Over the past 40 years, big efforts have been devoted to the developme
nt of novel folate antimetabolites. All of the potent antifolates have
reportedly been inhibitors of dihydrofolate reductase (DHFR). In 1985
, Taylor and et al. reported the synthesis of 5,10-dideaza-5,6,7,8-tet
rahydrofolic acid, DDATHF, which exhibits broad and selective antitumo
r activity as an inhibitor of glycinamide ribonucleotide formyltransfe
rase (GARFT). DDATHF is a close analog of tetrahydrofolic acid, differ
s only by replacement of the 5- and 10- position nitrogen atoms by car
bon. It may exist in two diastereomeric forms, differing in configurat
ion at carbon 6. Both diastereomers of DDATHF are potent inhibitors of
cell growth in culture. DDATHF is currently in Phase II clinical tria
ls.