Synthesis, Activity and Binding with DNA of [{trans-PtCl(NH ) }2μ-{trans- Pd(4-hydroxypyridine) (H N(CH ) NH ) ]Cl (TH8)

Fazlul      Huq; Hasan      Tayyem; Jun   Qing   Yu; Philip      Beale; Keith      Fisher

Abstract

This paper describes the synthesis, characterization, cytotoxicity of a new trinuclear Pt-Pd-Pt complex code named TH8 containing two 4-hydroxypyridine ligands bound to the central metal ion. In addition to its activity against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, level of DNA-binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. TH8 is found to be less active than cisplatin against the parent cell line A2780 but is more active against the cisplatin-resistant cell line A2780cisR. Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780cisR, and A2780 and A2780ZD0473R are 12.9 and 3.0 respectively, the corresponding values for TH8 are 1.4 and 2.1. The results suggest that TH8 has been better able to overcome the resistance operating in A2780cisR cell line. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH8 is expected to bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation.

Keywords: Cisplatin, BBR3464, 4-hydroxypyridine, Ovarian cancer, MTT

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