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

Abstract

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 [¹H, ¹⁵N] 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(¹⁵NH₃)(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 1, 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 NH₃ 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 1 (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.