Chelate-ring-opened adducts of [Pt(en)(Me-Mal-O,O′)] (en = ethane-1,2-diamine, Me-Mal = 2-methylmalonate) with methionine derivatives: relevance to the biological activity of platinum anticancer agents

Abstract

The anticancer drug carboplatin [Pt(cbdca-O,O′)(NH ₃ ) ₂ ] which contains the chelated dicarboxylate ligand cbdca, cyclobutane-1,1-dicarboxylate, may be activated in vivo by reaction with sulfur ligands. The reactions between the analogue [Pt(en)(Me-Mal-O,O′)] 1 (en = ethane-1,2-diamine, Me-Mal = 2-methylmalonate) and the methionine derivatives N-acetyl-L-methionine (Ac-Met), glycyl-L-methionine (Gly-Met) and L-methionylglycine (Met-Gly) have been studied at pH 7 and 4, 310 K, using ¹ H and two-dimensional [ ¹ H, ¹⁵ N] heteronuclear single quantum coherence NMR spectroscopy and HPLC. The ring-opened species [Pt(en)(Me-Mal-O)(L-S)] (L = Ac-Met, Gly-Met or Met-Gly) containing monodentate malonate and S-bound monodentate methionine ligands were predominant in solution after 2 h. The second-order rate constant for the ring-opening reaction of 1 with Ac-Met at pH 6.56 was determined to be (1.48 ± 0.03) × 10 ^{- 1} s ^-1 M ^-1 , and was similar for reactions with Gly-Met. Methylmalonate α-CH deuteriation rates were determined to be free Me-Met > ring-opened complex 1. Molecular-mechanics modelling suggested that hydrogen bonding between the free carboxylate group of monodentate Me-Mal and the co-ordinated amine groups, and between the two ring-opened ligands may contribute to the stability of the mixed-ligand adducts. However, in the case of Met-Gly, the ring-opening rate [(5.26 ± 0.10) × 10 ^-2 s ^-1 M ^-1 ] was nearly three times slower than that for the reaction of 1 with Ac-Met. In contrast, the ring-closure rate of [Pt(en)(Me-Mal-O)(Met-Gly-S)] [k ₁ = (1.37 ± 0.03) × 10 ^-4 s ^-1 ] to give the S,N-chelated adduct was faster than that of [Pt(en)(Me-Mal-O)(Ac-Met-S)] ^- 2 [(2.27 ± 0.04) × 10 ^-5 s ^-1 ]. The S,N-chelated adducts [Pt(en)(Ac-MetH _-1 -S,N)] 3, [Pt(en)(Gly-MetH _-1 -S,N)] ⁺ and [Pt(en)(Met-GlyH _-1 -S,N)] ⁺ became the predominant products of the reactions after about 24 h. Ring-opened adducts of chelated dicarboxylate platinum anticancer complexes with methionine derivatives could play a significant role in their mechanism of action.