Dual action Smac mimetics–zinc chelators as pro-apoptotic antitumoral agents. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Manzoni, Leonardo; Gornati, Davide; Manzotti, Mattia; Cairati, Silvia; Bossi, Alberto; Arosio, Daniela; Lecis, Daniele; Seneci, Pierfausto
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4613
• Page End: 4619
• Publication Date: 2016-10-01
• Subjects: Dual action compounds -- Smac mimetics -- Zinc chelation -- Apoptosis -- Peptidomimetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.065
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn 2+ -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, Zn 2+ ) 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 Zn 2+ 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 Zn 2+ chelation.