Cladospolide D, a new 12-membered macrolide antibiotic produced by Cladosporium sp. FT-0012.

A new antibiotic termed cladospolide D was isolated along with the known cladospolides A and B from the fermentation broth of Cladosporium sp. FT-0012 by solvent extraction, ODS column chromatography and preparative HPLC. The structure of cladospolide D was deduced to be (E)-2-dodecen-5-hydroxy-11-olide-4-one. Cladospolide D showed antifungal activity against Pyricularia oryzae and Mucor racemosus.

Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor.

[structure: see text] Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor, has been accomplished by a convergent approach. The C1-C8 and C9-C18 segments were derived efficiently from D-glucose and (S)-(-)-2-methyl-1-butanol, respectively, coupled by stereoselective Julia olefination, and converted to nafuredin.

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.

An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria.

Infections with parasitic helminths are important causes of morbidity and mortality worldwide. New drugs that are parasite specific and minimally toxic to the host are needed to counter these infections effectively. Here we report the finding of a previously unidentified compound, nafuredin, from Aspergillus niger. Nafuredin inhibits NADH-fumarate reductase (complexes I + II) activity, a unique anaerobic electron transport system in helminth mitochondria, at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep. Thus, our study indicates that mitochondrial complex I is a promising target for chemotherapy, and nafuredin is a potential lead compound as an anthelmintic isolated from microorganisms.

Argadin, a new chitinase inhibitor, produced by Clonostachys sp. FO-7314.

A new chitinase inhibitor, designated as argadin (1), was isolated from the cultured broth of a fungal strain FO-7314. The strain was identified as Clonostachys sp. from the morphological characteristics. Argadin was purified from the cultured mycelium by a combination of cation exchange, adsorption and gel filtration chromatographic methods. The structure of argadin was elucidated as cyclo(Nomega-acetyl-L-arginyl-D-prolyl-homoseryl-histidyl-L- 2-aminoadipyl) in which homoseryl gamma-methylene bonded to histidyl alpha-amino residue. The IC50 value of argadin against Lucilia cuprina (blowfly) chitinase was 150 nM at 37 degrees C and 3.4 nM at 20 degrees C. Argadin arrested the moult of cockroach larvae upon injection into the ventral abdominal part.

Argifin, a new chitinase inhibitor, produced by Gliocladium sp. FTD-0668. I. Taxonomy, fermentation, and biological activities.

A new chitinase inhibitor, named argifin, was isolated from the cultured broth of a fungal strain FTD-0668. The strain was identified as Gliocladium sp. from morphological characteristics. The IC50 value of argifin against Lucilia cuprina chitinase was 3.7 microM. Argifin arrested the moult of cockroach larvae upon injection into the ventral abdominal part.

Arisugacins C and D, novel acetylcholinesterase inhibitors and their related novel metabolites produced by Penicilium sp. FO-4259-11.

The mutant of Penicillium sp. FO-4259, an arisugacins A and B producing strain, was found to produce a series of metabolites, designated arisugacins C, D, E, F, G and H, which were structurally related to arisugacins A and B. These compounds were isolated from the culture broth and the physico-chemical and biological properties were examined. The IC50 values of arisugacins C and D against acetylcholinesterase (AChE) were 2.5 microM and 3.5 microM, respectively. However arisugacins E, F, G and H did not inhibit AChE at 100 microM. Though they showed only weak or no activity against AChE compared with arisugacins A and B, they may be useful for the study of the structure-activity relationship.

Phenochalasins, inhibitors of lipid droplet formation in mouse macrophages, produced by Phomopsis sp. FT-0211.

Phomopsis sp. FT-0211, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. Structurally related new compounds designated phenochalasins A and B were isolated from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography and preparative HPLC. Phenochalasin A caused a dose-dependent reduction in the number and size of lipid droplets in macrophages without any cytotoxic effect at least up to 20 microm. On the other hand, phenochalasin B showed inhibition of lipid droplet formation with a severe cytotoxic effect on macrophages.

Roselipins, inhibitors of diacylglycerol acyltransferase, produced by Gliocladium roseum KF-1040.

