RESUMEN
New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/ß and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.
Asunto(s)
Indoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridazinas/química , Sitios de Unión , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Indoles/síntesis química , Indoles/farmacología , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/metabolismo , Piridazinas/síntesis química , Piridazinas/farmacología , Relación Estructura-Actividad , Quinasas DyrKRESUMEN
The asymmetric unit of the title hydrated salt, C22H26F2NO4(+)·Cl(-)·0.5H2O, consists of an (S,S,S,S)-nebivolol {nebivol = bis-[2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)-2-hy-droxy-eth-yl]ammonium} cation, a chloride anion and a half-occupancy water mol-ecule. The dihedral angle between the mean planes of the benzene rings is 50.34â (12)°. The pyran rings adopt half-chair conformations. The crystal packing features O-Hâ¯O hydrogen bonds and weak N-Hâ¯Cl, O-Hâ¯Cl, and O-Hâ¯Cl inter-actions, producing layers along (010).
RESUMEN
A series of novel 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles was synthesized through a newly developed approach. All these compounds were evaluated against DYRK1A, CDK5 and PI3Kα and showed promising inhibitory activities against PI3Kα with most IC(50) values in the micromolar range. Among them, compound 18 was strongly considered as the most interesting compound with an IC(50) value of 0.091 µM. This series exhibited also significant anti-proliferative effects in various human cancer cell lines including those resulting in activation of the PI3K pathway.
Asunto(s)
Antineoplásicos/síntesis química , Indoles/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Piridazinas/síntesis química , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/química , Quinasa 5 Dependiente de la Ciclina/metabolismo , Pruebas de Enzimas , Escherichia coli/genética , Humanos , Indoles/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/metabolismo , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Piridazinas/farmacología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Quinasas DyrKRESUMEN
In the course of our investigations on the synthesis of new nitrogen heterocyclic derivatives, we were interested in the synthesis and study of new 1,4-oxazine rings. To this aim, the desired bisvinylphosphate was prepared from N-Boc morpholine-3,5-dione and was then engaged in palladium-catalyzed reactions (reduction, Suzuki, and Stille cross-coupling reactions). The 1,4-oxazine and its corresponding 3,5-disubstituted derivatives were obtained in fair to good yields and were then functionalized under anionic conditions.