Activity of the new antifolate N10-propargyl-5,8-dideazafolate and its polyglutamates against human dihydrofolate reductase, human thymidylate synthetase, and KB cells containing different levels of dihydrofolate reductase.

The action of N10-propargyl-5,8-dideazafolate (PDDF) and its gamma-polyglutamyl analogues against human thymidylate synthetase and dihydrofolate reductase was examined. PDDF inhibited thymidylate synthetase in a noncompetitive fashion with respect to 5,10-methylenetetrahydrofolate and dihydrofolate reductase in a competitive fashion with respect to dihydrofolate. Ki values were estimated to be 20 and 250 nM, respectively. The addition of glutamyl moieties through gamma-linkage enhanced the inhibitory activity of PDDF against thymidylate synthetase without significant effect on dihydrofolate reductase. PDDF inhibited human KB cell growth, and its potency was found to be influenced less than that of methotrexate by the amount of cellular dihydrofolate reductase.