title: 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.
abstract: 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.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: A
authors.initials: A
authors.lastname: Rosowsky
authors.forename: R A
authors.initials: RA
authors.lastname: Forsch
authors.forename: R G
authors.initials: RG
authors.lastname: Moran
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019877:Hydroxymethyl and Formyl Transferases; D007939:Leukemia L1210 / Q000188:drug therapy; D008099:Liver / Q000201:enzymology; D051379:Mice; D010453:Peptide Synthases / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; C075800:2-desamino-5,8-dideazafolic acid; C075801:2-aza-2-desamino-5,8-dideazafolic acid; D005492:Folic Acid; D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase