Cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) or cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza = 3-chloro-7-azaindole and 3-iodo-7-azaindole) are quite toxic to the ovarian tumor cells, with IC50 values that are moderately better compared to that observed for cisplatin in the cisplatin sensitive cell line A2780, and noticeably much lower in the cisplatin-resistant line A2780cisR .
We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors to those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular uptake, different effects at the level of cell cycle regulation and reduced propensity of DNA adducts to repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, typically required of an active platinum drug, but retarded reactivity toward sulfur-containing nucleophiles, such as those associated with cellular resistance mechanisms.
An important feature of the cis-PtII dichlorido complexes containing 7-azaindole halogeno-derivatives is that its spectrum of activity is characterized by remarkably low resistance factors so that this class of cisplatin analogues may therefore be effective against cancer types that are typically resistant to platinum therapy.