title: 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.
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Hyeju
authors.initials: H
authors.lastname: Jo
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Arepalli
authors.initials: A
authors.lastname: Sateesh Kumar
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Joonkwang
authors.initials: J
authors.lastname: Lee
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Republic of Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Dongguk University, Goyang 410-773, Republic of Korea.
authors.forename: Jungsook
authors.initials: J
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea.
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Kyungsung University, Busan 608-736, Republic of Korea. Electronic address: jhkwak@ks.ac.kr.
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: Department of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea. Electronic address: medchem@chungbuk.ac.kr.
authors.forename: Heesoon
authors.initials: H
authors.lastname: Lee
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D001572:Benzofurans; D002264:Carboxylic Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; C105430:benzofuran
keywords: Anticancer activity; Benzofuran and 2,3-dihydrobenzofuran scaffolds; Inhibition of NF-κB transcriptional activity