TMC-171A,B,C and TMC-154, novel polyketide antibiotics produced by Gliocladium sp. TC 1304 and TC 1282

Four new antibiotics, TMC-171A (2), B (3), C (4) and TMC-154 (5) have been isolated from the fermentation of fungal strains Gliocladium sp. TC 1304 and TC 1282, respectively. Spectroscopic and degradation studies have shown that TMC-171s and TMC-154 were new members of the TMC-151 class of antibiotics, unique polyketides modified with a D-mannose and a D-mannitol or a D-arabitol. These compounds showed moderate cytotoxicity to various tumor cell lines.     

TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, production, isolation, and biological activities

In our course of screening for novel proteasome inhibitors, TMC-95A and its diastereomers, TMC-95B to D, were isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093. TMC-95A inhibited the chymotrypsin-like (ChT-L), trypsin-like (T-L), and peptidylglutamyl-peptide hydrolyzing (PGPH) activities of 20S proteasome with IC50 values of 5.4nM, 200nM, and 60nM, respectively. TMC-95B inhibited these activities to the same extent as TMC-95A, while the inhibitory activities of TMC-95C and D were 20 to 150 times weaker than that of TMC-95A and B. TMC-95A did not inhibit m-calpain, cathepsin L, and trypsin at 30 microM, suggesting its high selectivity for proteasome. Taxonomy of the producing strain is also described.     

Tensidols, new potentiators of antifungal miconazole activity, produced by Aspergillus niger FKI-2342

Two new furopyrrols, designated tensidols A and B, were isolated from the culture broth of Aspergillus niger FKI-2342 by solvent extraction, silica gel column chromatography and HPLC. Their structures were elucidated and shown to have the common skeleton of 6-benzyl-6H-furo[2,3-b]pyrrole. Tensidols A and B potentiated miconazole activity against Candida albicans. Tensidols also showed moderate antimicrobial activity only against Pyricularia oryzae.     

Deacetylravidomycin M, a new inhibitor of IL-4 signal transduction, produced by Streptomyces sp. WK-6326. II. Structure elucidation

The structure of deacetylravidomycin M, an inhibitor of interleukin-4 signal transduction, was elucidated to be 6H-benzo[d]naphtho[1,2-b]pyran-6-one, 4-[3,6-dideoxy-3-(dimethylamino)-alpha-altropyranosyl]-1-hydroxy-10,12-dimethoxy-8-methyl- by spectroscopic studies including NMR measurements.     

TMC-86A, B and TMC-96, new proteasome inhibitors from Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094. I. Taxonomy, fermentation, isolation, and biological activities

TMC-86A, B and TMC-96, new 20S proteasome inhibitors with an epoxy-beta-aminoketone moiety, were isolated from the fermentation broth of Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094, respectively. TMC-86A, B and TMC-96 inhibited the chymotrypsin-like and peptidylglutamyl-peptide hydrolyzing activities of 20S proteasome with the following IC50 values: TMC-86A, 5.1 microM and 3.7microM; TMC-86B, 1.1 microM and 31 microM; TMC-96, 2.9 microM and 3.5 microM, respectively. TMC-86A, B and TMC-96 exhibited the weak inhibitory activity against the trypsin-like activity of 20S proteasome with IC50 values of 51 microM, 250 microM, and 36 microM, respectively. They did not inhibit m-calpain, cathepsin L, and trypsin at 100 microM, suggesting their high specificity for proteasome. Taxonomy of the producing strains is also described.     

TMC-264, a novel inhibitor of STAT6 activation produced by Phoma sp. TC 1674

A novel inhibitor of STAT6 activation, named as TMC-264 (1), was discovered from the fermentation broth of Phoma sp. TC 1674. Based on spectroscopic analyses, TMC-264 was found to be a novel tricyclic polyketide with chloro-1H-dibenzo[b,d]pyran-4,6-dione. TMC-264 suppressed expression of IL-4 driven luciferase and germline Cepsilon mRNA with IC50 values of 0.3 microM and 0.4 microM, respectively. TMC-264 exhibited a potent inhibitory activity against tyrosine phosphorylation of STAT6 with an IC50 value of 1.6 microM, whereas TMC-264 weakly inhibited tyrosine phosphorylation of STAT5 with an IC50 value of 16 microM, but did not inhibit the phosphorylation of STAT1 up to 40 microM. TMC-264 blocked formation of the complexes between phosphorylated STAT6 and STAT6 oligonucleotides in a dose dependent manner, while TMC-264 did not affect the formation of phosphorylated STAT1/STAT1 oligonucleotides complexes. These results suggested that TMC-264 selectively inhibited IL-4 signaling by interfering both of phosphorylation of STAT6 and binding of the phosphorylated STAT6 to the recognition sequence.     

Deacetylravidomycin M, a new inhibitor of IL-4 signal transduction, produced by Streptomyces sp. WK-6326. I. Taxonomy, fermentation, isolation and biological activities

Streptomyces sp. WK-6326, a soil isolate, was found to produce an inhibitor of interleukin (IL)-4 signal transduction. Two structurally related compounds, a novel one designated deacetylravidomycin M and the known deacetylravidomycin, were isolated from the culture broth by solvent extraction, silica gel column chromatography and HPLC. Deacetylravidomycin M inhibited IL-4-induced CD23 expression in U937 cells without any cytotoxic effect, whereas deacetylravidomycin showed no inhibitory activity.     

