Putative dual action compounds (DACs 3a-d) based on azabicyclo[5.3.0]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.
4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents / L.P. Manzoni, A. Samela, S. Barbini, S. Cairati, M. Penconi, D. Arosio, D. Lecis, P. Seneci. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 27:11(2017 Jun 01), pp. 2336-2344.
Titolo: | 4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents | |
Autori: | MANZONI, LEONARDO PIERPAOLO (Primo) SENECI, PIERFAUSTO (Ultimo) (Corresponding) | |
Parole Chiave: | apoptosis; dual action compounds; peptidomimetics; Smac mimetics; zinc chelation; azabicyclo compounds; cell line, tumor; chelating agents; humans; intracellular signaling peptides and proteins; mitochondrial proteins; zinc; molecular mimicry; biochemistry; molecular medicine; molecular biology; 3003; drug discovery3003 pharmaceutical science; clinical biochemistry; organic chemistry | |
Settore Scientifico Disciplinare: | Settore CHIM/08 - Chimica Farmaceutica | |
Progetto: | Tumor-targeting peptidomimetics: synthesis and bio-medical applications | |
Data di pubblicazione: | 1-giu-2017 | |
Rivista: | ||
Tipologia: | Article (author) | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.bmcl.2017.04.032 | |
Appare nelle tipologie: | 01 - Articolo su periodico |
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