Kinetic analysis of and platinum(II) migration in the reactions of tetrazolato-bridged dinuclear platinum(II) complexes with nucleotides.

The series of tetrazolato-bridged complexes with the formula [{cis‑Pt(NH3)2}2(μ-OH)(μ-5-H-tetrazolato-N1,N2)]2+ (5-H-X) or [{cis‑Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]n+ (R=H (5-H-Y), CH3 (1), CH2COOCH2CH3 (2), CH2COO- (3), n=2 (5-H-Y, 1, 2) or 1 (3)) are promising candidate complexes for formulation as next-generation platinum-based anticancer drugs that form multimodal bindings with DNA molecules. These multimodal bindings involve both non-covalent and covalent interactions, the latter of which are acknowledged to be essential for platinum-based drugs to exert their anticancer activity. In the present study, the tetrazolato-bridged complexes reacted with two molar equivalents of guanosine-5'-monophosphate (GMP) to yield the 1:2 reaction products [{cis‑Pt(NH3)2(GMP-N7)}2(μ-5-R-tetrazolato-N1,N3)]2- or 1-. This reaction was accompanied by an intramolecular Pt(II) migration that contributed to the formation of diverse DNA crosslinking, such as interhelical crosslinks. The second-order reaction rate constants for the reactions performed in phosphate-buffered D2O solution showed that the reactivity of the complexes decreased in the order 5-H-X≳5-H-Y>2≳1>3 and that reactivity was correlated with the cytotoxicity of the complexes. A similar result was obtained for the reaction of the complexes with calf thymus DNA in which the formation of covalent DNA adducts was quantified by means of inductively coupled plasma mass spectrometry. These results suggest that overall charge affects the kinetics of the reactions of platinum complexes with GMP and calf thymus DNA. Thus, the positive charge of the complexes affects not only the non-covalent but also the covalent interactions between the complexes and nucleotides and DNA, which are negatively charged molecules.