Potential antitumor agents via inhibitors of L-asparagine synthetase: substituted sulfonamides and sulfonyl hydrazides related to glutamine

• Published in: Journal of pharmaceutical sciences Vol. 67; no. 11; p. 1550
• Main Authors: Brynes, S, Fiorina, V J, Cooney, D A, Milman, H A
• Format: Journal Article
• Language: English
• Published: United States 01-11-1978
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Aspartate-Ammonia Ligase - antagonists & inhibitors; Glutamine - analogs & derivatives; Glutamine - chemical synthesis; Glutamine - pharmacology; Hydrazines - chemical synthesis; Hydrazines - pharmacology; Leukemia, Experimental - drug therapy; Ligases - antagonists & inhibitors; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfones - chemical synthesis; Sulfones - pharmacology
• ISSN: 0022-3549
• DOI: 10.1002/jps.2600671115

A series of 4-(substituted aminosulfonyl)- and 4-(substituted hydrazinosulfonyl)-2-aminobutanoic acids, compounds structurally related to glutamine, was synthesized as potential inhibitors of L-asparagine synthetase and subjected to screening as antitumor agents. Target amino acids were obtained by condensation of a blocked reactive sulfonyl chloride with the appropriate amine or hydrazide, followed by deblocking with hydrogen--palladium or liquid hydrogen fluoride--anisole. Neither the target compounds nor their protected precursors inhibited the enzyme from L5178Y/AR or prolonged the life of mice with P-388 lymphocytic leukemia. However, DL-4,4'-dithiobis[2-(benzyloxycarbonylamino)butanoic acid], an intermediate in the synthesis of the target amino acids, exhibited 90% inhibition of L-asparagine synthetase at 10 mM.