Nitrogen-containing metabolites from marine cyanobacteria

Gerwick, William H.; Tan, Lik Tong; Sitachitta, Namthip

doi:10.1016/s0099-9598(01)57003-0

Cited by 163 publications

(242 citation statements)

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“…Features such as Nmethylation, the incorporation of polyketide units, and modified amino acids are biosynthetic signatures of cyanobacteria and probably serve to enhance the biological efficacy. 11 To date, the unusual Ahp unit has appeared in approximately 50 secondary metabolites isolated primarily from terrestrial and marine cyanobacteria (Microcystis, 12 Oscillatoria, 13 Anabaena, 14, Nostoc, 15 Microchaete, le Scyonema, 17 Lyngbya, 18 and Symploca 9 spp. ), although this moiety has appeared in natural products from Streptomyces resistomicificus.…”

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Tasipeptins A and B: New Cytotoxic Depsipeptides from the Marine CyanobacteriumSymplocasp.

et al. 2003

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Two new depsipeptides have been isolated from a Symploca sp. collected in Palau. The gross structures of tasipeptins A (1) and B (2) were determined by standard spectroscopic techniques, and the absolute configuration of the amino acid units was determined by chiral HPLC. The relative stereochemistry of the 3-amino-6-hydroxy-2-piperidone (Ahp) moiety in both structures was determined by analysis of 2 ' 3 JH,H values. Oxidation with PCC and acid hydrolysis unmasked this latent glutamic acid moiety, allowing for elucidation of the total configuration of 1 and 2. Tasipeptins A (1) and B (2) were cytotoxic toward KB cells with IC 5 o values of 0.93 and 0.82 fiM, respectively.Cyanobacteria are well-known sources of peptides and depsipeptides that display a variety of biological activities. 1 As part of a collaborative effort to discover new antitumor agents effective against solid and/or multidrug-resistant tumors, we began screening extracts of cyanobacteria collected in Micronesia. 2 The vast majority of these cyanobacteria belonged to the genus Lyngbya, 3 but among the samples collected in 1999 was a Symploca sp., the extracts of which displayed potent solid tumor selectivity. 4 Fewer reports have appeared in the literature on the chemistry and biological activity of this genus compared with Lyngbya; 5 ' 6 however, recent investigations have hinted at the pharmaceutical potential of Symploca." 1^9 Encouraged by these reports, a large collection of the cyanobacterium was made in the spring of 2000. From this Symploca sp., we have already described the isolation of tasiamide, 10 a cytotoxic acyclic peptide, and further examination of the aqueous extract has now led to the isolation and structure determination of the cyclic depsipeptides tasipeptins A (1) and B (2). Results and DiscussionSolvent partitioning and gel permeation chromatography of the aqueous extract of Symploca sp. NIH304 yielded a series of cytotoxic fractions. One fraction after separation by repeated reversed-phase HPLC provided 4.3 and 2.2 mg of tasipeptins A (1) and B (2) in 0.24% and 0.12% yield based on the crude aqueous extract. Tasipeptins A (1) and B (2) were cytotoxic toward KB cells with IC50 values of 0.93 and 0.82 fiM, respectively.Tasipeptin A (1) was a colorless amorphous powder whose UV/vis spectrum showed end absorptions only. Examination of the 1 H and 13 C NMR spectra of 1 recorded in CDCI3 indicated 14 sp 2 carbons, 13 methines, seven methylenes, and 11 methyl groups in accordance with a molecular weight of 892.5140 established by MADLI-TOF (C45H7]N70ioNa, A 1.5 mmu). Based on chemical shifts, eight of the 14 sp 2 carbons were carbonyls (dc 174.0, 173.5, 172.5, 172.4, 171.2, 170.2, 169.6, and 168.8), and the remainder constituted a monosubstituted phenyl ring (<5c 137.1, 129.2, 129.1, and 126.9). This accounted for a total of 12 of the 14 degrees of unsaturation implied by the molecular formula with the remaining two double bond equivalents in the form of rings. The thin-film IR spectrum of 1 suggested a depsipeptide with vibra...

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Tasipeptins A and B: New Cytotoxic Depsipeptides from the Marine CyanobacteriumSymplocasp.

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“…With few exceptions most secondary metabolites from Lyngbya arise by the incorporation of nitrogen into a combination of polyketide and peptide biosynthetic pathways. 2 Here we describe the isolation of a new nitrogen-containing compound, ulongapeptin (1), from a Palauan collection of Lyngbya sp.Results and Discussion.Lyophilized VP755 was extracted with 1:1 methanol/ ethyl acetate and the concentrated extract fractionated by normal and reversed-phase chromatography. After repeated RP-HPLC 1.1 mg of ulongapeptin (1), which had an IC50 of 0.63 ftM against KB cells, 3 was isolated in a yield of 0.10%.…”

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“…These diagnostic resonances implied an a-methyl-/3-amino acid unit common to cyanobacterial metabolites. 2 A second TOCSY experiment with a longer mixing time showed the secondary amide proton (3-NH) was relay-coupled to the terminal alkyne proton at <5H 1.98 (H-8). Considering all the fragments previously identified and the constraints imposed by the molecular formula, this had to be a Cg unit, viz., a 3-amino-2-methyloct-7-ynoic acid unit.…”

