Dual action Smac mimetics-zinc chelators as pro-apoptotic antitumoral agents

Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0] decane Smac mimetic scaffolds (ABDs) linked to a Zn2+-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn2+ chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn2+ chelation. (C) 2016 Elsevier Ltd. All rights reserved.