Tasiamide,a cytotoxic peptide from the marine cyanobacterium Symploca sp

The acyclic peptide tasiamide (1) has been isolated from the marine cyanobacterium Symploca sp. The planar structure and absolute stereochemistry of the peptide were deduced by 2D NMR techniques and chiral HPLC. Tasiamide (1) was cytotoxic against KB and LoVo cells with IC(50) values of 0.48 and 3.47 microg/mL, respectively.     

Symplocamide A, a potent cytotoxin and chymotrypsin inhibitor from the marine Cyanobacterium Symploca sp

Investigation of a Symploca sp. from Papua New Guinea has led to the isolation of symplocamide A (1), a potent cancer cell cytotoxin, which also inhibits serine proteases with a 200-fold greater inhibition of chymotrypsin over trypsin. The complete stereostructure of symplocamide A was determined by detailed NMR and MS analysis as well as chiral HPLC analysis of the component amino acid residues. The presence of several unusual structural features in symplocamide A provides new insights into the pharmacophore model for protease selectivity in this drug class and may underlie the potent cytotoxicity of this compound to H-460 lung cancer cells (IC50=40 nM) as well as neuro-2a neuroblastoma cells (IC50=29 nM).     

Tasipeptins A and B: new cytotoxic depsipeptides from the marine cyanobacterium Symploca sp

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)J(H,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(50) values of 0.93 and 0.82 microM, respectively.     

Chinikomycins A and B: isolation, structure elucidation, and biological activity of novel antibiotics from a marine Streptomyces sp. isolate M045

In our screening of marine Streptomycetes for bioactive principles, two novel antitumor antibiotics designated as chinikomycins A (2a) and B (2b) were isolated together with manumycin A (1), and their structures were elucidated by a detailed interpretation of their spectra. Chinikomycins A (2a) and B (2b) are chlorine-containing aromatized manumycin derivatives of the type 64-pABA-2 with an unusual para orientation of the side chains. They exhibited antitumor activity against different human cancer cell lines, but were inactive in antiviral, antimicrobial, and phytotoxicity tests.     

Moromycins A and B, isolation and structure elucidation of C-glycosylangucycline-type antibiotics from Streptomyces sp. KY002

Two new anticancer antibiotics of the angucycline class, moromycins A and B (1, 2), along with the known microbial metabolites saquayamycin B (3) and fridamycin D (4) were isolated from the ethyl acetate extract of a culture broth of the terrestrial Streptomyces sp. KY002. The structures consist of a tetrangomycin core and various C- and O-glycosidically linked deoxysugars. The chemical structures of the new secondary metabolites were elucidated by 1D and 2D NMR and by mass spectrometry. Moromycin B (2) showed significant cytotoxicity against H-460 human lung cancer and MCF-7 human breast cancer cells.     

Symplostatin 3, a new dolastatin 10 analogue from the marine cyanobacterium Symploca sp. VP452.

Symplostatin 3 (1), a new analogue of dolastatin 10 (2), has been isolated from a tumor selective extract of a Hawaiian variety of the marine cyanobacterium Symploca sp. VP452. Compound 1 differs from 2 only in the C-terminal unit; the dolaphenine unit is substituted by a 3-phenyllactic acid residue. Symplostatin 3 (1) possesses IC(50) values for in vitro cytotoxicity toward human tumor cell lines ranging from 3.9 to 10.3 nM. It disrupts microtubules, but at a higher concentration than 2, correlating with the weaker in vitro cytotoxicity.     

Malevamide D: isolation and structure determination of an isodolastatin H analogue from the marine cyanobacterium Symploca hydnoides

Malevamide D (1), a highly cytotoxic peptide ester, and the known compound curacin D (5) were isolated from a Hawaiian sample of Symploca hydnoides. The structure of 1 was elucidated by spectroscopic analysis including NMR and high-resolution MS/MS. Partial stereochemical assignments of 1 were made by chiral HPLC analysis of acid and base hydrolysates. Malevamide D (1) demonstrated toxicity against P-388, A-549, HT-29, and MEL-28 cell lines in the subnanomolar range, while curacin D (5) was weakly cytotoxic. Malevamide D (1) is closely related to isodolastatin H (2), which was previously isolated in low yield from the sea hare Dolabella auricularia. A second Hawaiian sample of S. hydnoides yielded curacin D (5) along with the known dolastatin-10 analogue symplostatin-1 (3).     

Fatty acid synthase inhibitors from plants: isolation,structure elucidation,and SAR studies

Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.     

(-)-Echinobetaine A: isolation, structure elucidation, synthesis, and SAR studies on a new nematocide from a southern Australian marine sponge, Echinodictyum sp

A nematocidal agent present in a southern Australian marine sponge of the genus Echinodictyum has been isolated and identified by detailed spectroscopic analysis and total synthesis as the novel betaine (-)-echinobetaine A (6). Preliminary SAR investigations have been undertaken.     

