Studies on the activity of two Trans-planaramine platinum(II) complexes coded as DH4 and DH5 in human ovarian tumour models.

In this article, we report the synthesis and the in vitro activity of trans-bis(2-methylimidazole)dichloroplatinum(II) (coded as DH4) and trans-(ammino)(2,3-diaminopyridine) dichloroplatinum(II) (coded as DH5) in the human ovarian tumour models. DH4 is less active than cisplatin against the parental A2780 cell line but more active than cisplatin against the resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) line. In contrast, DH5 is less active than cisplatin against all three cell lines. The higher activity of DH4 than cisplatin in the A2780(cisR) cell line is in line with the associated higher platinum-DNA binding level. Whereas cisplatin binds with DNA, forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH4 and DH5 are expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH4 and DH5 are less able to prevent BamH1 digestion than cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than do DH4 and DH5, although DH5 is more damaging to DNA. The difference in the activity of DH4 and DH5, with 2-methylimidazole and 2,3-diaminopyridine respectively as carrier ligands, can be seen to illustrate structure-activity relationships.