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Ulongapeptin, a Cytotoxic Cyclic Depsipeptide from a Palauan Marine Cyanobacterium Lyngbya sp.

et al. 2003

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Ulongapeptin (1), a cyclic depsipeptide, was isolated from a Palauan marine cyanobacterium Lyngbya sp. The gross structure was elucidated through one-dimensional TOCSY experiments and other spectroscopic techniques. The absolute and relative stereochemistry of the /?-amino acid, 3-amino-2-methyl-7-octynoic acid (AMO), in 1 was determined by synthesis of the saturated a-alkyl-/3-amino acid and Marfey's analysis of the acid hydrolysate of tetrahydro-1. Ulongapeptin (1) was cytotoxic against KB cells at an IC 50 value of 0.63 fM..Cyanobacteria are photosynthetic microorganisms that inhabit diverse habitats ranging from marine to terrestrial. These ancient prokaryotes are believed to have played a key role in the evolution of the modern ecosystem since they were presumably the first organisms to produce molecular oxygen. 1 Filamentous cyanobacteria of the genus Lyngbya are the most frequently encountered cyanobacteria in tropical areas and have the ability to fix nitrogen through heterocysts. With few exceptions most secondary metabolites from Lyngbya arise by the incorporation of nitrogen into a combination of polyketide and peptide biosynthetic pathways. 2 Here we describe the isolation of a new nitrogen-containing compound, ulongapeptin (1), from a Palauan collection of Lyngbya sp.Results and Discussion.Lyophilized VP755 was extracted with 1:1 methanol/ ethyl acetate and the concentrated extract fractionated by normal and reversed-phase chromatography. After repeated RP-HPLC 1.1 mg of ulongapeptin (1), which had an IC50 of 0.63 ftM against KB cells, 3 was isolated in a yield of 0.10%.Ulongapeptin (1) was found to have a molecular weight of 808 Da based on FABMS pseudo-molecular ion peaks

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“…By one estimate, almost 10% of the cyanobacterial genome may be devoted to this cause. 1 We have spent the past few years involved in the chemical characterization of secondary metabolites from a particular strain of Lyngbya sp. (Oscillatoriaceae) found in Palau and Guam.…”

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Continuing Studies on the Cyanobacterium Lyngbya sp.: Isolation and Structure Determination of 15-Norlyngbyapeptin A and Lyngbyabellin D

et al. 2003

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Re-collections of the cyanobacterium Lyngbya sp. have yielded two more members of the lyngbyapeptin and lyngbyabellin families. The gross structures of 15-norlyngbyapeptin A (1) and lyngbyabellin D (3) were deduced through standard 2D NMR techniques, with the absolute configuration of both elucidated through degradation and comparison with commercially available and synthetic standards. Degradation to the a-amino acid and NOE correlations determined the absolute and relative configuration of the 4-amino-3-hydroxy-5-methylhexanoic acid unit in 3. Lyngbyabellin D (3) displayed an IC50 value of 0.1 jiiM. against the KB cell line.The innumerable environmental pressures faced by marine cyanobacteria have undoubtedly catalyzed a tremendous genetic diversity, which often manifests itself in the production of secondary metabolites. By one estimate, almost 10% of the cyanobacterial genome may be devoted to this cause. 1 We have spent the past few years involved in the chemical characterization of secondary metabolites from a particular strain of Lyngbya sp. (Oscillatoriaceae) found in Palau and Guam. 2 This field-collected cyanobacterium, easily identifiable by the presence of a small shrimp 3 within the algal mat, produces an extraordinary array of secondary metabolites. Collections of this cyanobacterium made over the previous 10 years have yielded eight distinct classes of metabolites, consisting of some 26 different compounds. 24 Results and DiscussionSeveral large re-collections of the cyanobacterium were undertaken in Guam during the Spring of 2002 to facilitate further biological evaluation of two of these cytotoxins, the apratoxins 4 and lyngbyabellins. 2a Reported here are the isolation and structure determination, from these extracts, of 15-norlyngbyapeptin A (1) and lyngbyabellin D (3), which were both isolated in 3 x 10~4% of the cyanobacterium's dry weight. Lyngbyabellin D (3) displayed an IC50 value of 0.1 fiM against the KB cell line. 5 The richly detailed proton NMR spectrum of 1 ( a The numbering system for lyngbyapeptin A (2) has been adopted. 6a The NMR spectra of 1 and lyngbyapeptin A (2) were nearly superimposable, but 1 lacked the signals for the aromatic methoxy group on the tyrosine unit (C-15), which established 1 as 15-norlyngbyapeptin A. Fragments derived from 10

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Nitrogen-containing metabolites from marine cyanobacteria

Cited by 163 publications

References 242 publications

Tasipeptins A and B: New Cytotoxic Depsipeptides from the Marine CyanobacteriumSymplocasp.

Tasipeptins A and B: New Cytotoxic Depsipeptides from the Marine CyanobacteriumSymplocasp.

Ulongapeptin, a Cytotoxic Cyclic Depsipeptide from a Palauan Marine Cyanobacterium Lyngbya sp.

Continuing Studies on the Cyanobacterium Lyngbya sp.: Isolation and Structure Determination of 15-Norlyngbyapeptin A and Lyngbyabellin D

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