Synthesis and biological evaluation of geldanamycin analogs against human cancer cells.

Abstract

To find novel potential and less toxic benquinone anamycin heat shock protein 90 (Hsp90) inhibitors as anticancer agents, a limited series of 17-substituted or 17,19-disubstituted 17-demethoxygeldanamycin analogs were synthesized and tested for anti-proliferation activity against human cancer cells. Liver toxicity was also tested in vivo. Five 17-alkylamino-17-demethoxygeldanamycins and two 17-alkylamino-19-methylthio-17-demethoxygeldanamycins were synthesized from geldanamycin (GA) and 19-methylthiogeldanamycin (19-S(methyl)-GA), respectively. Anti-proliferation activities of the GA analogs were determined in MCF7, HeLa, HCT116 and HepG2 cells using the MTT method. Western blot and cell cycle analyses were performed for mechanistic study. The growth inhibition effect of potential geldanamycins was also investigated in normal Buffalo rat liver (BRL) cells. In vivo liver toxicity was tested in Institute of Cancer Research (ICR) mice by tail vein injection of the tested compounds. Most of the 17-alkylaminogeldanamycins exhibited obvious growth inhibition effects on multiple human cancer cell lines. The anti-proliferation activity of 19-methylthio-substituted geldanamycins was significantly lower compared with no 19-substitution geldanamycins in all tested cancer cells. The compound 1b (17-[2-(piperidinyl-1'-yl)-ethylamino]-17-demethoxygeldanamycin) exhibited the highest anti-proliferation activity in MCF7, HeLa and HCT116 cells, which was much more effective than GA and the developing Hsp90 inhibitor 17-AAG (17-allylamino-17-demethoxygeldanamycin). Meanwhile, compound 1b exhibited weaker growth inhibition effect on BRL cell line than GA and 17-AAG. 1b induced cell cycle arrest at the G2/M phase in MCF7 cells. Cleavage of PARP associated with apoptosis and degradation of the Hsp90 client protein Akt and Her2 was also induced by treatment of 1b in HeLa and MCF7 cell lines. In spite of the relatively weaker activity of 1b compared with GA and 17-AAG against HepG2 cells, 1b was further identified with lower hepatotoxicity than GA in vivo. Compound 1b is regarded as a new potential Hsp90 inhibitor with low hepatotoxicity for further study.