4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents |
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| Authors: | Leonardo Manzoni Alessandro Samela Stefano Barbini Silvia Cairati Marta Penconi Daniela Arosio Daniele Lecis Pierfausto Seneci |
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| Institution: | 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. 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 |
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| Abstract: | Putative dual action compounds (DACs 3a–d) based on azabicyclo5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn2+-chelating 2,2′-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn2+ chelation on in vitro activity of DPA-substituted DACs 3a–d was sometimes perceivable, but did not lead to strong cellular synergistic effects. In particular, the linker connecting DPA with the ABD scaffold seems to influence cellular Zn2+-chelation, with longer lipophilic linkers/DAC 3c being the optimal choice. |
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| Keywords: | Dual action compounds Smac mimetics Zinc chelation Apoptosis Peptidomimetics |
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