TMC-69, a new antitumor antibiotic with Cdc25A inhibitory activity, produced by Chrysosporium sp. TC1068. Taxonomy, fermentation and biological activities

A new antibiotic designated TMC-69 has been isolated from the fermentation broth of a fungal strain Chrysosporium sp. TC 1068. TMC-69 exhibited moderate in vitro cytotoxic activity. TMC-69-6H, a derivative of TMC-69 prepared by hydrogenation, possessed more potent in vitro cytotoxicity than TMC-69, and exhibited in vivo antitumor activity against murine P388 leukemia and B16 melanoma. TMC-69-6H was found to specifically inhibit Cdc25A and B phosphatases.     

TMC-66, a new endothelin converting enzyme inhibitor produced by Streptomyces sp. A5008.

A new endothelin converting enzyme (ECE) inhibitor, TMC-66 was isolated from the fermentation broth of Streptomyces sp. A5008. The structure of TMC-66 was elucidated by spectroscopic analyses to be a new member of benzo[a]naphthacenequinone class of antibiotics. TMC-66 had a highly selective inhibitory activity for ECE with an IC50 value of 2.9 microM. Taxonomy of the producing strain is also described.     

Nafuredin, a novel inhibitor of NADH-fumarate reductase, produced by Aspergillus niger FT-0554

A novel compound, nafuredin, was isolated as an inhibitor of anaerobic electron transport (NADH-fumarate reductase). It was obtained from culture broth of Aspergillus niger FT-0554 isolated from a marine sponge. The structure was elucidated as an epoxy-delta-lactone with an attached methylated olefinic side chain on the basis of spectral analysis.     

Characterization of nigerlysin, hemolysin produced by Aspergillus niger, and effect on mouse neuronal cells in vitro

Aspergillus niger produced a proteinaceous hemolysin, nigerlysin when incubated on sheep's blood agar (SBA) at both 23 and 37 degrees C. Nigerlysin was purified from tryptic soy broth (TSB) culture filtrate and found to have a molecular weight of approximately 72 kDa, with an isoelectric point of 3.45. Nigerlysin is heat stable up to 65 degrees C but unstable at 75 degrees C when incubated for 10 min. Circular dichroic analysis revealed that nigerlysin has an alpha helical structure. Exposure of mouse primary cortical neuronal cells to 0.1 microg ml(-1) of nigerlysin resulted in the rapid loss of their viability, approximately 50% in 24 h. The IC50 is estimated to be 0.037 microg ml(-1), or between 0.034 and 0.041 microg ml(-1) at the 95% confidence level.     

Terreulactones A,B, C,and D: novel acetylcholinesterase inhibitors produced by Aspergillus terreus. II. Physico-chemical properties and structure determination

Terreulactones A, B, C, and D, new meroterpenoid compounds with potent anti-acetylcholinesterase activity, were determined to be mixed polyketides-terpenoid structures by spectroscopic studies.     

Isolation and structural determination of phepropeptins A, B, C, and D, new proteasome inhibitors, produced by Streptomyces sp

We have isolated four related compounds named phepropeptins A, B, C, and D, as inhibitors of proteasome proposed to regulate many cellular functions. From an NMR analysis, the phepropeptins appeared as cyclic hexapeptides, differing in the two residues of the constituent amino acids from one another, with four conserved amino acid moieties. Based on an amino acid analysis, we synthesized two possible cyclic peptides to phepropeptin B that differ in the configurations. A comparison of the properties between the natural and synthesized compounds revealed that the structure of phepropeptin B was cyclo(-L-Leu-D-Phe-L-Pro-L-Phe-D-Leu-L-Val-). The phepropeptins showed inhibition to the proteasomal chymotrypsin-like activity but not to alpha-chymotrypsin.     

Nigerasperones A approximately C, new monomeric and dimeric naphtho-gamma-pyrones from a marine alga-derived endophytic fungus Aspergillus niger EN-13

Three new naphtho-gamma-pyrones, 5-hydroxy-6,8-dimethoxy-2-hydroxymethyl-4H-naphtho[2,3-b]pyran-4-one (1, nigerasperone A), 3,3'-dihydro-2,2',5,5'-tetrahy-droxy-8,8',10,10'- tetramethoxy-2,2'-dimethyl-(6',9-bi-4H-naphtho[1,2-b]pyran)-4,4'-dione (2, nigerasperone B), and 3'-hydro-2',5,5',8-tetrahydroxy-6,6',8'-trimethoxy-2,2'-dimethyl-(7,10'-bi-4H-naphtho[2,3-b]pyran)-4,4'-dione (3, nigerasperone C), together with nine related known compounds were characterized from Aspergillus niger EN-13, an endophytic fungus isolated from the marine brown alga Colpomenia sinuosa. Their structures were elucidated by detailed analysis of spectroscopic data and by comparison with literature reports. In the cytotoxic assay, these compounds did not show remarkable inhibitory effects against A549 and SMMC-7721 tumor cell lines. However, 3 and several known compounds showed weak antifungal activity against Candida albicans and moderate activity on DPPH scavenging.