Synthesis and SAR of [1,2,4]triazolo[1,5-a]pyrimidines, a class of anticancer agents with a unique mechanism of tubulin inhibition
Autor: | James Joseph Gibbons, Carl Beyer, Jay Afragola, Nguyen Thai Hiep, Judy Lucas, Richard Hernandez, Nan Zhang, Semiramis Ayral-Kaloustian |
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Rok vydání: | 2007 |
Předmět: |
Stereochemistry
Administration Oral Mice Nude Stereoisomerism Ring (chemistry) Chemical synthesis Mice Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Animals Humans Cell Proliferation chemistry.chemical_classification biology Chemistry Triazoles Xenograft Model Antitumor Assays Tubulin Modulators Tubulin Pyrimidines Mechanism of action Injections Intravenous biology.protein Thiol Molecular Medicine Amine gas treating Female medicine.symptom |
Zdroj: | Journal of medicinal chemistry. 50(2) |
ISSN: | 0022-2623 |
Popis: | The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel.1 Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously. |
Databáze: | OpenAIRE |
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