Design, synthesis, and biological evaluation of benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives as anticancer agents and inhibitors of NF-κB.

Abstract With the aim of developing novel scaffolds as anticancer agents and inhibitors of NF-κB activity, 60 novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N- (substituted)phenylamide derivatives ( 1a – s , 2a – k , 3a – s , and 4a – k ) were designed and synthesized from the reference lead compound KL-1156 , which is an inhibitor of NF-κB translocation to the nucleus in LPS-stimulated RAW 264.7 macrophage cells. The novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxamide derivatives exhibited potent cytotoxic activities (measured by the sulforhodamine B assay) at low micromolar concentrations against six human cancer cell lines: ACHN (renal), HCT15 (colon), MM231 (breast), NUGC-3 (gastric), NCI-H23 (lung), and PC-3 (prostate). In addition, these compounds also inhibited LPS-induced NF-κB transcriptional activity. The +M effect and hydrophobic groups on the N -phenyl ring potentiated the anticancer activity and NF-κB inhibitory activity, respectively. However, according to the results of structure–activity relationship studies, only benzofuran-2-carboxylic acid N -(4′-hydroxy)phenylamide ( 3m ) was the lead scaffold with both an outstanding anticancer activity and NF-κB inhibitory activity. This novel lead scaffold may be helpful for investigation of new anticancer agents that act through inactivation of NF-κB.