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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Synthesis, characterization and biological activity of new cyclometallated platinum(iv) complexes containing a
Mònica Solé1, Cristina Balcells, Margarita Crespo
1Departament de Química Inorgànica i Orgànica, Secció de Química Inorgànica, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028-Barcelona, Spain. margarita.crespo@qi.ub.es.
Abstract:
The synthesis of three new cyclometallated platinum(ii) compounds containing a para-tolyl ligand and a tridentate [C,N,N'] (cm1) or a bidentate [C,N] ligand and an additional ligand such as SEt2 (cm2) or PPh3 (cm3) is reported. The X-ray molecular structure of platinum(ii) compound cm3 is also presented. Intermolecular oxidative addition of methyl iodide or iodine upon cm1, cm2 and cm3 produced six novel cyclometallated platinum(iv) compounds. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), DNA interaction, topoisomerase I, IIα, and cathepsin B inhibition, and cell cycle arrest, apoptosis and ROS generation of the investigated complexes are presented. The best results for antiproliferative activity were obtained for platinum(iv) compounds cm1MeI and cm1I2 arising from oxidative addition of methyl iodide and iodine, respectively, to cm1. Cyclometallated platinum(iv) compounds cm1MeI and cm3MeI induce significant changes in the mobility of DNA and, in addition, cm1MeI, cm3MeI and cm1I2, showed considerable topoisomerase IIα inhibitory activity. Moreover, the compounds exhibiting the higher antiproliferative activity (cm1MeI and cm1I2) were found to generate ROS and to supress HCT-116 colon cancer cell growth by a mixture of cell cycle arrest and apoptosis induction. 1H NMR experiments carried out in a buffered aqueous medium (pH 7.40) indicate that compound cm1MeI is not reduced by common biologically relevant reducing agents such as ascorbic acid, glutathione or cysteine.
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