title: Synthesis and biological evaluation of N alpha-(4-amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithine.
abstract: N alpha-(4-Amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithi ne (AMPte-DL-4,4-F2Orn, 4) was synthesized and evaluated as an inhibitor of human folypoly-gamma-glutamate synthetase (FPGS), dihydrofolate reductase (DHFR), and cell growth. Synthesis of 4 involved the use of a protected form of DL-4,4-difluoroornithine 9 which was derived from DL-4,4-difluoroglutamic acid. Biological activities of 4 were compared directly to those of the corresponding nonfluorinated compound N alpha-(4-amino-4-deoxy-10-methylpteroyl)-L-ornithine (AMPte-L-Orn, 3). Although the fluorinated analogue is a potent inhibitor of DHFR, it is a poor inhibitor of FPGS. However, the compound is transported across the cell membrane and inhibits cell growth, presumably due to the inhibition of DHFR. The data obtained with the fluorinated analogue are in contrast to those of the corresponding nonfluorinated compound 3, which is a potent inhibitor of both FPGS and DHFR but shows very low cytotoxicity due to poor transport.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor 48109, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: W H
authors.initials: WH
authors.lastname: Haile
authors.forename: J J
authors.initials: JJ
authors.lastname: McGuire
authors.forename: J K
authors.initials: JK
authors.lastname: Coward
mesh_terms: D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; C100454:N alpha-(4-amino-4-deoxy-10-methylpteroyl)-4,4-difluoroornithine; D009952:Ornithine; D013762:Tetrahydrofolate Dehydrogenase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase