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

Abstract

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.

Mechanism of the palladium-catalyzed hydrothiolation of alkynes to thioethers: a DFT study

“…However, for C 1 and C 2 atoms, the NBO charges are 3b (0.02, −0.50), 5b (−0.38, −0.19) and 7b (−0.03, −0.44), respectively. Meanwhile, the orbitals responsible for HOMO-1 in intermediates 3b, 5b and 7b are shown in Figure 7 [58][59][60]. The calculated results are also in good agreement with the experimental observations of Frech et al [47].…”

Identification of Binding Targets of a Pyrrole-Imidazole Polyamide KR12 in the LS180 Colorectal Cancer Genome

“…While alkylation of occupied sites by KR12 did contribute to DNA damage and reduced gene expressions, the relatively few binding sites in promoter and coding regions perhaps explained the highly specific and directed suppression of mutant KRAS codon 12 by the polyamide. The relatively small subset of genomic binding by KR12 in contrast to the nonspecific alkylation of guanines and adenines by conventional alkylating neoplastic agents such as melphalan or mechlorethamine [57] could also lead to a potential reduction in the amount of adverse side effects. As more applications of PIP are explored, the need for similar sequencing and expression-driven exploratory analyses will also rise; incorporation of the workflow herein could then enhance the throughput of designing and optimizing new and existing polyamide designs, especially with further optimizations in the enrichment procedure and computational peak identification.…”

Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity

“…Previous studies established that most alkylating agents react particularly with the N7 position of guanine. [7][8][9] In the first place base alkylation prevents DNA replication and induces DNA fragmentation by hydrolytic reactions, which ultimately leads to cell death. However, the emergence of resistance to this class of drugs is also a substantial challenge in cancer therapy.…”