Replacement of the ammine group in antitumor
cisplatin by a heterocyclic
ligand (
piperidine,
piperazine, or 4-
picoline) results in reduction of cytotoxicity in human
ovarian cancer cells.
DNA is generally believed to be a major pharmacological target of antitumor
platinum complexes. Therefore, we examined conformation of
oligodeoxyribonucleotide duplexes containing a cross-link of cis-[PtCl(2)(NH(3))(
piperidine)], their recognition by
high mobility group proteins, and nucleotide excision repair; that is, some of the processes that may mediate antitumor effects of
platinum drugs. The replacement does not affect the
DNA binding mode including conformational alterations and excision of the cross-links. The results suggest that in certain
cancer cells the lower cytotoxicity of cis-[PtCl(2)(NH(3))(
piperidine)] might be partially associated with reduced affinity of the
high mobility group proteins to the major intrastrand cross-links of this analogue relative to the same adducts of
cisplatin. Besides this and a number of other biochemical factors, the reduced intracellular accumulation with subsequent effects on the level of
DNA platination in the cells may also contribute to the reduced cytotoxicity of cis-[PtCl(2)(NH(3))(
piperidine)]. The results support the view that the concept based on the design of the complexes structurally derived from
cisplatin that do not present an altered
DNA binding mode may be less effective in the search for new
platinum drugs that would overcome
cisplatin resistance.