Premium
Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N ‐nitroso compounds: nitrosoureas and nitrosamines
Author(s) -
Zhao Lijiao,
Ma Xinyan,
Zhong Rugang
Publication year - 2012
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.2970
Subject(s) - chemistry , alkylation , nitroso , nitrosourea , carcinogen , dna , stereochemistry , amine gas treating , combinatorial chemistry , biochemistry , organic chemistry , medicine , surgery , chemotherapy , catalysis
Nitrosamines and nitrosoureas are two families of N ‐nitroso compounds (NNCs) with a common nitroso group connected to the nitrogen atom; however, the two types of analogs often exhibit distinct bioactivities when they have similar substructures in the side chains. Nitrosamines are usually considered to be potent carcinogens to various organs and species, whereas nitrosoureas can inhibit cancer cell growth. This distinction between the two types of compounds complicates our understanding of the structure–bioactivity relationship of NNCs. In this work, the mechanisms for the formation of DNA interstrand crosslinks induced by nitrosoureas and nitrosamines, which are an important DNA damage related to the cytotoxicity of NNCs, were compared using the density functional theory method. 1,3‐Bis‐(2‐chloroethyl)‐1‐nitrosourea (BCNU) and the bifunctional metabolite of diethylnitrosamine, N ‐nitrosoethyl‐(2‐hydroxyethyl)amine sulfonate (NEHEAS), were used as the computational models. Four pathways for the formation of G–C crosslinks induced by BCNU and NEHEAS were compared. The results show that the crosslinking mechanisms initiated by α‐alkylation are energetically feasible for both BCNU and NEHEAS, and the decompositions of BCNU and NEHEAS represent the rate‐limiting steps. However, for the crosslinking mechanisms initiated by β‐alkylation, BCNU and NEHEAS exhibit different preferences. The energy barrier for the decomposition of the BCNU‐induced β‐alkylation product is much higher than that of NEHEAS. Such an energy barrier may inhibit the mechanism of BCNU initiated by β‐alkylation. Consequently, it is postulated that BCNU and NEHEAS induce DNA interstrand crosslinks via different mechanisms, which may distinguish the bioactivity of the two types of NNCs. Copyright © 2012 John Wiley & Sons, Ltd.