RESUMO
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.
Assuntos
Indóis/química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridazinas/química , Sítios de Ligação , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Indóis/síntese química , Indóis/farmacologia , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Piridazinas/síntese química , Piridazinas/farmacologia , Relação Estrutura-Atividade , Quinases DyrkRESUMO
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).
RESUMO
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.
Assuntos
Antineoplásicos/síntese química , Indóis/síntese química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Piridazinas/síntese química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/química , Quinase 5 Dependente de Ciclina/metabolismo , Ensaios Enzimáticos , Escherichia coli/genética , Humanos , Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Piridazinas/farmacologia , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Quinases DyrkRESUMO
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.