Latent inhibitors. Part 5. Latent inhibition of dihydrofolate reductase by a pteridine-spiro-cyclopropane

The design of cyclopropane-containing enzyme activated inhibitors of dihydrofolate reductase is presented. The synthesis of two examples, 2-amino-7,8-dihydro-6-hydroxymethylpteridine-7-spirocyclopropan-4(3H)-one and 2,4-diamino-5-(4-chlorophenyl)-6-cyclopropylpyrimidine, is described. Kinetic studies with dihydrofolate reductase from E. coil are presented to show that the former is a time-dependent inhibitor of the enzyme whereas the latter is a typical competitive inhibitor. The results are interpreted with regard to the active site structure of dihydrofolate reductase.