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

Leonardo Manzoni; Davide Gornati; Mattia Manzotti; Silvia Cairati; Alberto Bossi; Daniela Arosio; Daniele Lecis; Pierfausto Seneci

doi:10.1016/j.bmcl.2016.08.065

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

Leonardo Manzoni, Davide Gornati, Mattia Manzotti, Silvia Cairati, Alberto Bossi, Daniela Arosio, Daniele Lecis, Pierfausto Seneci

Fondazione IRCCS Istituto Nazionale dei Tumori

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	4613-4619
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	19
DOIs	https://doi.org/10.1016/j.bmcl.2016.08.065
Publication status	Published - Oct 1 2016

Keywords

Apoptosis
Dual action compounds
Peptidomimetics
Smac mimetics
Zinc chelation

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2016.08.065

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title = "Dual action Smac mimetics–zinc chelators as pro-apoptotic antitumoral agents",

abstract = "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.",

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author = "Leonardo Manzoni and Davide Gornati and Mattia Manzotti and Silvia Cairati and Alberto Bossi and Daniela Arosio and Daniele Lecis and Pierfausto Seneci",

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doi = "10.1016/j.bmcl.2016.08.065",

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AU - Manzoni, Leonardo

AU - Gornati, Davide

AU - Manzotti, Mattia

AU - Cairati, Silvia

AU - Bossi, Alberto

AU - Arosio, Daniela

AU - Lecis, Daniele

AU - Seneci, Pierfausto

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Dual action compounds

KW - Peptidomimetics

KW - Smac mimetics

KW - Zinc chelation

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

Abstract

Keywords

ASJC Scopus subject areas

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