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

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Abstract
The reactions of the dinuclear platinum(II) complexes, [{cis-Pt(NH3)2}2(μ-OH)(μ-pz)](NO3)2 (1, pz = pyrazolate), [{cis-Pt(NH3)2}2(μ-OH)(μ-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(μ-OH)(μ-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 1H 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(μ-pz)]3+ (4), [{cis-Pt(NH3)2(9EtG-N7)}2(μ-1,2,3-ta-N1,N3)]3+ (5), and [{cis-Pt(NH3)2(9EtG-N7)}2(μ-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 × 10-4, 2.53 × 10-4, and 2.56 × 10-4 M-1 s-1, respectively. The pKa 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.