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A Bifunctional Platinum( II ) Complex Capable of Intercalation and Hydrogen‐Bonding Interactions with DNA: Binding Studies and Cytotoxicity
Author(s) -
Ma DikLung,
Che ChiMing
Publication year - 2003
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200304964
Subject(s) - intercalation (chemistry) , dna , chemistry , cytotoxicity , bifunctional , stereochemistry , cisplatin , pyridine , biochemistry , medicinal chemistry , biology , in vitro , organic chemistry , chemotherapy , genetics , catalysis
The interactions of [Pt(CNN)(4‐dpt)]PF 6 , ( 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)]PF 6 ( 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)×10 5 and (2.3±0.3)×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, 1 is almost an order of magnitude less toxic to the normal cell line CCD‐19Lu (IC 50 =176±1.7 μ M ) and it selectively induced apoptosis leading to cancer cell death with less than 5 % detectable necrosis.