title: Folate analogues altered in the C9-N10 bridge region: 11-thiohomofolic acid.
abstract: The synthesis of 11-thiohomofolic acid (2) has been accomplished by an unambiguous procedure. Reaction of 1-chloro-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (10) with hydroxylamine under carefully controlled conditions gave the corresponding oxime 33. Conversion of this oxime to 1-phthalimido-4-[p-(carbomethoxy)thiophenoxy]-2-butanone oxime (4) was carried out by its reaction with potassium phthalimide using crown 18 ether as a catalyst. Hydrazinolysis of compound 4 gave 1-amino-4-[p-(carbomethoxy)thiophenoxy]-2-butanone oxime (5), which was used for the construction of the title compound 2 by modification of the Boon and Leigh procedure. An alternate synthesis utilizing 1-hydroxy-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (11) and 4-hydroxy-2,5,6-triaminopyrimidine has also been carried out. Compound 2 did not exhibit any antifolate activity against Lactobacillus casei or Streptococcus faecium. The dithionite reduction product, 7,8-dihydro-11-thiohomofolic acid, was able to function as a substrate of L. casei dihydrofolate reductase. The catalytic reduction product of 2, consisting of a mixture of diastereomers, exhibited powerful antifolate activity against both these organisms.
mesh_terms: D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000254:growth & development; D008722:Methods; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development
chemical_list: C020521:11-thiohomofolic acid; D005492:Folic Acid