Chemical synthesis and biological activities of 5-deazaaminopterin analogues bearing substituent(s) at the 5- and/or 7-position(s) Journal Article
| Authors: | Su, T. L.; Huang, J. T.; Chou, T. C.; Otter, G. M.; Sirotnak, F. M.; Watanabe, K. A. |
| Article Title: | Chemical synthesis and biological activities of 5-deazaaminopterin analogues bearing substituent(s) at the 5- and/or 7-position(s) |
| Abstract: | Condensation of cyanothioacetamide (4) with ethyl α-(ethoxymethylene)acetoacetate (5b), ethyl 4-ethoxy-2-(ethoxymethylene)-3-oxobutanoate (5c), ethyl 2-(ethoxymethylene)-3-oxo-4-phenylpropanoate (5d) afforded exclusively the corresponding 6-substituted pyridines (6b-d). Cyclization of 4 with 3-carbethoxybutane-2,4-dione (5e) gave 3-cyano-5-(ethoxycarbonyl)-4,6-dimethylpyridine-2(lif)-thione (6e), whereas reaction of 4 with 3-carbethoxy-lphenylpropane- 1,3-dione (5f) yielded two products, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-phenylpyridine-2(1H)-thione (6f) and the 6-methyl-4-phenyl isomer 6g. The structural assignments for 6f and 6g are made on the basis of 1H and 13C NMR spectral analyses of the 2-(methylthio)nicotinates (7f,g) prepared from 6f and 6g by treatment with MeI/K2CO3. Nicotinates 7b,d-g were converted into their corresponding 2,4-diaminopyrido[2,3-d]pyrimidines 12b,d-g in five steps, via reduction, protection, oxidation, condensation with guanidine, and deprotection. The 7-monoand 5,7-disubstituted-5-deazaaminopterins (1b,d-g) were prepared from the respective pyrido[2,3-d]pyrimidines 12b,d-g. Preliminary biological studies showed that 7-methyl and 5,7-dimethyl analogues (1b and 1e) were less active than methotrexate against human leukemic HL-60 and murine L-1210 cells in tissue culture. Compound le produced an ILS of 71% at 100 mg/kg per day × 5 (ip) in BDF mice inoculated ip with 106456 L-1210 cells. © 1988, American Chemical Society. All rights reserved. |
| Keywords: | unclassified drug; human cell; nonhuman; antineoplastic agents; methotrexate; animal cell; mouse; animal experiment; cytotoxicity; tumor cells, cultured; structure-activity relationship; cell culture; dihydrofolate reductase; nuclear magnetic resonance; aminopterin; intraperitoneal drug administration; cell strain hl 60; aminopterin derivative; human; support, u.s. gov't, p.h.s.; leukemia l 1210; 5 deazaaminopterin |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 31 |
| Issue: | 6 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1988-06-01 |
| Start Page: | 1209 |
| End Page: | 1215 |
| Language: | English |
| DOI: | 10.1021/jm00401a023 |
| PUBMED: | 3373490 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 August 2020 -- Source: Scopus |
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