Potential inhibitors of L-asparagine biosynthesis. 4. Substituted sulfonamide and sulfonylhydrazide analogues of L-asparagine.
Several N-substituted sulfonamides and N'-substituted sulfonylhydrazides have been prepared as sulfur analogues of L-asparagine with the potential of acting as inhibitors of L-asparagine synthetase (ASase, from Novikoff hepatoma). L-Cysteine was converted in known steps to N-carboxy-3-(sulfonylchloro)-L-alanine dibenzyl ester (1). Condensation of 1 with O-benzylhydroxylamine, p-(fluorosulfonyl)benzylamine, or monoethyl fumarylhydrazide (9), followed by deblocking with HF, gave 3-(hydroxysulfamoyl)-L-alanine (3a), 3-[p-(fluorosulfonylbenzyl)]sulfamoyl-L-alanine (3c), and 3-sulfo-L-alanine S-[2-[(E)-3-(ethoxycarbonyl)acryloyl]hydrazide] (3e), respectively. Similarly, 1 with 2-chloroethylamine and deblocking with H2-Pd gave 3-[(2-chloroethyl)sulfamoyl]-L-alanine (3b). tert-Butyl carbazate was allowed to react with 1 and the tert-butyl group was removed with HCl. The resulting sulfonylhydrazide 7 was condensed with p-(fluorosulfonyl)benzoyl chloride and then deblocked with HF to give 3-sulfo-L-alanine S-[2-[P-(fluorosulfonyl)benzoyl]hydrazide] (3d). The inhibition of ASase by 3a-e at 2 mM was 97, 0, 30, 43, and 37%, respectively, and 3a was competitive with L-aspartic acid. Neither 3a nor 3e was effective in increasing the life span of mice bearing P-388 lymphocytic leukemia.
D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D006834:Hydrazines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy; D008025:Ligases / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms / Q000201:enzymology; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use
D006834:Hydrazines; D013449:Sulfonamides; D001216:Asparagine; D008025:Ligases; D001217:Aspartate-Ammonia Ligase