Folate analogues. 20. Synthesis and antifolate activity of 1',2',3',4',5',6'-hexahydrohomofolic acid.

M G Nair, E B Otis, R L Kisliuk, Y Gaumont

Journal of medicinal chemistry 1983 Feb

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The synthesis of 1',2',3',4',5',6'-hexahydrohomofolic acid (3), a close analogue of homofolic acid (2), has been carried out by replacement of the benzene ring of 2 with a cyclohexane ring. The synthetic methods employed here were based on the Boon-Leigh strategy to obtain products with unambiguous structures. Based on a number of chemical and spectral observations, a tentative cis stereochemistry was assigned to the 1,4-substituents of the cyclohexane ring of both the homopteroate analogue 13 and the target compound 3. We investigated hexahydrohomopteroic acid (13), hexahydrohomofolic acid (3), and their 7,8-dihydro and d,l-5,6,7,8-tetrahydro derivatives for antifolate activity employing several biological test systems. The dihydro and tetrahydro derivatives of both 13 and 3 were active against Streptococcus faecium, whereas they were inactive against Lactobacillus casei. These compounds were neither substrates nor inhibitors of L. casei dihydrofolate reductase or thymidylate synthase.

Citation

M G Nair, E B Otis, R L Kisliuk, Y Gaumont. Folate analogues. 20. Synthesis and antifolate activity of 1',2',3',4',5',6'-hexahydrohomofolic acid. Journal of medicinal chemistry. 1983 Feb;26(2):135-40