Synthesis, Structure, and Biological Activity of New Azine‐Bridged Dinuclear Platinum(II) Complexes − a New Class of Anticancer Compounds

Abstract

AbstractA recently described new class of dinuclear platinum anticancer compounds, represented so far by the isomeric azine‐bridged complexes [{cis‐Pt(NH3)2Cl}2(µ‐pzn)]Cl2 (1) (pzn = pyrazine), [{cis‐Pt(NH3)2Cl}2(µ‐pmn)]Cl2 (2) (pmn = pyrimidine) and [{cis‐Pt(NH3)2Cl}2(µ‐pdn)](NO3)2 (3) (pdn = pyridazine), has been added to. Three new dinuclear complexes of this type, [{cis‐Pt(NH3)2Cl}2(µ‐2,5pzn)]Cl2 (4) (2,5pzn = 2,5‐dimethylpyrazine), [{cis‐Pt(NH3)2Cl}2(µ‐qzn)]Cl2 (5) (qzn = quinazoline), and [{cis‐Pt(NH3)2Cl}2(µ‐pht)](NO3)2 (6) (pht = phthalazine), have been newly synthesized and characterized by 1H and 195Pt 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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)