Folate analogues altered in the C9-N10 bridge region. 16. Synthesis and antifolate activity of 11-thiohomoaminopterin.
The synthesis of 11-thiohomoaminopterin (1), which is a close analogue of 11-thiohomofolic acid (2), has been carried out by modification of the Boon-Leigh procedure. Treatment of 1-chloro-4-[p-(carbomethoxy)thiopenoxy]-2-butanone (5) with sodium azide gave 1-azido-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (6). After protection of the carbonyl group of 6, the product 7 was catalytically hydrogenated to 1-amino-4-[p-(carbomethoxy)thiophenoxy]-2-butanone ketal (3). Reaction of 32 with 6-chloro-2,4-diaminmo-5-nitropyrimidine gave the desired pyrimidine intermediate, which was elaborated to 4-amino-4-deoxy-11-thiohomopteroic acid (20) by standard procedures. Alternately, 1-azido-4-[p-(carbomethoxy)thiophenoxy]-2-butanone ketal (7) was hydrolyzed to the corresponding acid (8) and coupled with diethyl L-glutamate to obtain diethyl N-[p-(1-azido-2-oxo-4-thiobutanoyl)benzoyl]-L-glutamate ketal (10), which was used for the large-scale preparation of 11-thiohomoaminopterin (1). Although 11-thiohomoaminopterin showed antifolate activity against two folate-requiring microorganisms and inhibited Lactobacillus casei dihydrogolate reductase, it did not exhibit any antitumor activity against L-1210 lymphoid leukemia in mice at a maximum dose of 48 mg/kg.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis*; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000254:growth & development; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; C100117:homofolic acid; C026241:11-thiohomoaminopterin; D005492:Folic Acid; D013940:Thymidylate Synthase