RESUMEN
The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a-h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling.
Asunto(s)
Antineoplásicos/farmacología , Glioma/tratamiento farmacológico , Quinazolinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Glioma/enzimología , Humanos , Modelos Moleculares , Quinazolinas/síntesis química , Quinazolinas/química , Ratas , Especies Reactivas de Oxígeno/metabolismo , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Microwave-accelerated synthesis and anticancer activity of novel imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole against a panel of seven cancer cell lines are reported for the first time. Compounds ARK-4, 10 and 12 in the series show promising in vitro anti proliferative activity with low micromolar IC50 values against A-459 (lung), Hep-G2 (liver) and H-460 (liver) cancer cell lines. Compounds caused the increase in ROS levels as well as mitochondrial membrane depolarization, which might induce apoptosis. Further, mechanistic interventions on biological and molecular modeling data supported that compounds inhibited topoisomerase-II selectively.
Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Imidazoles/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Antígenos de Neoplasias , Apoptosis , Proliferación Celular , ADN-Topoisomerasas de Tipo II , Humanos , Microondas , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2-aminopyridine with 2,3-epoxyesters toward synthesis of 2-arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIα-selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIα inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research.
RESUMEN
A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choice-based change" in target-specific mode of action for rapid drug discovery.