Antitumor trans-N-Heterocyclic Carbene鈥揂mine鈥揚t(II) Complexes: Synthesis of Dinuclear Species and Exploratory Investigations of DNA Binding and Cytotoxicity Mechanisms

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• 作者：M茅lanie Chtchigrovsky ; Laure Eloy ; H茅l猫ne Jullien ; Lina Saker ; Evelyne S茅gal-Bendirdjian ; Joel Poupon ; Sophie Bombard ; Thierry Cresteil ; Pascal Retailleau ; Angela Marinetti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：2074-2086
• 全文大小：491K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

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.