The mechanism of guanine alkylation by nitrogen mustards: a computational study.
The thermodynamics and kinetics for the monofunctional binding of nitrogen mustard class of anticancer drugs to purine bases of DNA were studied computationally using guanine and adenine as model substrates. Mechlorethamine and melphalan are used as model systems in order to better understand the difference in antitumor activity of aliphatic and aromatic mustards, respectively. In good agreement with experiments that suggested the accumulation of a reactive intermediate in the case of mechlorethamine, our model predicts a significant preference for the formation of corresponding aziridinium ion for mechlorethamine, while the formation of the aziridinium ion is not computed to be preferred when melphalan is used. Two effects are found that contribute to this difference. First, the ground state of the drug shows a highly delocalized lone pair on the amine nitrogen of the melphalan, which makes the subsequent cyclization more difficult. Second, because of the aromatic substituent connected to the amine nitrogen of melphalan, a large energy penalty has to be paid for solvation. A detailed study of energy profiles for the two-step mechanism for alkylation of guanine and adenine was performed. Alkylation of guanine is ∼6 kcal mol(-1) preferred over adenine, and the factors contributing to this preference were explained in our previous study of cisplatin binding to purine bases. A detailed analysis of energy profiles of mechlorethamine and melphalan binding to guanine and adenine are presented to provide an insight into rate limiting step and the difference in reactivity and stability of the intermediate in both nitrogen mustards, respectively.
Department of Chemistry, Indiana University, 800 E. Kirkwood Ave., Bloomington, Indiana 47405, USA.
Abhigna
A
Polavarapu
Jacob A
JA
Stillabower
Skyler G W
SG
Stubblefield
William M
WM
Taylor
Mu-Hyun
MH
Baik
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D007700:Kinetics; D008466:Mechlorethamine / Q000737:chemistry*; D008558:Melphalan / Q000737:chemistry*; D015394:Molecular Structure; D011789:Quantum Theory; D013816:Thermodynamics
D018906:Antineoplastic Agents, Alkylating; D008466:Mechlorethamine; D006147:Guanine; D000225:Adenine; D008558:Melphalan