RESUMEN
Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.
Asunto(s)
Cicloheptanos/química , Ciclooctanos/química , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Tiazoles/química , Animales , Células Cultivadas , Cicloheptanos/síntesis química , Cicloheptanos/farmacología , Ciclooctanos/síntesis química , Ciclooctanos/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Mutación , Transporte de Proteínas , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Glándula Tiroides/citologíaRESUMEN
A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc via a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
RESUMEN
Reductive heterocycle-heterocycle (heterocycle â heterocycle; H-H) transformations that give 4-aminoquinolines, 3-acylindoles, and quinolin-4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis(2-nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.
Asunto(s)
Aminoquinolinas/síntesis química , Indoles/química , Isoxazoles/síntesis química , Quinolonas/síntesis química , Aminoquinolinas/química , Isoxazoles/química , Estructura Molecular , Quinolonas/químicaRESUMEN
Practical and efficient methods have been developed for the diversity-oriented synthesis of isoxazolodihydropyridinones via the 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines. A select few of these isoxazolodihydropyridinones were further elaborated with triazoles by copper-catalyzed azide-alkyne cycloaddition reactions. A total of 70 compounds and intermediates were synthesized and analyzed for drug likeness. Sixty-four of these novel compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.