Synthesis and antifolate Properties of 5,10-ethano-5,10-dideazaaminopterin Journal Article


Authors: DeGraw, J. I.; Christie, P. H.; Colwell, W. T.; Sirotnak, F. M.
Article Title: Synthesis and antifolate Properties of 5,10-ethano-5,10-dideazaaminopterin
Abstract: 2-Carbomethoxy-4-(p-carbomethoxyphenyl)cyclohexanone was prepared in a four-step process and thermally condensed with 2,4,6-triaminopyrimidine to afford methyl 2,4-diamino-4-deoxy-7-hydroxy-5,10-ethano-5,10-dideazapteroate, Reduction of the 7-oxo function with borane gave the 7,8-dihydro pterin which was subsequently oxidized to the fully aromatic pteroate ester with dicyanodichlorobenzoquinone. Saponification of the benzoate ester, coupling with diethyl glutamate and final ester hydrolysis afforded the title compound. This novel deazaaminopterin analogue was approximately as potent as methotrexate in vitro in terms of DHFR and L1210 cell growth inhibition. There are indications of diastereomeric differences in the enzyme inhibition measurements. A significant transport advantage over MTX for influx into L1210 cells was observed. The compound was active against the E 0771 murine mammary solid tumor, but further investigation with individual diastereomers is required to define the ED50. © 1992, American Chemical Society. All rights reserved.
Keywords: unclassified drug; methotrexate; animal; mice; cell division; enzyme inhibition; antineoplastic activity; drug structure; tumor cells, cultured; drug synthesis; tumor cell; dihydrofolate reductase; folic acid antagonist; folic acid antagonists; drug transport; aminopterin; mammary neoplasms, experimental; leukemia l1210; aminopterin derivative; priority journal; article; support, u.s. gov't, p.h.s.; leukemia l 1210; 5,10 ethano 5,10 dideazaaminopterin
Journal Title: Journal of Medicinal Chemistry
Volume: 35
Issue: 2
ISSN: 0022-2623
Publisher: American Chemical Society  
Date Published: 1992-01-01
Start Page: 320
End Page: 324
Language: English
DOI: 10.1021/jm00080a017
PUBMED: 1732549
PROVIDER: scopus
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Francis M Sirotnak
    184 Sirotnak