Folate Analogues in the C9-N10 Bridge Region. 14. 11-Oxahomofolic Acid, a Potential Antitumor Agent

Article abstract of DOI:10.1021/jm00175a011

The chemical synthesis of 11-oxahomofolic acid (2) has been carried out using an unambiguous procedure.Reaction of methyl p-hydroxybenzoate with β-propiolactone gave 3-propionic acid (7), which was converted to 1-bromo-4--2-butanone (8) by the Arndt-Eistert procedure.Protection of the carbonyl group of 8 as the oxime resulted in the formation of 10, which on reaction with potassium phthalimide in the presence of crown-18 ether as a catalyst gave 1-phthalimido-4--2-butanone oxime (11).Hydrazinolysis of 11 gave 1-amino-4--2-butanone oxime (4), which was used as the key intermediate for the construction of 11-oxahomofolic acid (2) by modifications of the Boon and Leigh procedure.The dithionite reduction product of 2, 7,8-dihydro-11-oxahomofolic acid, served as a substrate of Lactobacillus casei dihydrofolate reductase and exhibited a relative rate of 50percent of the natural substrate under identical conditions.The catalytic reduction product of 11-oxahomofolic acid consisting of a mixture of diastereomers exhibited powerful antifolate activity against both MTX-sensitive and -resistant L. casei and Streptococcus faecium.The enzymatic reduction product of 7,8-dihydro-11-oxahomofolate having the "natural" configuration at C⁶ exhibited good antifolate activity against both MTX-sensitive and -resistant strains of L. casei and S. faecium.This paper details the synthesis and preliminary biological evaluation of an antifol, which is a substarate of L. casei dihydrofolate reductase in its 7,8-dihydro form and the resulting enzymatic reduction product capable of inhibiting the growth of the same organism from which the enzyme was derived.Thus, 7,8-dihydro-11-oxahomofolic acid has been showh to be potentially capable of inducing a "lethal synthesis" in L. casei.