Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10-dideazaaminopterin and an alternative synthesis of 10-ethyl-10-deazaaminopterin (edatrexate) Journal Article
| Authors: | Piper, J. R.; Johnson, C. A.; Otter, G. M.; Sirotnak, F. M. |
| Article Title: | Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10-dideazaaminopterin and an alternative synthesis of 10-ethyl-10-deazaaminopterin (edatrexate) |
| Abstract: | Previous findings suggesting that 5,10-dialkyl-substituted derivatives of 5,10-dideazaaminopterin warranted study as potential antifolates prompted synthesis of 10-ethyl-5-methyl-5,10-dideazaaminopterin (12a). The key step in the synthetic route to 12a was Wittig condensation of the tributylphosphorane derived from 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (7a) with methyl 4-propionylbenzoate. Reaction conditions for the Wittig condensation were developed using the tributylphosphorane prepared from 6-(bromomethyl)-2,4-pteridinediamine (7b) as a model. Each of the respective Wittig products 8a and 8b was obtained in 75-80% yield. Hydrogenation of 8a and 8b at their 9,10-double bond afforded 4-amino-4-deoxy-10-ethyl-5-methyl-5,10-dideazapteroic add methyl ester (9a) and 4-amino-4-deoxy-10-ethyl-10-deazapteroic add methyl ester (9b). This route to 9b intersects reported synthetic approaches leading to 10-ethyl-10-deazaaminopterin (10-EDAM, edatrexate), an agent now in advanced clinical trials. Thus the Wittig approach affords an alternative synthetic route to 10-EDAM. Remaining steps were ester hydrolysis of 9a,b to give carboxylic adds 10a,b followed by standard peptide coupling with diethyl L-glutamate to produce diethyl esters lla.b, which on hydrolysis gave 12a and 10-EDAM (12b), respectively. The relative influx of 12a was enhanced about 3.2-fold over MTX, but as an inhibitor of dihydrofolate reductase (DHFR) from L1210 cells and in the inhibition of L1210 cell growth in vitro, this compound was approximately 20-fold less effective than MTX (DHFR inhibition, Ki=4.82 ± 0.60 pM for MTX, 100 pM for 12a; cell growth, IC50= 3.4 ± 1.0 nM for MTX, 65 ± 18 nM for 12a). © 1992, American Chemical Society. All rights reserved. |
| Keywords: | unclassified drug; human cell; drug activity; dose response; antineoplastic agents; methotrexate; animal; drug potency; drug structure; drug screening; tumor cells, cultured; drug synthesis; dihydrofolate reductase; folic acid antagonist; folic acid antagonists; aminopterin; growth inhibition; 10 deazaaminopterin; leukemia l1210; edatrexate; human; priority journal; article; support, u.s. gov't, p.h.s.; leukemia l 1210; 10 ethyl 5 methyl 5,10 dideazaaminopterin |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 35 |
| Issue: | 16 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1992-08-07 |
| Start Page: | 3002 |
| End Page: | 3006 |
| Language: | English |
| DOI: | 10.1021/jm00094a011 |
| PUBMED: | 1501226 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
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