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

• Formed Pt(Me2dach)(oxalate), where Me2dach = N,N′-dimethyl-1,2-diaminocyclohexane.
• Stereochemistry determined to be (S,R,R,S) for Pt(Me2dach)(ox).
• Pt(dach)(ox) and Pt(Me2dach)(ox) react with N-acetylmethionine at similar rates.
• Pt(dach)(ox) can form [Pt(dach)(N-AcMet–S)2] or [Pt(dach)(N-AcMet–S,N)].
• Pt(Me2dach)(ox) can form only [Pt(Me2dach)(N-AcMet–S,O)]+.

We have synthesized an oxaliplatin derivative using N,N′-dimethyl-1,2-diaminocyclohexane (Me2dach) as the diamine ligand. The complex (S,R,R,S)-Pt(Me2dach)(oxalate), where S,R,R,S represents the chiralities at N,C,C,N, respectively, was prepared and characterized by 1H NMR spectroscopy, COSY, NOESY, and HMQC. Oxaliplatin reacts with N-acetylmethionine (N-AcMet) to form [Pt(dach)(N-AcMet–S)2] and [Pt(dach)(N-AcMet–S,N)], with the former favored at higher molar ratios of N-AcMet. In contrast, Pt(Me2dach)(oxalate) reacts to form [Pt(Me2dach)(N-AcMet–S,O)]+ even in the presence of excess N-AcMet. Molecular mechanics calculations are consistent with significant steric clashes in models of [Pt(Me2dach)(N-AcMet–S)2]. 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.

Oxaliplatin and an analog with chiral secondary amine nitrogen atoms were each reacted with N-acetylmethionine. Whereas the reaction at the first coordination position was unaffected by the size of the amine ligand, the analog was unable to coordinate a second methionine or chelate the amide nitrogen.Figure optionsDownload as PowerPoint slide