title: Synthesis and biological evaluation of N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine.
abstract: A novel folic acid analogue, N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine, 3, was prepared via a multistep synthetic sequence. The key steps involved the conversion of 5-deazapteroic acid to its N10-formyl derivative followed by catalytic hydrogenation of the pyridine ring and subsequent heating in dilute sodium hydroxide to afford the new 5-deaza-5,6,7,8-tetrahydropteroic acid. After trifluoroacetylation, this compound was coupled to N delta-(tert-butyl-oxycarbonyl)-L-ornithine using conventional peptide bond forming conditions. Deprotection first in base and then in acid gave the title compound. Compound 3 was an effective inhibitor of hog liver folylpolyglutamate synthetase (Kis, estimated = 64 nM), and was shown to retard the formation of polyglutamates of a structurally related folic acid analogue in HCT-8 cells in vitro.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.
authors.forename: S K
authors.initials: SK
authors.lastname: Singh
authors.forename: S C
authors.initials: SC
authors.lastname: Singer
authors.forename: R
authors.initials: R
authors.lastname: Ferone
authors.forename: K A
authors.initials: KA
authors.lastname: Waters
authors.forename: R J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: J B
authors.initials: JB
authors.lastname: Hynes
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D005493:Folic Acid Antagonists; D006801:Humans; D008099:Liver / Q000201:enzymology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D011099:Polyglutamic Acid / Q000378:metabolism; D013552:Swine; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; C075099:N(alpha)-(5-deaza-5,6,7,8-tetrahydropteroyl)ornithine; D011099:Polyglutamic Acid; D005492:Folic Acid; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase