Nitrosourea compounds are DNA alkylating agents, which are widely employed to clinical treatments of malignant tumors. However, some nitrosoureas were found to have carcinogenicity and even lead to the secondary cancer in their clinical applications. This greatly restricted the further development of nitrosoureas as anticancer chemotherapy. In this work, the carcinogenic mechanism of nitrosoureas was investigated using density functional theory. The mechanisms for the formation of ultimate alkylating agents and the alkylation of DNA bases were explored. The alkylating activity of various electrophilic agents generated from nitrosoureas on different alkylation sites were compared. The results indicated that the electrostatic repulsion between the alkylating agent and the nucleophile was the key determinant of the alkylation selectivity. Based on the carcinogenic activity obtained from animal experiments, the structure-carcinogenicity relationship of nitrosoureas was reasonably explained by the alkylating selectivity of ultimate alkylating agents with water and N7 site of guanine.

DNA damage induced by electrophilic alkylating agents generated from nitrosoureas: A theoretical investigation of mechanism and structure-carcinogenicity relationship

245th National Meeting (2013)

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