Bioactive heterocyclic natural products from actinomycetes having effects on cancer-related signaling pathways.

Abstract

During recent studies on the search for bioactive natural products from various types of organisms, the research group of the author has focused on targeting signaling molecules related to cancer-related biological pathways such as TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand), Wnt, and hedgehog signaling. For the screening studies conducted, natural product extracts including those of unexplored myxomycetes and marine nudibranches as well as medicinal plants collected from Thailand and Bangladesh have been evaluated. In addition, bioactive metabolites of actinomycete strains collected in several locations but mainly from the Chiba region of Japan were investigated, leading to the isolation of a series of new bioactive aromatic heterocyclic natural products, including izumiphenazines A-D from the cultured broth of Streptomyces sp. IFM 11204, izuminosides A-C from Streptomyces sp. IFM 11260, new pyranonaphthoquinones such as (+)-deacetylgriseusin A, yorophenazine, and yoropyrazone from Streptomyces sp. IFM 11307, and katorazone from Streptomyces sp. IFM 11299. The structures of these new compounds were elucidated on the basis of spectroscopic data interpretation, and their effects on cancer-related signaling pathways were evaluated. As a result, (+)-deacetylgriseusin A at 0.1 μM proved to be the most active in TRAIL-resistance overcoming activity, with 33 % decrease in cell viability in the presence of TRAIL (100 ng/cm3). Also isolated were fuzanins A-H, which are new carbamate- or pyridine-containing alkaloids, from Kitasatospora sp. IFM 10917, and a new tyrosine derivative, prenyltyrosine and its acetamide, with TRAIL-resistance overcoming activity from Streptomyces sp. IFM 10937. A screening study targeting enhancement of death-receptor 5 (DR5) promoter activity led to the identification of a known indole alkaloid, teleocidin A-2, which showed a 4.7-fold enhancement in DR5 promoter activity at 0.1 μM. Nonactins, griseoviridin, and nocardamines were isolated from the author’s collection of actinomycete strains using a screening procedure targeting Wnt signal inhibitory activity.