title: Abenzyl 10-formyl-trideazafolic acid (abenzyl 10-formyl-TDAF): an effective inhibitor of glycinamide ribonucleotide transformylase.
abstract: The synthesis of N-[7-(2-amino-3,4-dihydro-4-oxo-quinazolin-6-yl) -6-formyl-1-oxo-heptyl]-L-glutamic acid (2, abenzyl 10-formyl-5,8,10-trideazafolic acid) as a potential enzyme-assembled tight binding inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) or aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) is reported. The inhibitor was prepared by a convergent synthesis utilizing the sequential alkylations of acetaldehyde dimethylhydrazone with 6 and 8. The agent exhibited effective inhibition of GAR Tfase (Ki = 4.5 +/- 0.3 microM) and more modest inhibition of AICAR Tfase (Ki = 42 +/- 11 microM).
authors.affiliation: Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
authors.forename: N E
authors.initials: NE
authors.lastname: Haynes
authors.forename: M S
authors.initials: MS
authors.lastname: Warren
authors.forename: J
authors.initials: J
authors.lastname: Ramcharan
authors.forename: A E
authors.initials: AE
authors.lastname: Marolewski
authors.forename: P A
authors.initials: PA
authors.lastname: Kitos
authors.forename: S J
authors.initials: SJ
authors.lastname: Benkovic
mesh_terms: D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005971:Glutamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D051026:Phosphoribosylglycinamide Formyltransferase; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D005971:Glutamates; D011799:Quinazolines; C109264:abenzyl 10-formyltrideazafolic acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase