2. Academic Validation
  3. Dual action Smac mimetics-zinc chelators as pro-apoptotic antitumoral agents

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

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: pierfausto.seneci@unimi.it.
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.

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