A new class of nitrosoureas. III. Synthesis and antitumor activity of 3,3-disubstituted-1-(2-chloroethyl)-1-nitrosoureas having an arabinopyranosyl, xylopyranosyl or ribopyranosyl moiety.

Publisher Website
Google Scholar
Abstract
Several 3,3-disubstituted-1-(2-chloroethyl)-1-nitrosourea derivatives of aldopentoses were synthesized and tested for antitumor activities against mouse leukemia L1210 cells and Ehrlich ascites carcinoma cells. The reaction of aldopentoses with primary amines followed by treatment with 2-chloroethyl isocyanate usually gave a mixture of 2 or 3 structural isomers of glycosylureas. Complete isomerization into thermodynamically stable glycopyranosylureas was observed when the mixture of the isomers was dissolved in formic acid. Glycopyranosylureas were nitrosated with 4 equivalents of dinitrogen tetroxide followed by treatment with methanol to give the corresponding nitrosoureas in good yields. A large number of nitrosoureas were remarkably active against leukemia L1210 and Ehrlich ascites carcinoma and showed greater therapeutic ratios than the positive controls. The effective nitrosoureas include 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(.beta.-D-glucopyranosyl)-1-nitrosourea. Many of the arabinopyranosylnitrosoureas had large therapeutic ratios (> 50) against leukemia L1210 cells and even larger ones (> 100) against Ehrlich ascites carcinoma cells. These nitrosoureas appear to be activated nonenzymatically by attack of the hydroxyl group of the sugar moiety on the carbonyl group to give the cyclic carbamate without generation of the isocyanate.