Folate analogues. 20. Synthesis and antifolate activity of 1',2',3',4',5',6'-hexahydrohomofolic acid.
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.
D001681:Biological Assay; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D005493:Folic Acid Antagonists; D007202:Indicators and Reagents; C100117:homofolic acid; C037425:1',2',3',4',5',6'-hexahydrohomofolic acid; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase