Stabilization of monofunctional platinum–nucleotide adducts: reactions of N-acetyl- L -methionine complexes with guanosine 5′-monophosphate and guanylyl(3′–5′)guanosine

The complexes [Pt(en)MeCO-Met-S)Cl]NO31, [Pt(en)(MeCO-Met-S)2][NO3]22(en = ethane-1,2-diamine, MeCO-Met =N-acetyl-L-methionine) and their 15N analogues (1n and 2n) have been prepared and characterized by 1H, 13C and two-dimensional [1H, 15N] spectroscopy. Complex 1(half-life 3.9 h at 310 K) hydrolysed more slowly than [Pt(en)Cl2], whereas 2 was stable in water. The reaction of 1n with guanosine 5′-monophosphate (5′-GMP) gave a stable mixed-ligand complex [Pt([15N]en){MeCO-Met(1–)-S}(5′-GMP-N7)]+, and the reaction with guanylyl(3′-5′)guanosine (GpG) gave two different monofunctional adducts [Pt([15N]en){MeCO-Met(1–)-S}(GpG-N7)]+, due to platination of either 3′- or 5′-G, with a preferential formation of one over the other (ratio 60:40). During the initial stages of the reaction the chelated complex [Pt([15N]en){MeCO-Met(2–)-S,N}]3 was also observed, which subsequently reacted with 5′-GMP or GpG via ring opening to give monofunctional adducts. Reactions of complex 2 with 5′-GMP and GpG also lead to such adducts, with release of MeCO-Met. Little conversion of monofunctional adducts into bifunctional adducts was observed. Methionine and its derivatives could play a role in the trapping of monofunctional adducts of platinum anticancer drugs with DNA in vivo.