O

form,48 gives the tetrahedral intermediate 5.36, which is decomposed into a primary amine, carbon dioxide, and 5.34. This elimination requires an anti-periplanar conformation for 5.37. Addition of a nucleophile other than water to the nitrosourea tautomer explains the isolation of carbamoylated products, formed by elimination of 5.34.

Most nitrosoureas contain one chloroethyl chain on the nitrosated nitrogen, which allows them to act as DNA cross-linking agents. Reaction of electrophilic diazonium species 5.37 with guanine is assumed to take place on O-6 to give 5.38 (see also Section 1). In fact, addition of O6-alkylguanine-DNA alkyltransferase, an enzyme that breaks O-6 guanine adducts, prevents cross-linking. This monoalky-lated product reacts subsequently with the N-3 atom of the cytosine unit in the complementary DNA strand, by anchimeric assistance of the guanine N-1 atom through intermediate 5.39, giving the cross-linked product 5.40 (Fig. 5.27).

In an alternative mechanism, intact nitrosourea molecules rather than diazo-nium species can directly alkylate DNA. Thus, nucleophilic attack of guanine O-6 to the nitrosourea tautomer 5.41 gives intermediate 5.42. Although alternative mechanisms have been proposed, according to labeling experiments it is probable that 5.42 cyclizes to the nitrosoisoxazolidine 5.43, which is attacked by another O-6 atom of a guanine unit neighboring in the DNA sequence to give 5.44. In this adduct, the O-6 of the first guanine is carbamoylated and the O-6 of the second guanine is alkylated with a 2-hydoxydiazoethyl group (Fig. 5.28). Diazonium generation and attack of N-3 from a cytosine of the opposite DNA strand, with anchimeric assistance from guanine N-1, finally gives the carbamoylated cross-linked product 5.45.

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