title: 10-Formyl-5,8,10-trideazafolic acid (10-formyl-TDAF): a potent inhibitor of glycinamide ribonucleotide transformylase.
abstract: The synthesis of 10-formyl-5,8,10-trideazafolic acid (3) as a potential inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) is reported. The target compound was prepared by a convergent synthesis utilizing the alkylation of hydrazone 5 with benzylic bromide 6 to construct the core heterocycle 7. The aldehyde 3 and related agents were evaluated as inhibitors of purN GAR Tfase and avian AICAR Tfase. Compound 3 exhibited potent inhibition of GAR Tfase with a Ki of 0.26 +/- 0.05 microM. In contrast, 3 exhibited more moderate inhibition of aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase), with Ki of 7.6 +/- 1.5 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: P A
authors.initials: PA
authors.lastname: Kitos
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: S J
authors.initials: SJ
authors.lastname: Benkovic
mesh_terms: D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D051026:Phosphoribosylglycinamide Formyltransferase; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase