Synthesis, structure, and biological activity of new azine-bridged dinuclear platinum(II) complexes - a new class of anticancer compounds

A recently described new class of dinuclear platinum anticancer compounds, represented so far by the isomeric azine-bridged complexes [{cis-Pt(NH3)(2)Cl}(2)(mu-pzn)]Cl-2 (1) (pzn = pyrazine), [{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), has been added to. Three new dinuclear complexes of this type, [{cis-Pt(NH3)(2)Cl}(2)(mu-2,5pzn)]Cl-2 (4) (2,5pzn = 2,5-dimethylpyrazine), [{cis-Pt(NH3)(2)Cl}(2)(mu-qzn)]Cl-2 (5) (qzn = quinazoline), and [{cis-Pt(NH3)(2)Cl}(2)(mu-pht)](NO3)(2) (6) (pht = phthalazine), have been newly synthesized and characterized by H-1 and Pt-195 NMR spectroscopy. The interaction of the new compounds with 2 equiv. of 9EtG in D2O at 310 K has been investigated. Complexes 4 and 5 undergo substitution of both chloride ligands by 9EtG similarly to the related complexes 1 and 2, respectively. The methyl substituents on the pyrazine ring induce steric hindrance in 4 resulting in a slower reaction rate as compared to 1. Similarly to the case of 3, interaction of complex 6 with 9EtG results in cleavage of the Pt-N(pht) bond and subsequent formation of the polymeric species. A cytotoxicity assay of 4-6 has been performed on seven human tumor cell lines and on L1210 murine leukemia cell lines, sensitive and resistant to cisplatin. Compounds 4 and 5 exhibit lower cytotoxicity than the analogous complexes with unsubstituted azines. Complex 6 is more active: its cytotoxicity in the L1210 cell lines is similar to that of cisplatin. Analysis of nuclear DNA fragmentation in L1210 cells treated with the azine-bridged complexes 1-6 has been carried out. The results clearly indicate induction of apoptosis by all the compounds, implying considerable anticancer potential. The structure-activity relationship for this class of dinuclear platinum(ii) complexes is discussed. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.