SYNTHESIS AND EVALUATION OF 8,10-DIDEAZATETRAHYDROFOLIC ACID AND DERIVATIVES

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 ac id. Coupling with diethyl L-glutamate followed by saponification gave 8,10-dideazafolic acid. Hydrogenation in acidic media gave the tetrahy dro compound, while hydrogenation in the presence of formaldehyde yiel ded 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 contra st to 5,10-DDTHF, the locus of action was apparently unrelated to inhi bition of GAR formyltransferase. Unfortunately, 5-CH3-8,10-DDTHF was n ot active in vivo against an L1210 challenge in mice.