A Bifunctional Platinum(II) Complex Capable of Intercalation and Hydrogen-Bonding Interactions with DNA: Binding Studies and Cytotoxicity

Abstract

The interactions of [Pt(CNN)(4-dpt)] PF6, (1; 4-dpt = 2,4-di-amino-6-(4-pyridyl)-1,3,5-triazine, HCNN = 6-phenyl-2,2′ -bipyridine) with double-stranded DNA, poly(dA-dT)2, and poly(dG-dC)2 were examined by spectroscopic, electrophoretic, and hydrodynamic methods. The spectroscopic data were analyzed with McGhee, van't Hoff, and Gibbs-Helmholtz equations. In a comparative study, [Pt(CNN)(py)]PF6 (2; py = pyridine) was prepared and the nature of its binding towards DNA was investigated [preliminary results: ChemBioChem 2003, 4, 62-68]. For reactions with calf thymus DNA at 20°C, the intrinsic binding constants for 1 and 2 are (4.6 ± 0.2) × 105 and (2.3 ± 0.3) × 104 mol-1 dm3, respectively. Results of DNA-binding reactions revealed that 1 and 2 preferentially bind to the AT sequence of duplex DNA. Intercalation is the preferred binding mode for 2, whereas both intercalation and minor-groove binding are observed for 1. Complex 1 is cytotoxic against a number of carcinoma cell lines, including KB-3-1, CNE-3, and HepG2, and remains potent against multidrug- or cisplatin-resistant KB-V-1 and CNE1 cell lines, for which the resistance ratios are 1.6 and 1.5, respectively. Importantly, 1 is almost an order of magnitude less toxic to the normal cell line CCD-19Lu (IC 50 = 176 ± 1.7 μm) and it selectively induced apoptosis leading to cancer cell death with less than 5% detectable necrosis.