Potential inhibitors of L-asparagine biosynthesis. 2. Chemistry and biological activity of beta-hydroxyaspartic acid and its derivatives.
Several derivatives of erythro-beta-hydroxy-DL-aspartic acid (1) were prepared as a potential inhibitors of L-asparagine synthetase (ASase) from rat Novikoff hepatoma. Benzylation of 1 gave the dibenzyl ester 2 which upon coupling with carbobenzoxyglycine afforded the blocked dipeptide 3. Deblocking of 3 gave glycl-erythro-beta-hydroxyl-DL-aspartic acid (4) which could not be diazotized. The dimethyl ester of 1 was coupled with carbobenzoxyglycine to give the blocked dipeptide 7a which was deblocked to give dimethyl glycel-erythro-beta-hydroxy-DL-aspartate hydrochloride (8). Diazotization of 8 gave impure diazo compound 9 which on reaction with HCl gave the chloro compound 10. The methods of isolation, assay, and inhibition of ASase are discribed. At 10 mM concentrations 10, 1, and its D and L enantiomers inhibit ASase by 45, 47, 36 and 66 percent, respectively.
D000818:Animals; D001216:Asparagine / Q000096:biosynthesis*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D003864:Depression, Chemical; D005973:Glutamine; D006880:Hydroxy Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008025:Ligases / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology; D008297:Male; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000201:enzymology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006880:Hydroxy Acids; D005973:Glutamine; D001224:Aspartic Acid; D001216:Asparagine; D008025:Ligases