N-[4-[[(3,4-dihydro-4-oxo-1,2,3-benzotriazin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, a novel A-ring analogue of 2-desamino-5,8-dideazafolic acid

• Published in: Journal of medicinal chemistry Vol. 35; no. 14; pp. 2626 - 2630
• Main Authors: ROSOWSKY, A, FORSCH, R. A, MORAN, R. G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 10.07.1992
• Subjects: Acyltransferases - metabolism; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Chemistry; Exact sciences and technology; Folic Acid - analogs & derivatives; Folic Acid - chemistry; Folic Acid - pharmacology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Hydroxymethyl and Formyl Transferases; Leukemia L1210 - drug therapy; Liver - enzymology; Mice; Organic chemistry; Peptide Synthases - metabolism; Phosphoribosylglycinamide Formyltransferase; Preparations and properties; Recombinant Proteins - antagonists & inhibitors; Thymidylate Synthase - antagonists & inhibitors; Tumor Cells, Cultured; α-Aminoacid; Cyclization; Enzyme; Nitrogen heterocycle; Bicyclic compound; Enzyme inhibitor; Dicarboxylic acid; Aromatic compound; Thymidylate synthase; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00092a013

N-[4-[[(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-6- yl)methyl]amino]benzoyl]-L-glutamic acid ("2-aza-2-desamino-5,8- dideazafolic acid", ADDF) was synthesized from 2-amino-5-methylbenzamide via a four-step sequence consisting of diazotization, benzylic bromination, condensation with dimethyl N-(4-aminobenzoyl)-L-glutamate, and ester hydrolysis. ADDF was an inhibitor of recombinant mouse thymidylate synthase; inhibition was competitive with 5,10-methylenetetrahydrofolate as variable substrate (Ki = 2.3 microM). It was a substrate for murine folylpolyglutamate synthetase with kinetic characteristics (Km = 28 microM) comparable to those of aminopterin, and it inhibited the growth of L1210 cells in culture (IC50 = 0.52 microM). The structural modification of the A-ring embodied in ADDF appears to offer a novel, heretofore unexplored approach to the design of TS inhibitors.