Synthesis and evaluation of the antitumor activity of 2-amino-4-tetrahydroindazole-substituted benzamide derivatives as HSP90 inhibitors

Abstract

A new series of 2-cycloalkylamino-4–3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl benzamide analogs was synthesized and evaluated for their in vitro antineoplastic activity. These compounds are analogs of 2-(4-hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl) benzamide (AT533), which has been previously identified as a potent inhibitor of heat shock protein 90 (HSP90). These newly synthesized analogs showed moderate-to-excellent anti-cancer activity against Eca109, A549, and MDA-MB-231 human carcinoma cells. In particular, JD-10, JD-13, and JD-14 demonstrated more potent antineoplastic effects than AT533 in tumor cells. Molecular docking studies indicated that these novel derivatives bind to the ATP-binding pocket of HSP90.