RESUMEN
Hypoxia is a very important feature of tumors, especially for solid tumors, and it was demonstrated highly relevant with aggressive biology, including anti-apoptosis, vasculogenesis and radiation or chemotherapy resistance. Correlatively, hypoxia-inducible factors 1-α (HIF-1α), which the wildest contribution of hypoxia-inducible factors (HIFs), plays a crucial role in the adaptation of tumor cells to hypoxia via upregulating the transcription of the oncogene and downregulating the transcription of suppressor gene. This review focus on the HIF-1α regulation including hydroxylation and acetylation, growth factors pathway, heat shock proteins(HSPs), and small molecule inhibitors for HIF-1α directly or indirectly.
Asunto(s)
Antineoplásicos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/química , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Estructura Molecular , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Ibrutinib (IBN), a first-in-class BTK-inhibitor, was approved by the FDA for the treatment of mantle cell lymphoma (MCL). Although IBN shows excellent performance as an anti-lymphoma agent, it has some undesirable side effects due to its off-target activities. Our studies yielded a novel series of 3-(6-phenoxypyridin-3-yl)-4-amine-1H-pyrazolo[3,4-d]pyrimidine derivatives capable of potent inhibition of Bruton's tyrosine kinase (BTK). Notably, compound 13e explained potent BTK inhibitory activity and could completely inhibit the phosphorylation of BTK and PLCγ2 in Z138 cells at low micromolar concentration. Compared with IBN, compound 13e improved anti-proliferative activities 3-40 folds in MCL cell lines with IC50 values lower than 1⯵M. Low micromolar doses of 13e could induce strong cell apoptosis in Jeko-1 and Z138 cells. In addition, compound 13e showed greater BTK selectivity and higher stability in human liver microsomes than IBN and potential safety improvement for the treatment of MCL.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Diseño de Fármacos , Linfoma de Células del Manto/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Agammaglobulinemia Tirosina Quinasa/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/patología , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Bruton's tyrosine kinase (BTK) is a key regulator of B-cell receptor (BCR) signaling pathway and takes effect in the regulation of B-cell activation, survival, proliferation and differentiation. It has been proved that BTK is commonly overexpressed in mantle cell lymphoma (MCL), which makes it a focus of targeted therapy for MCL. Our studies yielded a novel series of pyrazolopyrimidine derivatives capable of potent inhibition of BTK. Notably, 12a showed higher selectivity against BTK and exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 12a induced strong cell apoptosis in Jeko-1 and Z138 cells.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Agammaglobulinemia Tirosina Quinasa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/patología , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirazoles/química , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
Two new isoquinolines (1 and 3), along with 4 known isoquinolines were obtained from the ethanol extract of Corydalis saxicola Bunting. Their structures were elucidated based on detailed spectroscopic data (NMR, HR-ESIMS) and comparison with literature data. The absolute configurations of the new compounds were assigned by comparing computed electronic circular dichroism (ECD). The anti-inflammatory effects of the isolates were assessed by inhibiting NO production in LPS-induced RAW264.7 macrophage cells, and the results showed that compounds 1-6 exhibited anti-inflammatory activities, with IC50 values ranged from 44.24 ± 1.16 to 69.00 ± 5.41 µM.