Synthesis and biological activity of resolved C-10 diastereomers of 10-methyl- and 10-ethyl-10-deazaminopterin Journal Article
| Authors: | DeGraw, J. I.; Christie, P. H.; Tagawa, H.; Kisliuk, R. L.; Gaumont, Y.; Schmid, F. A.; Sirotnak, F. M. |
| Article Title: | Synthesis and biological activity of resolved C-10 diastereomers of 10-methyl- and 10-ethyl-10-deazaminopterin |
| Abstract: | Synthesis and evaluation of the antitumor drugs 10-methyl- and 10-ethyl- 10-deazaminopterin (15a,b) were previously reported for the diastereomeric mixtures, lacking resolution at the C-10 position. In order to assess biological properties of the individual diastereomers, the C-10 isomers of 4-amino-4-deoxy-10-methyl- and 10-ethyl-10-deazapteroic acids (13a,b) were prepared by total synthesis. Coupling with L-glutamate afforded the appropriate diastereomers of the title compounds. Biochemical, transport, and cell growth inhibitory properties in LI210 cells and folate-dependent bacteria were measured. Differences were generally less than 2-fold between diastereomeric pairs, but a factor of 3 was noted for d,L-15b vs. in inhibition of DHFR from L1210 cells and in cytotoxicity toward L1210 cells. An in vivo comparison of the isomers of 15b with racemic compound against L1210 in mice did not show a significant efficacy difference (ILS) among the compounds. However, d,L-15b showed an acute toxicity about 2.5 times that of U-15b. © 1986, American Chemical Society. All rights reserved. |
| Keywords: | cancer chemotherapy; unclassified drug; dose response; nonhuman; methotrexate; animal cell; mouse; animals; mice; animal experiment; animal model; drug structure; in vitro study; drug screening; drug synthesis; structure activity relation; structure-activity relationship; liver; drug response; drug toxicity; drug cytotoxicity; dihydrofolate reductase; folic acid antagonists; therapy; nuclear magnetic resonance; aminopterin; stereoisomerism; drug identification; chicken; intoxication; enantiomer; drug comparison; leukemia l1210; enterococcus faecalis; edatrexate; subcutaneous drug administration; new drug; priority journal; article; ultraviolet spectrophotometry; leukemia l 1210; lactobacillus casei; blood and hemopoietic system; drug analysis; 10 methyl 10 deazaaminopterin |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 29 |
| Issue: | 6 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1986-06-01 |
| Start Page: | 1056 |
| End Page: | 1061 |
| Language: | English |
| DOI: | 10.1021/jm00156a026 |
| PUBMED: | 3712374 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 18 August 2021 -- Source: Scopus |
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