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]NO3 1, [Pt(en)(MeCO-Met-S)(2)][NO3](2) 2 (en = ethane-1,2-diamine, MeCO-Met = N-acetyl-L-methionine) and their N-15 analogues (1n and 2n) have been prepared and characterized by H-1,C-13 and two-dimensional [H-1,N-15] spectroscopy. Complex 1 (half-life 3.9 h at 310 K) hydrolysed more slowly than [Pt(en)Cl-2], whereas 2 was stable in water. The reaction of 1n with guanosine 5'-monophosphate (5'-GMP) gave a stable mixed-ligand complex [Pt([N-15]en){MeCO-Met(1-)-S}(5'-GMP-N-7)](+), and the reaction with guanylyl(3'-5')guanosine (GpG) gave two different monofunctional adducts [Pt([N-15]en){MeCO-Met(1-)-S}(GpG-N-7)](+), 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([N-15]){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.