Studies on new tumour active platinum compounds

Abstract

Four mononuclear /ram-planaramineplatinum complexes code named JH1, JH2, JH3, and JH4, and two trinuclear complexes code named JH5 and JH6 have been prepared and characterised based on elemental analyses, IR, mass and *H NMR spectral measurements. The activity of the compounds against human ovarian cancer cell lines A2780, A2780clsR and A2780ZD0473R, cell uptake, level of binding with DNA and nature of interaction with pBR322 plasmid DNA and salmon sperm DNA have been determined. Among the mononuclear complexes JH1 is found to be most active: four times more active than cisplatin in the resistant cell line A2780clsR and six times more active in the resistant cell line A2780zdo473r. Between the two trinuclear compounds, JH6 is found to be more active than JH5 in all three ovarian cancer cell lines A2780, A2780usR and A2780zdo473R. JH6 is also more active than cisplatin in all the ovarian cell lines A2780, A2780cisR and A2780ZD0473R: two times more active than cisplatin in the parent cell line A2780, three times more active in the resistant cell line A2780cisR and about two times more active in the resistant cell line A2780ZD0473R. All of the designed complexes have lower resistance factors than cisplatin as applied to the resistant cell lines, indicating that at the level of their activity the compounds have been better able to overcome mechanisms of resistance operating in A2780usR and A2780ZD0473R cell lines. Among the mononuclear complexes, JH1 has the highest level of binding with DNA in all three ovarian cancer cell lines following 24 h of incubation, in line with the highest activity of the compound. The higher cytotoxicity of JH6 over JH5 is not found to be in line with the corresponding platinum-DNA binding levels. However, binding of JH6 to DNA is believed to be more sequence dependent than that of JH5, influencing downstream processes such as protein recognition, cell cycle arrest, DNA repair and other cellular events; this may explain why JH6 is more cytotoxic than JH5. While JH1, JH2, JH3 and JH4 are expected to form mainly mono functional adducts, 1,2-interstrand adduct, and 1,3-intrastrand adducts with DNA, JH5 and JH6 are expected to form longrange intra- and inter-strand adducts. Covalent and non-covalent interactions associated with the formation of the adducts would cause more of a global change in DNA conformation and also DNA damage as is observed in the interaction of increasing concentrations of the compounds with pBR322 plasmid DNA. XIII