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

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• 作者：Leonardo Manzoni^a ; Davide Gornati^c ; Mattia Manzotti^c ; Silvia Cairati^a ; Alberto Bossi^a ; ^b ; Daniela Arosio^a ; ^b ; Daniele Lecis^d ; Pierfausto Seneci^c ; ^{pierfausto.seneci@unimi.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Dual action compounds ; Smac mimetics ; Zinc chelation ; Apoptosis ; Peptidomimetics
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：26
• 期：19
• 页码：4613-4619
• 全文大小：963 K

文摘

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.