The action of N10-propargyl-5,8-dideazafolate (PDDF) and its γ-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 γ-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.
Preliminary results were presented at the 1984 Proceedings of the Federation (9). This work was supported by Grant CA27364 from the NIH and Grant CH236 from the American Cancer Society USA.