RESUMEN
Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/química , Tiazoles/farmacología , Animales , Dominio Catalítico , Femenino , Humanos , Ratones , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Transducción de Señal/efectos de los fármacos , Tiazoles/farmacocinéticaRESUMEN
[reaction: see text] The scope and limitations of the conjugate addition of 2- and the first 4-pyridyl Gilman homocuprates to various alpha,beta-unsaturated Michael acceptors are delineated. The conjugate addition of the cuprate of 2-bromo-3-methylpyridine to (E)-methyl crotonate then diastereoselective enolate alkylation and lipase-mediated enantioselective ester hydrolysis have enabled an efficient four-step first asymmetric synthesis of the Celastraceae sesquiterpenoid esterifying ligand (-)-(1'S,2'S)-evoninic acid.