title: Synthesis and evaluation of 1-acyl-1,2-bis(methylsulfonyl)-2-(2- chloroethyl)hydrazines as antineoplastic agents.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: K
authors.initials: K
authors.lastname: Shyam
authors.forename: P G
authors.initials: PG
authors.lastname: Penketh
authors.forename: A A
authors.initials: AA
authors.lastname: Divo
authors.forename: R H
authors.initials: RH
authors.lastname: Loomis
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: A C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000215:Acylation; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D004355:Drug Stability; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006834:Hydrazines / Q000138:chemical synthesis* / Q000627:therapeutic use; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; C084463:1-acetyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine; D005978:Glutathione