Studies on Synthesis, Activity and Binding with DNA of a New Trinuclear Platinum Compound [{trans-PtCl(NH3)2}2{trans-Pt(thiazole)2}{H2N(CH2)6 NH2}2]Cl3(NO3)

Jehad      Al-Shuneigat; Yu      Qing; Philip      Beale; Keith      Fisher; Fazlul      Huq

Abstract

A new trinuclear platinum compound [{trans-PtCl(NH3)2}2{trans-Pt(thiazole)2}{H2N(CH2)6NH2}2]Cl3(NO3) has been synthesized and characterized. The activity of the compound against three human ovarian cancer cell lines A2780, A2780cisR and A2780ZD0473R, its cell uptake and level of binding with DNA have been determined. JH5 is found to be less active than cisplatin against parent A2780 cell line but more active than cisplatin against the A2780cisR and A2780ZD0473R resistant cell lines indicated by the lower resistance factors. The results indicate that at the level of its activity JH5 has been better able to overcome mechanisms of resistance operating in A2780cisR and A2780ZD0473R cell lines. JH5 has higher cellular accumulation of platinum than cisplatin in the A2780cisR and A2780ZD0473R resistant cell lines but lower than cisplatin in the parents A2780 cell line. Cisplatin binds with DNA forming mainly bifunctional intrastrand 1,2- Pt(GG) and 1,2-Pt(AG) adducts that cause local bending of DNA strand. In contrast, JH5 is expected to bind with DNA to form mainly interstrand long-range G-Pt..Pt..Pt(G) adducts that would induce more of a global change in DNA conformation.

Keywords: Cisplatin, polynucler platinum, ovarian cancer, A2780, thiazole, resistant factor, DNA, dose-limiting toxicity, sodium bicarbonate, Dhara method, potassium tetrachloroplatinate, JH5, silver nitrate, transplatin filtrate, microanalyses, spectral studies, atomic absorption spectroscopy, Biomedical Sciences, diffuse reflectance accessory, air-cooled DTGS detector, IR, Mass Spectrum, electrospray ionization, 1H NMR, DMSO (di-methylsulfoxide), molar conductivity, Cytotoxicity Assays, Platinum-DNA Binding, phosphatebuffered saline, atomic absorption spectrophotometer, Tris, –, HCl buffer, UV spectrophotometry, Gel Electrophoresis, agarose, drug-DNA mixtures, ethidium bromide, UV light, phosphodiester, dichloromethane, thia-zole ligands, electrostatic interaction, hydrogen bonding, drug efflux, pBR322 plasmid DNA, electrophoretograms, coalesced band, BamH1 digestion