THE CHEMISTRY OF DDATHF (5,10-DIDEAZA-5,6,7,8-TETRAHYDROFOLIC ACID) AS ANTITUMOR AGENT

Over the past 40 years, big efforts have been devoted to the development 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-tetrahydrofolic acid, DDATHF, which exhibits broad and selective antitumor activity as an inhibitor of glycinamide ribonucleotide formyltransferase (GARFT). DDATHF is a close analog of tetrahydrofolic acid, differs only by replacement of the 5- and 10- position nitrogen atoms by carbon. It may exist in two diastereomeric forms, differing in configuration at carbon 6. Both diastereomers of DDATHF are potent inhibitors of cell growth in culture. DDATHF is currently in Phase II clinical trials.