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-kB activity and anticancer agents

Abstract

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.