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 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.
authors: Istituto di Scienze e Tecnologie Molecolari (ISTM), Consiglio Nazionale delle Ricerche (CNR), Via Golgi 19, I-20133 Milan, Italy.
authors: Leonardo
authors: L
authors: Manzoni
authors: Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133 Milan, Italy.
authors: Davide
authors: D
authors: Gornati
authors: Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133 Milan, Italy.
authors: Mattia
authors: M
authors: Manzotti
authors: Istituto di Scienze e Tecnologie Molecolari (ISTM), Consiglio Nazionale delle Ricerche (CNR), Via Golgi 19, I-20133 Milan, Italy.
authors: Silvia
authors: S
authors: Cairati
authors: 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.
authors: Alberto
authors: A
authors: Bossi
authors: 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.
authors: Daniela
authors: D
authors: Arosio
authors: Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, I-20133 Milan, Italy.
authors: Daniele
authors: D
authors: Lecis
authors: Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133 Milan, Italy. Electronic address: pierfausto.seneci@unimi.it.
authors: Pierfausto
authors: P
authors: Seneci
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D024101:Mitochondrial Proteins / Q000737:chemistry*; D018716:Molecular Mimicry; D013056:Spectrophotometry, Ultraviolet; D015032:Zinc / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002614:Chelating Agents; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D015032:Zinc
keywords: Apoptosis; Dual action compounds; Peptidomimetics; Smac mimetics; Zinc chelation