RESUMEN
A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Tiofenos/farmacología , Animales , Antineoplásicos/química , Aurora Quinasas , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Biología Computacional , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Células HL-60 , Humanos , Masculino , Ratones , Ratones SCID , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Pirazoles/síntesis química , Pirazoles/química , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Trasplante HeterólogoRESUMEN
Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Piperazinas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirroles/síntesis química , Adenosina Trifosfato/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasas , Sitios de Unión , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Pirroles/química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
In recent years telomerase has been identified as a new promising target in oncology and consequently new telomerase inhibitors have been intensely explored as anticancer agents. Focused screening of several polyhydroxylated flavonoids has allowed us to identify 7,8,3',4'-tetrahydroxyflavone 1 as a new telomerase inhibitor with an interesting in vitro activity in a Flash-Plate assay (IC50 = 0.2 microM) that has been confirmed in the classical TRAP assay. Starting from this compound, we developed a medicinal chemistry program to optimize our lead, and in particular to replace one of the two catechols with potential bioisosteres. From this study, new structural analogues characterized by submicromolar potencies have been obtained. Their synthesis and biological activity are described.