4-Aroyl-1-nitrosohydrazinecarboxamides: synthesis, in vivo and in vitro antitumor activity

Abstract

4-Benzoyl-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide ( I), 1-(2-chloroethyl)-1-nitroso-4-phenylacetylhydrazinecarboxamide ( II), 1-(2-chloroethyl)-4-(2-hydroxybenzoyl)-1-nitrosohydrazinecarboxamide ( III), 4-(4-aminobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide ( IV), 4-(4-chlorobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide ( V), all novel class nitrosoureas, were synthesized. All five compounds showed a dose-dependent activity against leukemias L1210, P388 and Ehrlich ascites tumor (EAT). Compound I was superior, yielding T/C% values of 400%, resulting in many cures, reaching 100% in EAT mice. The effect of the above substances on the incorporation of radioactive precursors into DNA, RNA and proteins of EAT cells was investigated. It was found that treatment of cells with 50 μg/ml of the compounds causes significant inhibition (approximately 70%) of the incorporation of 3H-thymidine into DNA. Finally, the effect of these compounds on sister chromatid exchange (SCE) values and on cell kinetics in cultured human lymphocytes was studied. Compound I was found to be the most effective in causing markedly increased SCE values and cell division delays.