title: 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.
authors.affiliation: Department of Inorganic and Physical Chemistry and ‡Department of Molecular Reproduction and Genetics, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Koushambi
authors.initials: K
authors.lastname: Mitra
authors.forename: Shilpa
authors.initials: S
authors.lastname: Patil
authors.forename: Paturu
authors.initials: P
authors.lastname: Kondaiah
authors.forename: Akhil R
authors.initials: AR
authors.lastname: Chakravarty
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001555:Benzene Derivatives / Q000737:chemistry; D001692:Biological Transport; D002396:Catechols / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003603:Cytotoxins / Q000138:chemical synthesis / Q000494:pharmacology*; D004126:Dimethylformamide / Q000737:chemistry; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008024:Ligands; D008027:Light; D061986:MCF-7 Cells; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism
chemical_list: D001555:Benzene Derivatives; D002396:Catechols; D003603:Cytotoxins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008024:Ligands; D009944:Organoplatinum Compounds; D017319:Photosensitizing Agents; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D017382:Reactive Oxygen Species; C029569:diacetyldichlorofluorescein; D004126:Dimethylformamide; C009405:tetrabutylammonium; D005978:Glutathione