Comparison of N-acetylmethionine reactivity between oxaliplatin and an oxaliplatin derivative with chiral () amine nitrogen atoms.

We have synthesized an oxaliplatin derivative using N,N'-dimethyl-1,2-diaminocyclohexane (Medach) as the diamine ligand. The complex (S,R,R,S)-Pt(Medach)(oxalate), where S,R,R,S represents the chiralities at N,C,C,N, respectively, was prepared and characterized by H NMR spectroscopy, COSY, NOESY, and HMQC. Oxaliplatin reacts with N-acetylmethionine (N-AcMet) to form [Pt(dach)(N-AcMet-)] and [Pt(dach)(N-AcMet-)], with the former favored at higher molar ratios of N-AcMet. In contrast, Pt(Medach)(oxalate) reacts to form [Pt(Medach)(N-AcMet-)] even in the presence of excess N-AcMet. Molecular mechanics calculations are consistent with significant steric clashes in models of [Pt(Medach)(N-AcMet-)]. When N-AcMet was reacted with an excess of each platinum complex, the rate of N-AcMet decrease was very similar for both complexes. Thus, the methyl groups at the nitrogen atoms had little to no effect on the addition of the sulfur atom of a single N-acetylmethionine, but they prevented chelation of the amide nitrogen or coordination of a second N-acetylmethionine residue.