Potent antimalarial activities of polyether antibiotic, X-206.

In the course of our screening program to discover antimalarial antibiotics, which are active against drug resistant Plasmodium falciparum in vitro and rodents infected with P. berghei in vivo, from the culture broth of microorganisms, we found a selective and potent active substance produced by an actinomycete strain K99-0413. It was identified as a known polyether antibiotic, X-206. We also compared the in vitro antimalarial activities and cytotoxicities of 12 known polyethers with X-206. Among them, X-206 showed the most selective and potent inhibitory effect against both drug resistant and sensitive strains of P. falciparum. Comparison of biological activities and ion-affinities of the above antibiotics suggests that monovalent cations play an important biological role for the intracellular growth of P. falciparum in parasitized erythrocytes. Moreover, X-206 showed potent in vivo antimalarial activity on the rodent model, though the therapeutic window was narrow compared with its selective toxicity in vitro. These observations are the first report of antimalarial activity of X-206.

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.

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.

Inhibition of phosphatidylinositol-specific phospholipase C activity by fluvirucin B2.

We isolated fluvirucin B2 from the culture broth of Streptomyces as an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). It inhibited PI-PLC of A431 cell cytosol with an IC50 of 1.6 micrograms/ml. Fluvirucin B2 also inhibited PI-PLC in cultured A431 cells, whereas it did not inhibit phosphatidylinositol synthesis and macromolecular synthesis markedly. It also inhibited epidermal growth factor-induced rapid rounding of A431 cells, in which PI turnover is involved.

Involvement of tyrosine kinase in growth factor-induced phospholipase C activation in NIH3T3 cells.

Tyrosine kinase inhibitors such as erbstatin and lavendustin derivative inhibited platelet-derived growth factor (PDGF)- and bombesin-induced inositol phosphate formation and phospholipase C (PLC) activation in quiescent NIH3T3 cells. However, bombesin-induced PLC activation was only partially inhibited by tyrosine kinase inhibitors, whereas PDGF-induced activation was completely. Moreover, although bombesin-induced PLC activation was partially inhibited by pertussis toxin alone, this toxin inhibited almost completely in the presence of tyrosine kinase inhibitors. Thus, tyrosine kinase was suggested to be involved in PDGF- and bombesin-induced PLC activation in a different manner.

Inhibition of EGF-induced phospholipase C activation in A431 cells by erbstatin, a tyrosine kinase inhibitor.

Erbstatin, a tyrosine kinase inhibitor, inhibited epidermal growth factor (EGF)-induced inositol phosphate production in cultured A431 cells. However, it did not inhibit ATP-induced inositol phosphate production. Cytosolic but not membrane-associated phospholipase C was activated by EGF, and erbstatin inhibited enhancement of the phospholipase C activity in EGF-treated cells. Thus, tyrosine kinase of A431 cells is suggested to be functionally involved in phospholipase C activation.