Inhibition of hog liver folylpolyglutamate synthetase by 5-substituted 5,8-dideaza analogues of folic acid bearing a terminal L-ornithine residue.
Five new N alpha-(5,8-dideazapteroyl)-L-ornithines have been prepared using multistep synthetic sequences. These include N alpha-[5-(trifluoromethyl)-5,8-dideazapteroyl]-L-ornithine, 3, as well as N alpha-[5-(trifluoromethyl)-5,8-dideazaisopteroyl]-L-ornithine, 4, and its 5-fluoro and 5-chloro analogues. Both of the compounds containing a 5-(trifluoromethyl) group (3 and 4) were found to be excellent inhibitors of homogeneous hog liver folylpolyglutamate synthetase, having Ki values in the same range as N alpha-(5-chloro-5,8-dideazapteroyl)-L-ornithine, 2, (approximately 10 nM). However, the bridge-reversed isomer of 2 was 60-fold less inhibitory than 2.
Hynes
J B
JB
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.
Singh
S K
SK
Fetzer
O
O
Shane
B
B
D000818:Animals; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine
D005492:Folic Acid; D009952:Ornithine; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase