Synthesis and characterization of O6-(2-chloroethyl)guanine: a putative intermediate in the cytotoxic reaction of chloroethylnitrosoureas with DNA

The chloroethylnitrosoureas are useful antitumor agents which evidently exert a significant part of their cytotoxic action through the formation of a unique 1-(3-deoxycytidyl), 2-(1-deoxyguanosinyl)ethane cross-link in DNA. It has been suggested that this cross-link is formed from O6-(2-chloro-ethyl)guanine, an initial product of DNA alkylation by the chloroethylnitrosoureas; however, O6-(2-chloroethyl)guanine has never been described. We have synthesized this derivative from the reaction of thionyl chloride with O6-(2-hydroxyethyl)guanine, and have found that it decomposes to 1-(2-hydroxyethyl)guanine through an intermediate, presumably 1,O6-ethanoguanine. Its half life at 37 degrees and pH 7.4 is 17.8 min.