New isomeric azine-bridged dinuclear platinum(II) complexes circumvent cross-resistance to cisplatin

Four new isomeric azine-bridged complexes ([{cis-Pt(NH3)(2)Cl}(2)(mu-pzn)]Cl-2(1a) (pzn = pyrazine) and its corresponding nitrate salt (1b), [{cis-Pt(NH3)(2)Cl}(2)(mu-pmn)]Cl-2 (2) (pmn = pyrimidine), and [{cis-Pt(NH3)(2)Cl}(2)(mu-pdn)](NO3)(2) (3) (pdn = pyridazine) have been newly synthesized as potential anticancer compounds. These complexes have been characterized by H-1 and Pt-195 NMR spectroscopy, and also the X-ray crystal structure of 1b has been determined. The reactions of la, 2, and 3 with guanosine-5'-monophosphate (GMP) have been monitored and kinetically investigated in D2O solutions at 310 K using 1H NMR spectroscopy. Both la and 2 react with 2 equiv of GMP to form 1:2 complexes. The reactions involve a stepwise direct substitution of chloride ligands by GMP, with similar reaction rates for both complexes. On the other hand, the reaction of 3 with GMP results in the cleavage of one of the Pt-N(pyridazine) bonds to form an N7,O6-platinated polymer. The reaction products have been separated and have been characterized by H-1 and Pt-195 NMR spectroscopy. A cytotoxicity assay of the azine-bridged complexes (1a, 1b, 2, and 3) has been performed on human tumor cell lines and two L1210 murine leukemia cell lines (one sensitive to and one resistant to cisplatin). In general, the complexes show lower cytotoxicity than cisplatin for the human tumor cell lines except for the IGROV cell line. Their cytotoxicity for the mouse cell lines is comparable to or higher than that of cisplatin. Furthermore, these complexes appeared to largely or partly overcome the cross-resistance to cisplatin. Implications of these findings are discussed in the context of a structure- activity relationship for this class of compounds.