Gliocladium roseum KF-1040, a marine isolate, was found to produce a series of new inhibitors of diacylglycerol acyltransferase (DGAT). Four active compounds, designated roselipins 1A, 1B, 2A and 2B, were isolated from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography and preparative HPLC. The highest production of roselipins was observed when cultured in the medium containing natural sea water. Roselipins inhibit DGAT activity with IC50 values of 15 approximately 22 microM in an enzyme assay system using rat liver microsomes.

Beauveriolides, specific inhibitors of lipid droplet formation in mouse macrophages, produced by Beauveria sp. FO-6979.

Beauveria sp. FO-6979, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. A new compound beauveriolide III was isolated along with a known compound beauveriolide I from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography, silica gel column chromatography and preparative HPLC. Beauveriolides I and III caused a reduction in the number and size of cytosolic lipid droplets in macrophages at 10 microM without any cytotoxic effect on macrophages.

Funalenone, a novel collagenase inhibitor produced by Aspergillus niger.

Funalenone, a phenalene compound that inhibits type I collagenase (MMP-1), was isolated from mycelium of Aspergillus niger FO-5904 by solvent extaction, ODS column chromatography, Sephadex LH-20 column chromatography and reversed phase HPLC. Funalenone inhibited 50% of type I collagenase activity at a concentration of 170 microM, but inhibited 18.3% and 38.7% against 72 kDa and 92 kDa type IV collagenase, respectively, at a concentration of 400 microM.

Erabulenols, inhibitors of cholesteryl ester transfer protein produced by Penicillium sp. FO-5637. I.Production, isolation and biological properties.

Penicillium sp. FO-5637, a soil isolate, was found to produce a series of inhibitors of cholesteryl ester transfer protein (CETP). Novel active compounds, designated erabulenols A and B, were isolated from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography and HPLC. Erabulenols A and B inhibit human CETP activity with IC50 values of 47.7 and 58.2 microM in an in vitro assay system containing 200 microM BSA, respectively.

Antimalarial activity of radicicol, heptelidic acid and other fungal metabolites.

In the course of our screening program for artemisinin-like antimalarial compounds from microorganisms, seven fungal metabolites such as radicicol and heptelidic acid were identified as active compounds. Some of them exhibited antimalarial activity in vitro against the human malaria parasite Plasmodium falciparum to the extent of approximately 1/10 as potent as artemisinin. Radicicol was moderately active in vivo against Plasmodium berghei in mice.

New brominated and halogen-less derivatives and structure-activity relationship of azaphilones inhibiting gp120-CD4 binding.

Novel brominated and halogen-less azaphilone (oxoisochromane) derivatives, 5-bromoochrephilone and dechloroisochromophilone IV, and known derivatives, dechloroisochromophilone III and isorotiorin, were isolated from the culture broth of a producing organism of isochromophilones I and II (azaphilones inhibiting gp120-CD4 binding), Penicillium multicolor FO-2338, fermented in a medium containing potassium bromide. Nineteen azaphilone-related compounds isolated from the above strain and from other fungi were tested for the inhibition of gp120-CD4 binding and the structure-activity relationship is discussed. Consequently, 5-bromoochrephilone is the strongest inhibitor (IC50, 2.5 microM). A halogen atom at C-5, a proton at C-8 and a diene structure in C-3 side chain of 6-oxoisochromane ring are necessary for gp120-CD4 binding.

Chemical synthesis and structural study of lincomycin sulfoxides and a sulfone.

Oxidation of lincomycin with dimethyldioxirane resulted in the sulfoxide-glycosides 3a and 3b, whose treatment with osmium tetraoxide and N-methylmorpholine-N-oxide afforded the same sulfone; 4. According to FAB-MS and CD investigations, the absolute configuration of the sulfur atom in 3a and 3b is R and S, respectively. The new, unsaturated antibiotic analog (6) derived from clindamycin exists in the 4C1 conformation. The antibiotic activities of the synthesized compounds were also studied.

Two new components of the aspochalasins produced by Aspergillus sp.

Aspergillus sp. FO-4282 was found to produce two new components of the aspochalasins. Their structures were determined by spectroscopic analyses.