Isolation and structure determination of malevamide E, a dolastatin 14 analogue, from the marine cyanobacterium Symploca laete-viridis

A new depsipeptide, malevamide E (1), was isolated from field-collected colonies of the filamentous cyanobacterium Symploca laete-viridis. The gross structure of 1 was determined by spectroscopic analyses, including one- and two-dimensional NMR and accurately measured MS/MS. Chiral HPLC analyses of an acid hydrolysate of 1 allowed the stereochemical assignments of its amino acid residues, which include N-methyl-L-alanine, alpha-N,gamma-N-dimethyl-L-asparagine, N-methyl-L-phenylalanine, L-proline, D-valine, and N-methyl-L-valine. LC-MS/MS analysis of S. laete-viridis fractions established the co-occurrence of malevamide E (1) and its homologue dolastatin 14 (2), which was previously reported in low yield from the sea hare Dolabella auricularia. Malevamide E (1) demonstrated a dose-dependent (2-45 microM) inhibition of store-operated Ca(2+) entry in thapsigargin-treated human embryonic kidney (HEK) cells, indicating an inhibitory effect on Ca(2+) release-activated Ca(2+) (CRAC) channels.     

Turnagainolides A and B, cyclic depsipeptides produced in culture by a Bacillus sp.: isolation, structure elucidation, and synthesis

Two new cyclic depsipeptides, turnagainolides A (1) and B (2), have been isolated from laboratory cultures of a marine isolate of Bacillus sp. The structures of 1 and 2, which are simply epimers at the site of macrolactonization, were elucidated by analysis of NMR data and chemical degradation. A total synthesis of the turnagainolides confirmed their structures. Turnagainolide B (2) showed activity in a SHIP1 activation assay.     

Venturamides A and B: antimalarial constituents of the panamanian marine Cyanobacterium Oscillatoria sp

Two new modified cyclic hexapeptides, venturamides A (1) and B (2), were isolated from the marine cyanobacterium Oscillatoria sp. by antimalarial bioassay-guided fractionation. The isolation of 1 and 2 represents the first example of the identification of cyanobacterial peptides with selective antimalarial activity. The planar structures of 1 and 2 were determined by 1D and 2D NMR analyses and, in the case of venturamide A (1), comparison with the literature data for a previously reported synthetic compound. The absolute configuration of the amino acid residues was determined by selective hydrolysis in conjunction with Marfey's analysis. Compounds 1 and 2 were tested for biological activity against a range of tropical parasites.     

Izumiphenazines A-C: isolation and structure elucidation of phenazine derivatives from Streptomyces sp. IFM 11204

Three new phenazine derivatives, named izumiphenazines A-C (1-3), and the known phenazine-1,6-dicarboxylic acid (4) were isolated from Streptomyces sp. IFM 11204. The structures of the isolated compounds were elucidated by means of spectroscopic methods including UV, IR, HRESIMS, and 1D and 2D NMR. Compounds 1-3 were evaluated for their activity in overcoming TRAIL (TNF-related apoptosis-inducing ligand) resistance in human gastric adenocarcinoma cells. Compounds 2 (30 μM) and 3 (20 μM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistant AGS cells.     

Isolation, structure elucidation, and antibacterial activity of methiosetin, a tetramic acid from a tropical sooty mold (Capnodium sp.)

Drug-resistant bacteria continue to make many existing antibiotic classes ineffective. In order to avoid a future epidemic from drug-resistant bacterial infections, new antibiotics with new modes of action are needed. In an antibiotic screening program for new drug leads with new modes of action using antisense Staphylococcus aureus Fitness Test screening, we discovered a new tetramic acid, methiosetin, from a tropical sooty mold, Capnodium sp. The fungus also produced epicorazine A, a known antibiotic. The structure and relative configuration of methiosetin was elucidated by 2D NMR and ESIMS techniques. Methiosetin and epicorazine A showed weak to modest antibacterial activity against S. aureus and Haemophilus influenzae. The isolation, structure elucidation, and antibacterial activity of both compounds are described.     

Production and structure elucidation of glycoglycerolipids from a marine sponge-associated microbacterium species

The bacterium Microbacterium sp., isolated from the sponge Halichondria panicea, produced four unusual cell-associated glycoglycerolipids and one diphosphatidylglycerol when grown on marine broth and on artificial seawater media. The lipids were isolated by chromatography on silica columns and their structures elucidated using a combination of multidimensional NMR and MS techniques. The main compound was 1-O-acyl-3-[alpha-glucopyranosyl-(1-3)-(6-O-acyl-alpha-mannopyranosyl )]glycerol (GGL.2) with 14-methyl-hexadecanoic acid and 12-methyl-tetradecanoic acid positioned at C-6 of the mannose unit and at the glycerol moiety. Glycolipid production was correlated with growth and reached a maximum value of 200 mg/L when grown on artificial seawater medium with 20 g/L glucose. The main compound decreased the surface tension of water down to 33 mN/m and the interfacial tension of the water/n-hexadecane system down to 5 mN/m. In addition to this good surface-active behavior, the main glycoglycerolipid showed antitumor activities.     

