A bifunctional platinum(II) complex capable of intercalation and hydrogen-bonding interactions with DNA: Binding studies and cytotoxicity

The interactions of [Pt(CNN)(4-dpt)]PF6, (1; 4-dpt=2,4-diamino-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 20degreesC, the intrinsic binding constants for 1 and 2 are (4.6 +/- 0.2)x10(5) and (2.3 +/- 0.3)x 10(4) mol(-1) dm(3), 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, I is almost an order of magnitude less toxic to the normal cell line CCD-19Lu (IC50 = 176 +/- 1.7 mum) and it selectively induced apoptosis leading to cancer cell death with less than 5% detectable necrosis.