med. 2000, 66,
418−423.
(126) Ikegami, F.; Kusama-Eguchi, K.; Sugiyama, E.; Watanabe, K.;
Lambein, F.; Murakoshi, I. Biol. Pharm. Bull. 1995, 18, 360−362.
(127) Mitchell, R. E.; Greenwood, D. R.; Sarojini, V. Phytochemistry
2008, 69, 2704−2707.
(128) Parameswaran, P. S.; Naik, C. G.; Hegde, V. R. J. Nat. Prod.
1997, 60, 802−803.
(129) Mishra, P. D.; Wahidullah, S.; Kamat, S. Y. Indian J. Chem.
1998, 37B, 199−200.
(130) Rao, K. V.; Santarsiero, B. D.; Mesecar, A. D.; Schinazi, R. F.;
Tekwani, B. L.; Hamann, M. T. J. Nat. Prod. 2003, 66, 823−828.
(131) Mallavadhani, U. V.; Sudhakar, A. V. S.; Satyanarayana, K. V.
S.; Mahapara, A.; Li, W.; van Breemen, R. B. Food Chem. 2005, 95,
58−64.
(132) (a) Hori, M.; Ito, E.; Takita, T.; Koyama, G.; Takeuchi, T.;
Umezawa, H. J. Antibiot. Ser. A 1964, 17, 96−99. (b) Robins, R. K.;
Townsend, L. B.; Cassidy, F.; Gerster, J. F.; Lewis, A. F.; Miller, R. L. J.
Heterocycl. Chem. 1966, 3, 110−114.
(133) Koyama, G.; Umezawa, H. J. Antibiot. Ser. A 1964, 18, 175−
177.
(134) Sawa, T.; Fukagawa, Y.; Homma, I.; Wakashiro, T.; Takeuchi,
T.; Hori, M.; Komai, T. J. Antibiot. 1968, 21, 334−339.
(135) Bzowska, A. In Modified Nucleosides; Wiley-VCH Verlag
GmbH & Co. KGaA: 2008; pp 473−510.
(136) Gerzon, K.; Williams, R. H.; Hoehn, M.; Gorman, M.; DeLong,
D. C. In 2nd International Congress of Heterocyclic Chemistry;
Montpellier, France, 1969; p C-30.
(137) (a) De Bernardo, S.; Weigele, M. J. Org. Chem. 1976, 41, 287−
290. (b) Gutowski, G. E.; Chaney, M. O.; Jones, N. D.; Hamill, R. L.;
Davis, F. A.; Miller, R. D. Biochem. Biophys. Res. Commun. 1973, 51,
312−317.
(138) (a) Elgemeie, G. H.; Zaghary, W. A.; Amin, K. M.; Nasr, T. M.
Nucleosides, Nucleotides, Nucleic Acids 2005, 24, 1227−1247. (b) De
Clercq, E. Med. Res. Rev. 2009, 29, 611−645.
(139) Dix, D. E.; Lehman, C. P.; Jakubowski, A.; Moyer, J. D.;
Handschumacher, R. E. Cancer Res. 1979, 39, 4485−4490.
(140) Schröter, H. B.; Neumann, D. Tetrahedron 1966, 22, 2895−
2897.
(141) Adesanya, S. A.; Nia, R.; Fontaine, C.; Païs, M. Phytochemistry
1994, 35, 1053−1055.
(142) Wube, A. A.; Wenzig, E. M.; Gibbons, S.; Asres, K.; Bauer, R.;
Bucar, F. Phytochemistry 2008, 69, 982−987.
(143) Aladesanmi, A. J.; Nia, R.; Nahrstedt, A. Planta Med. 1998, 64,
90−91.
811
dx.doi.org/10.1021/np400124n | J. Nat. Prod. 2013, 76, 794−812
Journal of Natural Products
Review
(177) El-Gendy, M. M. A.; Shaaban, M.; Shaaban, K. A.; El-Bondkly,
A. M.; Laatsch, H. J. Antibiot. 2008, 61, 149−157.
(178) (a) Battaglia, U.; Moody, C. J. J. Nat. Prod. 2010, 73, 1938−
1939. (b) Tee, E. H. L.; Karoli, T.; Ramu, S.; Huang, J. X.; Butler, M.
S.; Cooper, M. A. J. Nat. Prod. 2010, 73, 1940−1942.
(179) 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.
(180) Zhu, Y.; Yoshida, W. Y.; Kelly-Borges, M.; Scheuer, P. J.
Heterocycles 1998, 49, 355−360.
(181) Cao, L.; Maciejewski, J. P.; Elzner, S.; Amantini, D.; Wipf, P.
Org. Biomol. Chem. 2012, 10, 5811−5814.
(182) Shimogawa, H.; Kuribayashi, S.; Teruya, T.; Suenaga, K.;
Kigoshi, H. Tetrahedron Lett. 2006, 47, 1409−1411.
(183) Okwu, D. E.; Uchegbu, R. Res. J. Biotechnol. 2008, 331−334.
(184) Lee, H. K.; Lee, I. H.; Yim, J. S.; Kim, Y. H.; Lee, S. H.; Lee, K.;
Koo, Y. M.; Kim, S. J.; Jeong, B. C. J. Microbiol. Biotechnol. 2005, 15,
734−739.
(185) Nagamatsu, T. Recent Res. Dev. Org. Bioorg. Chem. 2001, 4, 97−
121.
(186) 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.
(187) Miller, T. W.; Chaiet, L.; Arison, B.; Walker, R. W.; Trenner,
N. R.; Wolf, F. J. Antimicrob. Agents Chemother. 1963, 161, 58−62.
(188) Valencia, E.; Madinaveitia, A.; Bermejo, J.; González, A. G.;
Gupta, M. P. Fitoterapia 1995, 66, 476.
(189) Shoeb, M.; Celik, S.; Jaspars, M.; Kumarasamy, Y.; MacManus,
S. M.; Nahar, L.; Thoo-Lin, P. K.; Sarker, S. D. Tetrahedron 2005, 61,
9001−9006.
(190) Zelenkova, N. F.; Vinokurova, N. G.; Arinbasarov, M. U. Appl.
Biochem. Microbiol. 2003, 39, 44−54.
(191) Zhang, Q.; Mandi, A.; Li, S.; Chen, Y.; Zhang, W.; Tian, X.;
Zhang, H.; Li, H.; Zhang, W.; Zhang, S.; Ju, J.; Kurtan, T.; Zhang, C.
Eur. J. Org. Chem. 2012, 5256−5262.
(192) Xu, Z.; Baunach, M.; Ding, L.; Hertweck, C. Angew. Chem., Int.
Ed. 2012, 51, 10293−10297.
(193) Kearns, P. S.; Coll, J. C.; Rideout, J. A. J. Nat. Prod. 1995, 58,
1075−1076.
(194) Kearns, P. S.; Rideout, J. A. J. Nat. Prod. 2008, 71, 1280−1282.
812
dx.doi.org/10.1021/np400124n | J. Nat. Prod. 2013, 76, 794−812