Antitumor trans-N-Heterocyclic Carbene-Amine-Pt(II) Complexes: Synthesis of Dinuclear Species and Exploratory Investigations of DNA Binding and Cytotoxicity Mechanisms.

Mélanie Chtchigrovsky (1) , Laure Eloy (1) , Hélène Jullien (1) , Lina Saker (2) , Evelyne Ségal-Bendirdjian (2) , Joel Poupon (3) , Sophie Bombard (4) , Thierry Cresteil (1) , Pascal Retailleau (1) , Angela Marinetti (1)

1 ICSN - Institut de Chimie des Substances Naturelles
2 U1007 - Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives
3 Laboratoire de Toxicologie Biologique, Hôpital Lariboisière
4 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques

A series of bimetallic [(NHC)PtX2]2(diamine) complexes have been prepared as a new chemotype for potential anticancer agents. These complexes display an uncommon set of structural features as far as they combine two bifunctional, trans-configured platinum centers. They display cytotoxic activities in the micromolar range on many cancerous cell lines and do not cross-react with cisplatin in A2780/DDP cell lines. They bind slowly to double-stranded DNAs, giving monoadducts as the major products. Pathways for cellular toxicity have been investigated for both mono- and bimetallic trans-(NHC)PtX2(amine) complexes. It has been highlighted that, unlike cisplatin, these complexes do not induce cell cycle arrest. They trigger apoptosis in A2780 cells by a pathway involving translocation of apoptosis-inducing factor and caspase 12 to the nucleus. Moreover, bimetallic complexes may induce necrosis.

Domaines: Chimie organique

Mélanie Chtchigrovsky, Laure Eloy, Hélène Jullien, Lina Saker, Evelyne Ségal-Bendirdjian, et al.. Antitumor trans-N-Heterocyclic Carbene-Amine-Pt(II) Complexes: Synthesis of Dinuclear Species and Exploratory Investigations of DNA Binding and Cytotoxicity Mechanisms.. Journal of Medicinal Chemistry, 2013, 56 (5), pp.2074-86. ⟨10.1021/jm301780s⟩. ⟨hal-00816591⟩