The kinetics of substitution reactions of mixed platinum(II)-bis(nucleoside) complexes in aqueous solution in the presence of thiourea; X-ray crystal structure determination of cis-
In aqueous solution, bis(nucleoside) complexes formed by the reaction of cis-[Pt(NH3)2(H2O)2]2+ with an excess of either adenosine (ado) or a mixture of adenosine and guanosine (guo) undergo a slow N7--> N1 linkage isomerisation in the adenine moiety. The isomerisation probably involves the breaking and reformation of Pt-nucleoside bonds, thus favouring the more stable N1 binding mode of the adenine base. Dynamic processes due to the presence of adenosine in the platinum coordination sphere are slow on the NMR time scale. The N7 binding mode of PtII in cis-[Pt(NH3)2(ado-N7)2](ClO4)2. 3.5H2O was confirmed by X-ray crystal structure analysis. In both of the crystallographically independent cations, the PtII coordination sphere is almost ideally square planar, with typical Pt-N bond lengths and angles. The most significant difference between the two cations lies in the sugar conformation of the coordinated nucleosides. In one cation, both have an anti (-ap) conformation, whilst in the other cation one has an anti (-ap) conformation and the other a syn (+sc) conformation stabilised by a relatively strong H-bond. Substitution of the nucleoside(s) by thiourea follows an associative mechanism with only a negligible contribution by the solvent path. For symmetric complexes, the order of lability of different binding modes is ado-N1 <guo-N7 < ado-N7 for substitution of the first nucleoside, whereas for the second nucleoside it is guo-N7 < ado-N1 < ado-N7. For asymmetric complexes, the concomitant cleavage of different PtII-nucleoside bonds can be explained by two parallel reaction pathways. The change in the PtII coordination sphere affects the lability of the coordinating nucleosides in a different manner. The ado-N1 binding mode renders all binding modes less labile, whereas the ado-N7 mode has the opposite effect, and the guo-N7 mode increases the lability of the ado-N1 mode but decreases that of the ado-N7 mode. The mixed-ligand complex with (ado-N7)(guo-N7) mode is far more susceptible to attack by thiourea than the symmetric (guo-N7)2 species. These two species can be considered as models for the two most abundant Cisplatin-DNA adducts.
Mikola
M
Department of Chemistry, University of Turku, Finland.
Klika
KD
Arpalahti
J