title: Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin bearing a terminal L-ornithine.
abstract: Six new 5,8-dideaza analogues of folic acid and aminopterin containing a terminal L-ornithine residue were prepared by using multistep synthetic sequences. Each was evaluated as an inhibitor of hog liver folylpolyglutamate synthetase and human dihydrofolate reductase. Structural modifications at positions 2, 4, 5, and 10 were included to help define structure-activity relationships for compounds of this type. The compound N alpha-(4-amino-4-deoxy-5-chloro-5,8-dideazapteroyl)-L-ornithine (3f) was identified as the most potent inhibitor of mammalian folylpolyglutamate synthetase reported thus far (Ki congruent to 2 nM). Its 4-oxy counterpart, N alpha-(5-chloro-5,8-dideazapteroyl)-L-ornithine, was only 5-fold less inhibitory than 3f toward folylpolyglutamate synthetase but was found to be a much weaker inhibitor of dihydrofolate reductase than 3f.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.
authors.forename: S A
authors.initials: SA
authors.lastname: Patil
authors.forename: B
authors.initials: B
authors.lastname: Shane
authors.forename: J H
authors.initials: JH
authors.lastname: Freisheim
authors.forename: S K
authors.initials: SK
authors.lastname: Singh
authors.forename: J B
authors.initials: JB
authors.lastname: Hynes
mesh_terms: D000630:Aminopterin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D005493:Folic Acid Antagonists; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009952:Ornithine; D010084:Oxidation-Reduction; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D013552:Swine
chemical_list: D005493:Folic Acid Antagonists; D005492:Folic Acid; D009952:Ornithine; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D000630:Aminopterin