Design and synthesis of 2,3-dihydro- and 5-chloro-2,3-dihydro-naphtho-[1,2- b ]furan-2-carboxylic acid N -(substitutedphenyl)amide analogs and their biological activities as inhibitors of NF-κB activity and anticancer agents

A series of 2,3-dihydro- and 5-chloro-2,3-dihydro-naphtho-[1,2- b ]furan-2-carboxylic acid N -(substitutedphenyl)amide analogs ( 1a–k and 2a–i ) were designed and synthesized for developing novel naphthofuran scaffolds as anticancer agents and inhibitors of NF-κB activity. Compound 1d , which had a 4′-chloro group on the N -phenyl ring, exhibited inhibitory activity of NF-κB. Compound 2g , which had a 5′-chloro group on the naphthofuran ring and a 3′,5′-bistrifluoromethane group on the N -phenyl ring, had the best NF-κB inhibitory activity. In addition, the novel analogs exhibited potent cytotoxicity at low concentrations against HCT-116, NCI-H23, and PC-3 cell lines. The two electron-withdrawing groups, especially at the 3′,5′-position on the N -phenyl ring, increased anticancer activity and NF-κB inhibitory activity. However, only 5-chloro-2,3-dihydronaphtho[1,2- b ]furan-2-carboxylic N -(3′,5′-bis(trifluoromethyl)phenyl)amide ( 2g ) exhibited both outstanding cytotoxicity and NF-κB inhibitory activities. This novel lead scaffold may be helpful for investigation of new anticancer agents by inactivation of NF-κB.