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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)]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 degrees C, the intrinsic binding constants for 1 and 2 are (4.6+/-0.2)x10(5) and (2.3+/-0.3)x10(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 microM) and it selectively induced apoptosis leading to cancer cell death with less than 5 % detectable necrosis.
AuthorsDik-Lung Ma, Chi-Ming Che
JournalChemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 9 Issue 24 Pg. 6133-44 (Dec 15 2003) ISSN: 0947-6539 [Print] Germany
PMID14679525 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Intercalating Agents
  • Organoplatinum Compounds
  • Polydeoxyribonucleotides
  • Pyridines
  • Triazines
  • platinum(II) 6-phenyl-2,2'-bipyridine
  • Poly dA-dT
  • poly(dC-dG)
  • DNA
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology)
  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cisplatin (pharmacology)
  • DNA (chemistry, drug effects)
  • Drug Screening Assays, Antitumor
  • Humans
  • Hydrogen Bonding
  • Intercalating Agents (chemistry, pharmacology)
  • Necrosis
  • Organoplatinum Compounds (chemistry, pharmacology)
  • Poly dA-dT (chemistry)
  • Polydeoxyribonucleotides (chemistry)
  • Pyridines (chemistry)
  • Triazines (chemistry)

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