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2-Chloroethyl (Methylsulfonyl)methanesulfonate (NSC-338947), a More Selective DNA Alkylating Agent Than the Chloroethylnitrosoureas

Laboratory of Molecular Pharmacology [N. W. G., J. A. H., K. W. K.], and Laboratory of Biological Chemistry [J. M. S.], Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205

The novel chloroethylating agent 2-chloroethyl (methylsulfonyl)methanesulfonate (ClEtSoSo) has been shown to act like the chloroethylnitrosoureas (ClEtNu's) in its DNA damaging and cytotoxic effects in human cell lines and has similar activity to the ClEtNu's in the National Cancer Institute antitumor screening tests. Its simpler chemistry, however, suggests that it may alkylate DNA more selectively than do the ClEtNu's. The DNA base adducts produced in calf thymus DNA by ClEtSoSo have been compared to a representative, non-carbamoylating ClEtNu, 1-(2-chloroethyl)-3-(cis-2-OH)cyclohexyl-1-nitrosourea, using high-pressure liquid chromatography. Two major modified base peaks were observed from the nitrosourea treated sample which have been subsequently identified by high-pressure liquid chromatography comparison of synthesized standards and by electron impact gas chromatography/mass spectrometric analysis to be 7-hydroxyethylguanine and 7-chloroethylguanine. In contrast only 7-chloroethylguanine was obtained from the ClEtSoSo treated DNA at equimolar doses. Thus ClEtSoSo was found to be more specific in its reaction with DNA in that it produced less variety of products than the nitrosourea, with no apparent generation of hydroxyethyl products, which are major side reactions of the ClEtNu's.

¹ Present address: Department of Pharmacology, Fox Chase Cancer Center, American Oncologic Hospital, Central and Shelmire Avenues, Philadelphia, PA 19111. To whom requests for reprints should be addressed.

Received 7/30/85. Revised 10/22/85. Accepted 10/24/85.