INHIBITION OF HOG LIVER FOLYLPOLYGLUTAMATE SYNTHETASE BY 5-SUBSTITUTED 5,8-DIDEAZA ANALOGS 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-dideazaisopteroy1]-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 K(i) 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.