Chemistry and bioactivity on P19 neuron-like cells of Geldanamycins

Abstract

Geldanamycin (1), the antitumor antifungal ansamycin, was isolated from the fermentation broth of Streptomyces hygroscopicus var. geldanus. Geldanamycin (1) was later obtained in high yield from the fermentation broth of Streptomyces sp. TRA9875-2 from the mangrove forest along the Andaman coast, Trang province, Thailand. Eighteen geldanamycin derivatives were mainly prepared by modification at the quinone moiety. Their chemical structures were determined by analyses of ID-NMR, 2D-NMR, MS, and UV spectral data as well as comparison with the literatures. The biological activities on P19 cells and P19 neuron-like cells of geldanamycin derivatives were evaluated. The results revealed that at 1 nM concentration, 1, 17-O-ethyl-17-O-demethylgeldanamycin (6), 17-O-n-propyl-17-O-demethylgeldanamycin (8), 17-O-benzyl-17-O-demethylgeldanamycin (9), and 19-O-methylgeldanamycin (18), exhibited no cytotoxicity on P19 cells, but possessed neuritogenic activity on P19 neuron-like cells. They also protected P19 neuron-like cells cultures from toxicity of the anticancer agent taxol at IC₅₀ of 0.65 µM. Among the neuritogenic active compounds, only 18 showed no cytotoxicity and neurotoxicity at higher concentration of 10 µM. Compounds 1, 6, 8, and 9 exhibited cytotoxicity on P19 cells and neurotoxicity on P19 neuron-like cells at IC₅₀ of 0.1 µM and 2.0 µM, 0.1 µM and 1.6 µM, 0.2 µM and 6.7 µM, and 0.5 µM and >10 µM, respectively.