Synthesis and biological activities of 5-deaza analogues of aminopterin and folic acid Journal Article
| Authors: | Su, T. L.; Huang, J. T.; Burchenal, J. H.; Watanabe, K. A.; Fox, J. J. |
| Article Title: | Synthesis and biological activities of 5-deaza analogues of aminopterin and folic acid |
| Abstract: | N-[p-(2,4Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid (la, 5-deazaaminopterin) and the 5-methyl analogue (lb) were synthesized in 14 steps from 5-cyanouracil (4a) and 5-cyano-6-methyluracil (4b), respectively, by exploitation of the novel pyrimidine to pyrido[2,3-d]pyrimidine ring transformation reaction. The 5-cyanouracils 4 were treated with chloromethyl methyl ether to the l,3-bis(methoxymethyl)uracils (5, which were treated with malononitrile in NaOEt/EtOH to give the pyrido[2,3-d] pyrimidines 6. Diazotization of 6 in concentrated HC1 afforded the 7-chloro derivatives 8 in high yield. After reduction of 8, the 7-unsubstituted products 9 were reduced in the presence of Ac20 and the products, 6-(acetamidomethyl)pyridopyrimidines 10, were converted into the 6-acetoxymethyl derivatives 12 via nitrosation. After removal of the N-methoxymethyl groups from 12, the 6-(acetoxymethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones 14 were converted into 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine (15a) and its 5-methyl analogue 15b by the silylation-amination procedure. Compounds 15 were brominated to the 6-bromomethyl derivatives 16, which were treated with diethyl (p-aminobenzoyl)-L-glutamate, and the products 17 were saponified to afford 5-deazaaminopterin (la) and its 5-methyl analogue lb. Compound lb was also prepared by an alternative procedure in 10 steps from cyanothioacetamide and ethyl β-(ethoxy-methylene)acetoacetate via 2,4-diamino-6-(hydroxymethyl)-5-methylpyrido[2,3-d]pyrimidine (15b). 5-Deaza-5-methylfolic acid (2) was also prepared in four steps from 15b. The aminopterine analogues 1 showed significant anticancer activity in vitro and in vivo, whereas the folic acid analogue 2 did not exhibit any significant toxicity. © 1986, American Chemical Society. All rights reserved. |
| Keywords: | cancer chemotherapy; unclassified drug; nonhuman; methotrexate; mouse; animals; mice; animal experiment; animal model; in vitro study; drug screening; drug synthesis; magnetic resonance spectroscopy; drug toxicity; folic acid; drug cytotoxicity; therapy; nuclear magnetic resonance; aminopterin; drug identification; intoxication; drug comparison; intraperitoneal drug administration; spectrophotometry, ultraviolet; leukemia l1210; new drug; priority journal; article; ultraviolet spectrophotometry; leukemia p 388; leukemia l 1210; 5 deazaaminopterin; blood and hemopoietic system; drug analysis; 5 methyl 5 deazaaminopterin; 5 methyl 5 deazafolic acid |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 29 |
| Issue: | 5 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1986-05-01 |
| Start Page: | 709 |
| End Page: | 715 |
| Language: | English |
| DOI: | 10.1021/jm00155a021 |
| PUBMED: | 3754585 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 18 August 2021 -- Source: Scopus |
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