A novel isomerization on interaction of antitumor-active azole-bridged dinuclear platinum(II) complexes with 9-ethylguanine. Platinum(II) atom migration from N2 to N3 on 1,2,3-triazole

The reactions of the dinuclear platinum(II) complexes, [{cis-Pt(NH3)(2)}(2)(u-OH)(u-pz)](NO3)(2) (1, pz = pyrazolate), [{cis-Pt(NH3)(2)}(2)(u-OH)(u-1,2,3-ta-N1,N2)](NO3)(2) (2, 1,2,3-ta = 1,2,3-triazolate), and a newly prepared [{cis-Pt(NH3)(2)}(2)(u-OH)(u-4-phe-1,2,3-ta-N1,N2)](NO3)(2) (3, 4-phe-1,2,3-ta = 4-phenyl-1,2,3-triazolate), whose crystal structure was determined, with 9-ethylguanine (9EtG) have been monitored in aqueous solution at 310 K by means of H-1 NMR spectroscopy. The dinuclear platinum(II) complexes 1-3 each react with 9EtG in a bifunctional way to form 1:2 complexes, [{cis-Pt(NH3)(2)(9EtG-N7)}(2)(u-pz)](3+) (4), [{cis-Pt(NH3)(2)(9EtG-N7)}(2)(u-1,2,3-ta-N1,N3)](3+) (5), and [{cis-Pt(NH3)(2)(9EtG-N7)}(2)(u-4-phe-1,2,3-ta-N1,N3)](3+) (6). The reactions of 2 and 3 involve a novel isomerization, in which the Pt atom, initially bound to N2 on the 1,2,3-ta, migrates to N3 after the first substitution by N7 of 9EtG. This isomerization reaction has been unambiguously characterized by 1D and 2D NMR spectroscopy and pH titration. The reactions of 2 and 3 with 9EtG show faster kinetics, and the second-order rate constants (k) for the reactions of 1-3 are 1.57 x 10(-4), 2.53 x 10(-4), and 2.56 x 10(-4) M-1 s(-1), respectively, The pK(a) values at the N1H site of 9EtG were determined for 4-6 from the pH titration curves. Cytotoxicity assays of 1-3 were performed in L1210 murine leukemia cell lines, respectively sensitive and resistant to cisplatin. In the parent cell line, 2 and 3 exhibit higher cytotoxicity compared to cisplatin, especially, 2 is 10 times as active as cisplatin, 1 was found to be less cytotoxic than cisplatin, but still in the active range and more active than cisplatin in a cisplatin-resistant cell line.