| Abstract: |
Syntheses of 8,10-dideazatetrahydrofolic acid and its 5-N-methyl and 5-N-formyl derivatives are reported. Hydrolysis of 2,4-diamino-4-deoxy-8,10-dideazapteroic acid in hot alkali afforded 8,10-dideazapteroic acid. Coupling with diethyl L-glutamate followed by saponification gave 8,10-dideazafolic acid. Hydrogenation in acidic media gave the tetrahydro compound, while hydrogenation in the presence of formaldehyde yielded the 5-N-CH3 analog. The 5-N-CH3 compound was more potent than 5,10-DDTHF as an inhibitor of growth for L1210 cells in culture. In contrast to 5,10-DDTHF, the locus of action was apparently unrelated to inhibition of GAR formyltransferase. Unfortunately, 5-CH3-8, 10-DDTHF was not active in vivo against an L1210 challenge in mice. © 1993. |
