Mechanism of action of the nitrosoureas-1. Role of fluoroethylcytidine in the reaction of bis-fluoroethyl nitrosourea with nucleic acids

The nitrosoureas are known to react covalently with nucleic acids and have been shown to decompose in aqueous solution to generate the equivalent of haloethyl carbonium ions. Evidence is presented in this paper that these carbonium ions react with nucleosides to form intermediate haloethyl derivatives. One such haloethyl nucleoside, 3-β-fluoroethylcytidine, has been identified as a reaction product of bis-fluoroethyl nitrosourea (BFNU) and cytidine. Fluoroethylcytidine undergoes an unusual intramolecular cyclization reaction to form 3,N⁴-ethanocytidine. This is a simple intramolecular crosslinking reaction in the terminology of alkylating agent chemistry, and haloethyl nucleosides formed by the nitrosoureas can probably undergo either inter- or intrastrand cross-linking reactions in analogy with the classical alkylating agents. It seems probable that these reactions are important to the cytotoxic and mutagenic actions of these agents.