RESUMEN
We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.
Asunto(s)
Compuestos de Anilina/química , Antineoplásicos/química , Guanidinas/química , Proteínas Hedgehog/metabolismo , Neoplasias/metabolismo , Pirroles/química , Moduladores de Tubulina/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colchicina/química , Ensayos de Selección de Medicamentos Antitumorales , Guanidinas/síntesis química , Guanidinas/farmacología , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Ratones , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Polimerizacion , Unión Proteica , Pirroles/síntesis química , Pirroles/farmacología , Transducción de Señal , Relación Estructura-Actividad , Tubulina (Proteína)/química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacologíaRESUMEN
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.