Further evaluation of 5‐alkyl‐5‐deaza antifolates. 5‐propyl‐ and 5‐butyl‐5‐deaza analogues of aminopterin and methotrexate Journal Article
| Authors: | Piper, J. R.; Ramamurthy, B.; Johnson, C. A.; Maddry, J. A.; Otter, G. M.; Sirotnak, F. M. |
| Article Title: | Further evaluation of 5‐alkyl‐5‐deaza antifolates. 5‐propyl‐ and 5‐butyl‐5‐deaza analogues of aminopterin and methotrexate |
| Abstract: | 5‐Propyl‐5‐deaza and 5‐butyl‐5‐deaza analogues of classical antifolates were synthesized by extensions of a previously reported general route which proceeds through 2,4‐diamino‐5‐alkylpyrido[2,3‐d]pyrimidine‐6‐carbonitrile intermediates followed by reductive condensation with diethyl N‐4‐(aminobenzoyl)‐L‐glutarnate to give diethyl esters of 5‐alkyl‐5‐deazaaminopterin types. N10‐Methyl derivatives, i.e., derivatives of 5‐alkyl‐5‐deazamethotrexate, were also prepared by reductive methylation of the N10‐H compounds. 5‐Ethyl‐5‐deazamethotrexate was prepared using an alternative route through 6‐(bromomethyl)‐2,4‐diamino‐5‐ethylpyrido[2,3‐d]pyrimidine. These antifolates were evaluated for inhibition of dihydrofolate reductase (DHFR) from L1210 cells, their effect on L1210 and S180 tumor cell growth in culture, and carrier‐mediated transport through L1210 cell membranes. Inhibitory effect on DHFR was lowered relative to methotrexate in 5‐propyl‐5‐deazaaminopterin and 5‐propyl‐5‐deazamethotrexate by 2‐ to 3‐fold (Ki = 9.3 and 11.7 pM, respectively, vs. 4.3 pM for methotrexate) and by 17‐ to 18‐fold in 5‐butyl‐5‐deaza‐aminopterin and 5‐butyl‐5‐deazamethotrexate (Ki = 74 and 78 pM, respectively). Molecular modeling using graphics derived from human DHFR show the propyl and butyl compounds interacting with the enzyme in conformations that account for these slight decreases in binding. Copyright © 1995 Journal of Heterocyclic Chemistry |
| Keywords: | controlled study; unclassified drug; nonhuman; methotrexate; animal cell; mouse; enzyme inhibition; molecular dynamics; drug synthesis; cell membrane; tumor cell; dihydrofolate reductase; folic acid antagonist; drug transport; nuclear magnetic resonance; quantitative structure activity relation; article; leukemia l 1210; sarcoma 180; 5 butyl 5 deazaaminopterin; 5 butyl 5 deazamethotrexate; 5 propyl 5 deazaaminopterin; 5 propyl 5 deazamethotrexate |
| Journal Title: | Journal of Heterocyclic Chemistry |
| Volume: | 32 |
| Issue: | 4 |
| ISSN: | 0022-152X |
| Publisher: | Wiley-Blackwell Publishing, Inc. |
| Date Published: | 1995-07-01 |
| Start Page: | 1205 |
| End Page: | 1212 |
| Language: | English |
| DOI: | 10.1002/jhet.5570320419 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 28 August 2018 -- Source: Scopus |
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