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

  • Bioorg Med Chem Lett. 2016 Oct 1;26(19):4613-4619. doi: 10.1016/j.bmcl.2016.08.065.
Leonardo Manzoni  1 ,  Davide Gornati  2 ,  Mattia Manzotti  2 ,  Silvia Cairati  1 ,  Alberto Bossi  3 ,  Daniela Arosio  3 ,  Daniele Lecis  4 ,  Pierfausto Seneci  5
Affiliations
  • 1. Istituto di Scienze e Tecnologie Molecolari (ISTM), Consiglio Nazionale delle Ricerche (CNR), Via Golgi 19, I-20133 Milan, Italy.
  • 2. Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133 Milan, Italy.
  • 3. Istituto di Scienze e Tecnologie Molecolari (ISTM), Consiglio Nazionale delle Ricerche (CNR), Via Golgi 19, I-20133 Milan, Italy; SmartMatLab, Centre, Via Golgi 19, I-20133 Milan, Italy.
  • 4. Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, I-20133 Milan, Italy.
  • 5. Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133 Milan, Italy. Electronic address: [email protected].
PMID: 27578248 DOI: 10.1016/j.bmcl.2016.08.065
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.

Keywords
Apoptosis; Dual action compounds; Peptidomimetics; Smac mimetics; Zinc chelation.