Synthesis and biological evaluation of N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine.
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.
Singh
S K
SK
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.
Singer
S C
SC
Ferone
R
R
Waters
K A
KA
Mullin
R J
RJ
Hynes
J B
JB
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
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