RESUMO
A series of new heterocycles-linked chalcone conjugates has been designed and synthesized by varying different alkane spacers. These conjugates were tested for their in vitro cytotoxic potential against a panel of selected human cancer cell lines namely, lung (A549 and NCI-H460), prostate (DU-145 and PC-3), colon (HCT-15 and HCT-116), and brain (U-87 glioblastoma) by MTT assay. Notably, among all the tested compounds, 4a exhibited potent cytotoxicity on NCI-H460 (lung cancer) cells with IC50 of 1.48±0.19µM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC50 of 9.66±0.06µM). Moreover, phase contrast microscopy and DAPI staining studies indicated that compound 4a can induce apoptosis in NCI-H460 cells. Further, the flow-cytometry analysis revealed that compound 4a arrests NCI-H460 cells in the G2/M phase of the cell cycle. In addition, molecular docking studies of the most active compounds 4a and 4b into the colchicine site of the tubulin, revealed the possible mode of interaction by these new conjugates.
Assuntos
Chalcona/química , Chalcona/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Chalcona/síntese química , Chalcona/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Concentração Inibidora 50 , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial , Microscopia de Contraste de Fase , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/toxicidadeRESUMO
A series of new benzimidazole-thiazolidinedione hybrids has been synthesized and evaluated for their cytotoxic potential against a selected human cancer cell lines of prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal breast epithelial cells (MCF10A). Among the tested compounds, 11p exhibited promising cytotoxicity with IC50 value of 11.46 ± 1.46 µM on A549 lung cancer cell line and did not show significant toxicity on normal MCF10A cells. Lung cancer cells (A549) have been used to know the mechanism of cell growth inhibition and apoptosis inducing effect with compound 11p. The treatment of A549 cells with 11p showed typical apoptotic morphology like cell shrinkage, chromatin condensation and horseshoe shaped nuclei formation. Flow-cytometry analysis revealed the G2/M phase of cell cycle arrest in a dose dependent manner. Preliminary mechanistic studies suggested that the cell migration was inhibited through the disruption of F-actin protein. Acridine orange-ethidium bromide (AO-EB), DAPI, annexin V-FITC/propidium iodide, rhodamine-123 and MitoSOX assays suggested the induction of apoptosis in A549 cells by compound 11p.
