The
cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian
tumor cells, with moderately better IC50 values than for
cisplatin in the
cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with 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 accumulation, different effects at the level of cell cycle regulation, and reduced propensity for
DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to
DNA, which is typically required for an active
platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to
cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and
cisplatin in
tumor cells. The results of this work reinforce the idea that direct analogues of conventional
cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.