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2-Chloroethanol Formation as Evidence for a 2-Chloroethyl Alkylating Intermediate during Chemical Degradation of 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea¹

Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331

Chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea in buffer under physiological conditions resulted in the formation of a significant quantity of 2-chloroethanol (18 to 25% of the initial nitrosourea concentration). Other degradation products observed included acetaldehyde (5 to 10%), vinyl chloride (1 to 2%), ethylene (1 to 2%), and cyclohexylamine (32%), but not 1,3-dicyclohexylurea. The 2-chloroethyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was trapped with halide ions, Cl^-, Br^-, and I^-, to form the corresponding dihaloethanes which were identified by gas chromatography-mass spectrometry techniques. High-pressure liquid chromatographic procedures were developed for the separation and quantitation of the nitrosoureas and many of their degradation products.

It is postulated that a new mode of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea degradation can occur that is not the loss of the chloro group as chloride ion, but the loss of the N-3 hydrogen as a proton. Then the corresponding isocyanate and 2-chloroethylidazene hydroxide are formed, with the latter intermediate becoming an alkylating species, possibly in part as a 2-chloroethyl carbonium ion.

¹ This work was supported by National Cancer Institute Contract NO1-CM-23201 from the NIH.

² To whom requests for reprints should be addressed.

Received 9/18/74. Accepted 11/22/74.