On the stability and biological behavior of cyclometallated Pt(IV) complexes with halido and aryl ligands in the axial positions

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 22; pp. 5804 - 5815
• Main Authors: Escolà, Anna, Crespo, Margarita, López, Concepción, Quirante, Josefina, Jayaraman, Anusha, Polat, Ibrahim H, Badía, Josefa, Baldomà, Laura, Cascante, Marta
• Format: Journal Article
• Language: English
• Published: England 15.11.2016
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ligands; Molecular Structure; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Structure-Activity Relationship; Anticancer drugs; Platinum(IV); Cytotoxicity; Redox potential; Cyclometallated compounds; Platinum(II)
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.09.037

A series of cyclometallated platinum(IV) compounds (3a, 3a' and 3b') with a meridional [C,N,N'] terdentate ligand, featuring an halido and an aryl group in the axial positions has been evaluated for electrochemical reduction and preliminary biological behavior against a panel of human adenocarcinoma (A-549 lung, HCT-116 colon, and MCF-7 breast) cell lines and the normal bronquial epithelial BEAS-2B cells. Cathodic reduction potentials (shifting from -1.463 to -1.570V) reveal that the platinum(IV) compounds under study would be highly reluctant to be reduced in a biological environment. Actually ascorbic acid was not able to reduce complex 3a', the most prone to be reduced according its reduction potential, over a period of one week. These results suggest an intrinsic activity for the investigated platinum(IV) complexes (3a, 3a' and 3b'), which exhibit a remarkable cytotoxicity effectiveness (with IC values in the low micromolar range), even greater than that of cisplatin. The IC for A-549 lung cells and clog P values were found to follow the same trend: 3b'>3a'>3a. However, no correlation was observed between reduction potential and in vitro activity. As a representative example, cyclometallated platinum(IV) compound 3a', exercise its antiproliferative activity directly over non-microcytic A-549 lung cancer cells through a mixture of cell cycle arrest (13% arrest at G1 phase and 46% arrest at G2 phase) and apoptosis induction (increase of early apoptosis by 30 times with regard to control). To gain further insights into the mode of action of the investigated platinum(IV) complexes, drug uptake, cathepsin B inhibition and ROS generation were also evaluated. Interestingly an increased ROS generation could be related with the antiproliferative activity of the cyclometallated platinum(IV) series under study in the cisplatin-resistant A-549 lung and HCT-116 cancer cell lines.