Aberrant activation of NF-κB is linked with the progression of human
malignancies including
hepatocellular carcinoma (HCC), and blockade of NF-κB signaling could be a potential target in the treatment of several
cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation is of prime importance in the treatment of several
cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-
oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (
annexin V-
propidium iodide-
FITC staining), and phosphorylation of NF-κB signaling pathway
proteins (IκB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the
DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and
caspase-3 in a time-dependent manner. In addition, transfection with p65
small interfering RNA blocks CMO-induced
caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65
protein. Thus, we are reporting CMO as an inhibitor of NF-κB signaling pathway.