Synthesis and biological evaluation of 8-deazahomofolic acid and its tetrahydro derivative.

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DeGraw JI, Colwell WT, Brown VH, Sato M, Kisliuk RL, Gaumont Y, Thorndike J, Sirotnak FM

Synthesis and biological evaluation of 8-deazahomofolic acid and its tetrahydro derivative.

J Med Chem. 1988 Jan;31(1):150-3.

PubMed ID

3121855 [ View in PubMed

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Abstract

The syntheses of 8-deazahomofolic acid and its tetrahydro derivative, potential inhibitors of thymidylate synthase (TS) and other folate related enzymes, are described. Wittig condensation of 2-acetamido-6-formyl-4-pyrimidinol with the triphenylphosphine ylide 3 derived from N-acetyl-4-(p-carbethoxyanilino)-1-chloro-2-butanone, hydrogenation of the enone intermediate 5, introduction of a 5-amino group via diazonium coupling, and reductive ring closure yielded ethyl N11-acetyl-8-deazahomopteroate (8). Alkaline hydrolysis gave 8-deazahomopteroic acid, which was blocked as the 11-trifluoroacetyl derivative, coupled with diethyl L-glutamate, and the blocking groups saponified to afford 8-deazahomofolic acid (12). Hydrogenation of the glutamate diester intermediate and subsequent saponification yielded the tetrahydro-8-deazahomofolate (14). Growth inhibition of Streptococcus faecium, Lactobacillus casei, and L1210 cells in culture by the target compounds was modest. They were also weak inhibitors of thymidylate synthase, dihydrofolate reductase, glycinamide-ribonucleotide transformylase, and aminoimidazolecarboxamide ribonucleotide transformylase. In contrast, 8-deazafolate showed moderate inhibition of aminoimidazolecarboxamide ribonucleotide transformylase, suggesting that inhibition of this enzyme may be related to its cytotoxic action. Tetrahydro-8-deazahomofolate showed low substrate activity with thymidylate synthase.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methotrexate	Bifunctional purine biosynthesis protein PURH	IC 50 (nM)	>20000	N/A	N/A	Details
Methotrexate	Thymidylate synthase	IC 50 (nM)	86000	N/A	N/A	Details