RESUMEN
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
Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II-inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities.
Asunto(s)
Antineoplásicos/farmacología , Indoles/química , Indoles/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Topoisomerasa II/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Humanos , Indoles/uso terapéutico , Modelos Moleculares , Neoplasias/enzimología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/uso terapéuticoRESUMEN
Design, synthesis and anticancer activity of a series of imine-pyrazolopyrimidinones is reported for the first time. Compounds 9d, 9n and 9o in the series show encouraging in vitro anticancer activity with low micromolar IC50 values against prostate (PC3) and breast (MCF7) cancer cell lines. Some notions about structure-activity relationships and plausible mechanism of biological activity are presented.
Asunto(s)
Antineoplásicos/síntesis química , Iminas/química , Pirazoles/química , Piridinas/química , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HeLa , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/toxicidad , Piridinas/síntesis química , Piridinas/toxicidad , Relación Estructura-ActividadRESUMEN
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.
RESUMEN
On the basis of structures of known topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase IIα (hTopoIIα) in decatenation, relaxation, cleavage complex, and DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic scaffolds, it was found that imidazopyridine, imidazopyrazole, and imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic activity of hTopoIIα while not showing DNA intercalation. Molecular docking studies and molecular dynamics (MD) simulation analysis, ATPase-kinetics and ATP-dependent plasmid relaxation assay revealed the catalytic mode of inhibition of the title compounds plausibly by blocking the ATP-binding site. N-Fused aminoimidazoles showed potent anticancer activities in kidney and breast cancer cell lines, low toxicity to normal cells, relatively higher potency compared to etoposide and 5-fluorouracil in kidney cancer cell lines, and potent inhibition in cell migration. These compounds were found to exert apoptotic effect in G1/S phase.