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Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34.
Singleton, Justin D; Dass, Reuben; Neubert, Nathaniel R; Smith, Rachel M; Webber, Zak; Hansen, Marc D H; Peterson, Matt A.
Afiliación
  • Singleton JD; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.
  • Dass R; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.
  • Neubert NR; Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
  • Smith RM; Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
  • Webber Z; Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
  • Hansen MDH; Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
  • Peterson MA; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA. Electronic address: matt_peterson@byu.edu.
Bioorg Med Chem Lett ; 30(2): 126813, 2020 01 15.
Article en En | MEDLINE | ID: mdl-31831383
A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (20-93%, ave. = 59%). The straightforward synthesis involved sequential treatment of commercially-available acetonitrile derivatives with DMF-dimethylacetal (120 °C, 20 min), followed by treatment with NH2NH2·HBr (120 °C, 20 min), and 1,1,3,3-tetramethoxypropane or 2-aryl-substituted malondialdehdyes (120 °C, 20 min). Compounds were screened for antimitotic activities against MCF7 breast cancer and/or A2780 ovarian cancer cell lines in vitro. The most active compounds exhibited EC50 values ranging from 0.5 to 4.3 µM, with the 3-(4-(trifluoromethyl)phenyl)-6-[4-(2-(piperidin-1-yl)ethoxy]phenyl analogue (34e) and the 3-(2-fluorophenyl)-6-[4-(2-(4-methylpiperizin-1-yl)ethoxy]phenyl analogue (35a) being two to three fold more active than Compound C (Dorsomorphin) in A2780 and MCF7 assays, respectively. Importantly, a monosubstituted 3-(benzothiazol-2-yl) derivative (13) was equipotent with the more synthetically challenging 3,6-disubstituted derivatives (34a-e and 35a-e), and exhibited a promising and unique selectivity profile when screened against a panel consisting of 403 protein kinases (Kinomescan™ selectivity score = 0.005, Kd = 0.55 ± 0.055 µM and 0.410 ± 0.20 µM for JAK1 JH2 pseudokinase and VPS34, respectively).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Janus Quinasa 1 / Fosfatidilinositol 3-Quinasas Clase III Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Janus Quinasa 1 / Fosfatidilinositol 3-Quinasas Clase III Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido