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-kappa B

作者：Choi Minho; Jo Hyeju; Park Hyun Jung; Kumar Arepalli Sateesh; Lee Joonkwang; Yun Jieun; Kim Youngsoo; Han Sang Bae; Jung Jae Kyung; Cho Jungsook; Lee Kiho; Kwak Jae Hwan^*; Lee Heesoon

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(12): 2545-2549.

DOI：10.1016/j.bmcl.2015.04.050

• Anticancer activity
• Inhibition of NF-kappa B transcriptional activity
• Benzofuran and 2,3-dihydrobenzofuran scaffolds

With the aim of developing novel scaffolds as anticancer agents and inhibitors of NF-kappa B 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-kappa B 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-kappa B transcriptional activity. The +M effect and hydrophobic groups on the N-phenyl ring potentiated the anticancer activity and NF-kappa B 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-kappa B inhibitory activity. This novel lead scaffold may be helpful for investigation of new anticancer agents that act through inactivation of NF-kappa B.

• 出版日期2015-6-15