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

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.