Kinetic control of reactions of a sterically hindered platinum picoline anticancer complex with guanosine 5′-monophosphate and glutathione

Kinetic studies (296 K, 0.1 M NaClO4, pH 6-7) of reactions of the anticancer complex cis-[PtCl2(NH3)(2-pic)] 1 (AMD473) (2-pic = 2-picoline) with guanosine 5'-monophosphate (5'-GMP) and the tripeptide glutathione (GSH) using 2D [H-1, N-15] HSQC NMR spectroscopy have been made, and compared to reactions of the isomeric complex cis-[PtCl2(NH3)(3-pic)] 2. Reactions with 5'-GMP followed two pathways with either hydrolysis trans to NH3 or picoline as the first step, with subsequent formation of Cl/GMP and H2O/GMP intermediates, and cis-[Pt((NH3)-N-15)(pic)(5'-GMP-N7)(2)](2+) as the final product. Eight rate constants were determined for each starting platinum complex 1 and 2. The rates of ligand substitution (Cl- by H2O and H2O by 5'-GMP) cis to 2-picoline were 2-12 times slower than the same ligand substitution cis to 3-picoline. This was also the case for ligand substitution trans to 2-picoline (2-3 times slower), except that when 5'-GMP was present as the cis ligand (second stage of substitution) the rate of substitution was enhanced for the 2-picoline complex. Slow rotation about the Pt-N picoline bond (0.62 s(-1)) and fast rotation about Pt-N7 GMP bonds on the NMR timescale were observed at 296 K for the bis(GMP) adduct of complex I, while these were both fast for the analogous adduct of complex 2. Reactions of GSH with 1 were ca. 3 times slower than those with 2, and appeared to proceed via aquated intermediates with initial substitution trans to 2-picoline for 1 and trans to NH, for 2, but no kinetic analyses were attempted due to the complexity of the reactions. Both mono- and bis-GMP adducts were observed during competitive reactions of GSH and 5'-GMP with complex I (molar ratio: 2:2: 1) at pH 7, 296 K. These features of the chemistry of 1 may play an important role in its altered spectrum of biological activity compared to cisplatin.