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

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Nair MG, Chen SY, Kisliuk RL, Gaumont Y, Strumpf D

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

J Med Chem. 1980 Aug;23(8):899-903.

PubMed ID
6772788 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MethotrexateDihydrofolate reductaseIC 50 (nM)7.9N/AN/ADetails
MethotrexateDihydrofolate reductaseIC 50 (nM)9.6N/AN/ADetails
MethotrexateThymidylate synthaseIC 50 (nM)40000N/AN/ADetails