Synthesis and evaluation of 1-acyl-1,2-bis(methylsulfonyl)-2-(2- chloroethyl)hydrazines as antineoplastic agents.

Autor: Shyam K; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510., Penketh PG, Divo AA, Loomis RH, Rose WC, Sartorelli AC
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 1993 Nov 12; Vol. 36 (23), pp. 3496-502.
DOI: 10.1021/jm00075a002
Abstrakt: A series of 1-acyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazines, conceived as more potent analogs of 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine, were synthesized and evaluated for antineoplastic activity against the L1210 leukemia in mice. Of these, 1-acetyl-1,2-bis-(methylsulfonyl)-2-(2-chloroethyl)hydrazine produced "cures" of mice bearing the L1210 leukemia at dosage levels that were considerably less than those at which the tris(sulfonyl) analog produced its antineoplastic effects. This compound was also found to have pronounced activity against the P388 leukemia and against several solid tumors, including the B16F10 melanoma, the M5076 reticulum cell sarcoma, and the M109 lung carcinoma. Furthermore, the acyl derivatives were in general considerably more resistant to hydrolysis in aqueous media and more prone to protease- and thiol-mediated activation than the tris(sulfonyl) analog. The former property is important to formulation, while the latter properties may result in some degree of drug targeting and enhancement of the therapeutic indices of these agents.
Databáze: MEDLINE