title: Rational design, synthesis and in vitro evaluation of novel exo-methylene butyrolactone salicyloylamide as NF-κB inhibitor.
abstract: (-)-Dehydroxymethylepoxyquinomicin ((-)-DHMEQ, 1) is a specific inhibitor of NF-κB. It binds to SH group in the specific cysteine residue of NF-κB components with its epoxide moiety to inhibit DNA binding. In the present research, we have designed and synthesized an epoxide-free analog called (S)-β-salicyloylamino-α-exo-methylene-ƴ-butyrolactone (SEMBL, 3). SEMBL inhibited DNA binding of NF-κB component p65 in vitro. It inhibited LPS-induced NF-κB activation, iNOS expression, and inflammatory cytokine secretions. It also inhibited NF-κB and cellular invasion in ovarian carcinoma ES-2 cells. Moreover, its stability in aqueous solution was greatly enhanced compared with (-)-DHMEQ. Thus, SEMBL has a potential to be a candidate for a new anti-inflammatory and anticancer agent.
authors.affiliation: Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
authors.forename: Kulrawee
authors.initials: K
authors.lastname: Sidthipong
authors.affiliation: Shenzhen Wanhe Pharmaceutical Co., Ltd., Hi-tech Industrial Park, Nanshan District, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Shenzhen Wanhe Pharmaceutical Co., Ltd., Hi-tech Industrial Park, Nanshan District, Shenzhen, China.
authors.forename: Wei Lin
authors.initials: WL
authors.lastname: Yu
authors.affiliation: Shenzhen Wanhe Pharmaceutical Co., Ltd., Hi-tech Industrial Park, Nanshan District, Shenzhen, China.
authors.forename: Yan Feng
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Chiba 278-8510, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, 2-522-1, Kiyose, Tokyo 204-0004, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishino
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
authors.affiliation: Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
authors.forename: Kuniki
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Pharmacology, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
authors.forename: Shoshiro
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan. Electronic address: umezawa@aichi-med-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D015107:4-Butyrolactone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D012457:Salicylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012457:Salicylamides; C000620856:beta-salicyloylamino-alpha-exo-methylene-gamma-butyrolactone; D015107:4-Butyrolactone
keywords: (−)-DHMEQ; Bioconjugate; Cysteine; NF-κB; α-Exomethylene-γ-lactone