The Mechanism of Guanine Alkylation by Nitrogen Mustards: A Computational Study

摘要

The thermodynamics and kinetics for thenmonofunctional binding of nitrogen mustard class ofnanticancer drugs to purine bases of DNA were studiedncomputationally using guanine and adenine as modelnsubstrates. Mechlorethamine and melphalan are used asnmodel systems in order to better understand the differencenin antitumor activity of aliphatic and aromatic mustards,nrespectively. In good agreement with experiments that suggested the accumulation of a reactive intermediate in the case ofnmechlorethamine, our model predicts a significant preference for the formation of corresponding aziridinium ion fornmechlorethamine, while the formation of the aziridinium ion is not computed to be preferred when melphalan is used. Twoneffects are found that contribute to this difference. First, the ground state of the drug shows a highly delocalized lone pair on thenamine nitrogen of the melphalan, which makes the subsequent cyclization more difficult. Second, because of the aromaticnsubstituent connected to the amine nitrogen of melphalan, a large energy penalty has to be paid for solvation. A detailed study ofnenergy profiles for the two-step mechanism for alkylation of guanine and adenine was performed. Alkylation of guanine is ∼6 kcalnmol−1 preferred over adenine, and the factors contributing to this preference were explained in our previous study of cisplatinnbinding to purine bases. A detailed analysis of energy profiles of mechlorethamine and melphalan binding to guanine and adeninenare presented to provide an insight into rate limiting step and the difference in reactivity and stability of the intermediate in bothnnitrogen mustards, respectively.