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Carbamoylation of Amino Acids, Peptides, and Proteins by Nitrosoureas¹

Biochemistry Research Department [G. P. W., B. J. B.], and Organic Chemistry Research Department [R. F. S.], Southern Research Institute, Birmingham, Alabama 35205

Incubation at approximately physiological conditions of amino acids, peptides, and proteins with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or cyclohexyl isocyanate resulted in carbamoylation of the -amino groups of amino acids, the terminal amino groups of peptides and proteins, and the -amino groups of lysine moieties. Carbamoylation of the -amino groups and the terminal amino groups occurred as readily as, or more readily than, the carbamoylation of the -amino groups.

Carbamoylation of the amino groups of amino acids or peptides by 1,3-bis(2-chloroethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea altered the electrophoretic mobility of those compounds. Cyclization of (2-chloroethylcarbamoyl)-amino groups to form (2-oxazolin-2-yl)amino groups occurred at room temperature, and the resulting oxazolinyl compounds migrated electrophoretically similarly to the parent compounds. Since such cyclization did not occur with cyclohexylcarbamoylamino groups, treatment of amino acids, peptides, or proteins with 1,3-bis(2-chloroethyl)-1-nitrosourea might result in less permanent alteration of the respective charges on the resulting products than would treatment with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or other nitrosoureas lacking a 2-chloroethyl group on N-3. The relevance of these differences in charge to differences in physiological effects is not presently known.

Although the present study does not establish a definite relationship between carbamoylation of any specific protein and the physiological effects of nitrosoureas, it does reinforce and expand the existing evidence that carbamoylation of proteins is a process that must be considered in efforts to explain the physiological effects of these agents, and it points to terminal amino groups of proteins as possible primary sites of carbamoylation.

¹ This work was performed under Contracts NO1-CM-60029 and NO1-CM-43784, Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education and Welfare.

Received 2/13/75. Accepted 6/26/75.