Half-Sandwich Ir(III) and Os(II) Complexes of Pyridyl-Mesoionic Carbenes as Potential Anticancer Agents

A series of cationic chlorido arene-iridium(III) and arene-osmium(II) complexes with bidentate pyridyl functionalized mesoionic carbenes (MIC) of the 1,2,3-triazol-5-ylidene type have been prepared. The variations in the ligand structures include the position of the pyridyl substituent relative to the triazolylidene ring (N-wingtip vs C-wingtip), phenyl versus ethyl substituents, and incorporation of several functional groups at the phenyl substituents. Five complexes have been characterized by X-ray structural analysis. All complexes, including osmium(II) and ruthenium(II) analogues having a pyrimidyl in place of the pyridyl group, have been studied for their cytotoxic activity on a human cervical carcinoma HeLa cell line. Two of the compounds, Ir-5 and Ir-9, were the most cytotoxic with IC50 values of 7.33 mu M and 2.01 mu M, respectively. Examination of their cytotoxic effect on different cell lines revealed that they preferentially kill cancer over normal cells. The Ir-5 and Ir-9 compounds arrested cells in G2 and induced a dose-dependent increase in SubG0/G1 cell population. Apoptosis, as the primary mode of cell death, was confirmed by Annexin V/PI staining, detection of cleaved PARP, and caspases 3 and 7 activity upon treatment of HeLa cells with both compounds. The higher toxicity of Ir-9 is probably due to its increased accumulation in the cells compared to Ir-5. The role of glutathione (GSH) in the protection of cells against Ir-5 and Ir-9 cytotoxicity was confirmed by pretreatment of cells either with buthionine sulfoximine (inhibitor of GSH synthesis) or N-acetyl-cysteine (precursor in GSH synthesis).