Potential antitumor agents via inhibitors of L-asparagine synthetase: substituted sulfonamides and sulfonyl hydrazides related to glutamine.
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D005973:Glutamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006834:Hydrazines / Q000138:chemical synthesis / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000188:drug therapy; D008025:Ligases / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; D013450:Sulfones; D005973:Glutamine; D008025:Ligases; D001217:Aspartate-Ammonia Ligase