2-(Phenylazo)pyridineplatinum(II) Catecholates Showing Photocytotoxicity, Nuclear Uptake, and Glutathione-Triggered Ligand Release

Abstract

Platinum(II) complexes [Pt(pap)(an-cat)] (1) and [Pt(pap)(py-cat)] (2) with 2-(phenylazo)pyridine (pap), 4-[2-[(anthracen-9-ylmethylene)amino]ethyl]benzene-1,2-diol (H2an-cat), and 4-[2-[(pyren-1-ylmethylene)amino]ethyl]benzene-1,2-diol (H2py-cat) were prepared, and their photoinduced cytotoxicity was studied. The complexes were found to release catecholate ligand in the presence of excess glutathione (GSH), resulting in cellular toxicity in the cancer cells. The catecholate complex [Pt(pap)(cat)] (3) was prepared and used as a control. Complex 3, which is structurally characterized by X-ray crystallography, has platinum(II) in a distorted square-planar geometry. The complexes are redox-active, showing responses near 0.6 and 1.0 V versus SCE in N,N-dimethylformamide/0.1 M tetrabutylammonium perchlorate corresponding to a two-step catechol oxidation process and at −0.3 and −1.3 V for reduction of the pap ligand. Complex 1 showed remarkable light-induced cytotoxicity in HaCaT (human skin keratinocytes) and MCF-7 (human breast cancer) cells, giving IC50 value of ∼5 μM in visible light of 400–700 nm and >40 μM in the dark. The 2′,7′-dichlorofluorescein diacetate (DCFDA) assay showed the generation of reactive oxygen species (ROS), which seems to trigger apoptosis, as is evident from the annexin V–fluorescein isothiocyanate (FITC)/propidium iodide (PI) assay. The fluorescence microscopic images showed significant nuclear localization of the complexes and free ligands. A mechanistic study revealed possible reduction of the coordinated azo bond of pap by cellular GSH, releasing the catecholate ligand and resulting in remarkable photochemotherapeutic action of the complexes.