Micromide and guamamide: cytotoxic alkaloids from a species of the marine cyanobacterium Symploca

Two new cytotoxins have been isolated from a species of marine cyanobacterium belonging to the genus Symploca that was collected in Guam. These new compounds, micromide (1) and guamamide (2), were accompanied by the known lipopeptides apramides A (3), B (4), and G (5). The planar structures of both alkaloids were elucidated by standard 2D NMR techniques, and the configurations of the amino acid-derived units in 1 were determined by chiral HPLC. The stereochemistry of the beta-methoxyhexanoic acid in 1 was determined by derivatization with methyl d-mandelate, after acid hydrolysis, and comparison with synthetic standards.     

Symplocin A, a linear peptide from the Bahamian cyanobacterium Symploca sp. Configurational analysis of N,N-dimethylamino acids by chiral-phase HPLC of naphthacyl esters

The absolute stereostructures of the components of symplocin A (3), a new N,N-dimethyl-terminated peptide from the Bahamian cyanobacterium Symploca sp., were assigned from spectroscopic analysis, including MS, 2D NMR, and Marfey's analysis. The complete absolute configuration of symplocin A, including the unexpected D-configurations of the terminal N,N-dimethylisoleucine and valic acid residues, was assigned by chiral-phase HPLC of the corresponding 2-naphthacyl esters, a highly sensitive, complementary strategy for assignment of N-blocked peptide residues where Marfey's method is ineffectual or other methods fall short. Symplocin A exhibited potent activity as an inhibitor of cathepsin E (IC(50) 300 pM).     

Isolation and structure determination of lyngbyastatin 3, a lyngbyastatin 1 homologue from the marine cyanobacterium Lyngbya majuscula. Determination of the configuration of the 4-amino-2,2-dimethyl-3-oxopentanoic acid unit in majusculamide C, dolastatin 12, lyngbyastatin 1, and lyngbyastatin 3 from cyanobacteria

The structure of lyngbyastatin 3 (1), including the configurations of the two unusual amino acid residues, viz., the 3-amino-2-methylhexanoic acid (Amha) and 4-amino-2,2-dimethyl-3-oxopentanoic acid units (Ibu), has been established by chemical degradation. Analysis of the cyanobacterial samples of lyngbyastatin 3 (1), lyngbyastatin 1 (2), and dolastatin 12 (3) demonstrated that they are mixtures of Ibu epimers [R (major) and S (minor)], whereas the structurally related majusculamide C (4) is a single diastereomer having an S-Ibu unit.     

黑乳海参三萜皂苷的提取分离及其结构鉴定

目的研究黑乳海参Holothuria nobilis的化学成分。方法应用多种色谱技术对黑乳海参的化学成分进行分离纯化,根据化合物的理化性质和波谱数据鉴定结构。结果分离得到了2个三萜皂苷元类化合物,应用化学方法和各种光谱技术鉴定其结构为3-O-{3’’’’-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4′-O-磺酸钠-β-D-吡喃木糖}-海参烷-22,25-环氧-9-烯-3β,12α,17α,25β-四醇(1)和3-O-{β-D-吡喃奎诺糖-(1→2)-4′-O-磺酸钠-β-D-吡喃木糖}-海参烷-9-烯-18,16-内酯环-22,25环氧-3β,12α,17α-三醇(2)。结论 2个化合物均为新化合物,命名为黑乳海参苷I(nobiliside I,1)和黑乳海参苷II(nobiliside II,2)。     

Isolation and structure elucidation of an isoflavone and a sesterterpenoic acid from Henriettella fascicularis

A new isoflavone, 4',5,7-trihydroxy-6,8-dimethylisoflavone (1), and a new sesterterpenoic acid (2), together with five known compounds, lichexanthone (3), (-)-pinoresinol (4), betulinic acid, palmitic acid, and beta-sitosterol, were isolated from a dichloromethane extract of the branches of Henriettella fascicularis. Their structures were established by extensive spectroscopic methods. An attempt to determine the absolute stereochemistry of (2E,6S)-6-[(1R,5Z,3aS,9R,10Z,12aR)-1,2,3,3a,4,7,8,9,12,12a-decahydro-9-hydroxy-3a,6,10-trimethylcyclopentanocycloundecen-1-yl]-2-methylhept-2-enoic acid (2) was performed by single-crystal X-ray analysis, using Cu Kalpha radiation. Compound 1 showed significant competitive binding to estrogen receptor beta and moderate antiestrogenic activity with cultured Ishikawa cells.