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

  • Bioorg Med Chem Lett. 2015 Jun 15;25(12):2545-9. doi: 10.1016/j.bmcl.2015.04.050.
Minho Choi  1 ,  Hyeju Jo  1 ,  Hyun-Jung Park  1 ,  Arepalli Sateesh Kumar  1 ,  Joonkwang Lee  1 ,  Jieun Yun  2 ,  Youngsoo Kim  1 ,  Sang-Bae Han  1 ,  Jae-Kyung Jung  1 ,  Jungsook Cho  3 ,  Kiho Lee  4 ,  Jae-Hwan Kwak  5 ,  Heesoon Lee  6
Affiliations
  • 1. Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
  • 2. Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Republic of Korea.
  • 3. College of Pharmacy, Dongguk University, Goyang 410-773, Republic of Korea.
  • 4. College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea.
  • 5. College of Pharmacy, Kyungsung University, Busan 608-736, Republic of Korea. Electronic address: [email protected].
  • 6. Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea. Electronic address: [email protected].
PMID: 25953156 DOI: 10.1016/j.bmcl.2015.04.050
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.

Keywords
Anticancer activity; Benzofuran and 2,3-dihydrobenzofuran scaffolds; Inhibition of NF-κB transcriptional activity.