Cytotoxic effect of (1-methyl-1H-imidazol-2-yl)-methanamine and its derivatives in PtII complexes on human carcinoma cell lines: A comparative study with cisplatin

The synthesis and pharmacological characterisation of (1-methyl-1H-imidazol-2-yl)-methanamine and its derivatives in PtII complexes are described. Six out of eleven new PtII complexes showed a significant cytotoxic effect on NCI-H460 lung cancer cell line with EC50 values between 1.1 and 0.115mM, determined by MTT assay. Compound Pt-4a showed a particularly more potent cytotoxic effect than the previously described PtII complex with 2,2'-bipyridine, [Pt(bpy)Cl2], with an EC50 value equal to 172.7μM versus 726.5μM respectively, and similar potency of cisplatin (EC50=78.3μM) in NCI-H460 cell line. The determination of the intracellular and DNA-bound concentrations of 195Pt, as marker of the presence of the complexes, showed that the cytotoxic compound Pt-4a readily diffused into the cells to a similar extent of cisplatin and directly interacted with the nuclear DNA. Pt-4a induced both p53 and p21Waf expression in NCI-H460 cells similar to cisplatin. A direct comparison of the cytotoxic effect between compound Pt-4a and cisplatin on 12 different cancer cell lines demonstrated that compound Pt-4a was in general less potent than cisplatin, but it had a comparable cytotoxic effect on non-small-cell lung cancer NCI-H460 cells, and the colorectal cancer cells HCT-15 and HCT-116. Altogether, these results suggested that the PtII complex with 1-methyl-1H-imidazol-2-yl)-methanamine (compound Pt-4a), displayed a significant cytotoxic activity in cancer cells. Similarly to cisplatin this compound interacts with nuclear DNA and induces both p53 and p21waf, and thus it represents an interesting starting point for future optimisation of new PtII complexes forming DNA adducts.