Hsp90 Inhibitors(National Academy of Sciences of Belarus)

A series of 2-benzyl-4-substituted-2-azabicyclo[3.2.1]octanes, derived from the E-F ring of aconitine scaffold, were designed as potential anticancer agents. Utilizing two key reactions, asymmetric aza-Diels-Alder addition and S_N2 type ring expansion, to construct the core bicyclic skeleton, forty-one target compounds (11a-v and 13a-s) were successfully synthesized. Most of the target compounds exhibited considerable antiproliferative effects against four cancer cell lines (A549, HT-29, HepG2 and MDA-MB 231) with low IC₅₀ values. Among them, compound 13l showed the most potent antiproliferative activity against HT-29 colorectal cancer (CRC) cells, and displayed significant heat shock protein 90 (Hsp90) inhibitory activity. Molecular modeling studies supported the experimental results and the key interactions were identified. Further investigation indicated that 13l could effectively suppress the proliferation and migration of HT-29 cells, along with inducing cell cycle arrest and mild apoptosis via down-regulation of CDK12, CDK13 and Bcl-2 protein expressions, and up-regulation of Bax. Mechanistic studies revealed that 13l could inhibit Hsp90 to destabilize EGFR and suppress the activation of the EGFR-Akt signaling pathway to reduce proliferation of HT-29 cells. Consistent with in vitro results, 13l significantly repressed tumor growth in an HT-29 xenograft mouse model without causing evident cytotoxicity. Therefore, 13l could be considered as a novel and potentially effective candidate for the future treatment of CRC.