Folate analogues altered in the C9-N10 bridge region. 16. Synthesis and antifolate activity of 11-thiohomoaminopterin.

Abstract

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.

• Authors: M G Nair, S Y Chen, R L Kisliuk, Y Gaumont, D Strumpf
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 23 Issue 8 Pg. 899-903 (Aug 1980) ISSN: 0022-2623 [Print] United States
• PMID: 6772788 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Folic Acid Antagonists
• homofolic acid
• 11-thiohomoaminopterin
• Folic Acid
• Thymidylate Synthase

Topics

• Animals
• Antineoplastic Agents (chemical synthesis)
• Folic Acid (analogs & derivatives, chemical synthesis, pharmacology)
• Folic Acid Antagonists (chemical synthesis)
• Lacticaseibacillus casei (drug effects, growth & development)
• Leukemia L1210 (drug therapy)
• Mice
• Streptococcus (drug effects, growth & development)
• Thymidylate Synthase (antagonists & inhibitors)