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The synthesis of t w o new pteridine-7-spirocyclopropanes that are time-dependent irreversible inhibitors of dihydrofolate reductase is described. Several related compounds including a cyclopropyl substituted quinoxaline and 2-aminopteridine-4(3H),6(5H) -dione were also prepared but these compounds were not found to be time-dependent inhibitors. The inhibitors were assessed using several dihydrofolate reductases, Escherichia cob RT/39, two mutants of the E. coli enzyme, L actobacillus casei, and chicken liver. Activity was found against all enzymes tested but most strongly against E. coIi wild type enzyme.

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Acylation of 6( RS)-tetrahydrofolate with (-)-menthy1 chloroformate afforded an N-5 derivative which was separable into its diastereoisomers by extraction with n-butanol; these derivatives were converted separately into the 6(R)and 6( S)-diastereoisomers of 5-formyltetrahydrofolate by treatment with a mixture of formic acid and hydrogen bromide in acetic acid followed by hydrolysis.

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