title: Screening, Synthesis, and In Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica.
abstract: Neuromyelitis optica (NMO) is a demyelinating autoimmune disease of the optic nerve and spinal cord triggered by binding of NMO-specific immunoglobulin G (NMO-IgG) auto-antibodies to the water channel aquaporin-4 (AQP4) in astrocytes. To find potential NMO therapeutics, a screening system was established and used to identify inhibitors of NMO-IgG-mediated complement-dependent cytotoxicity (CDC). The screening of approximately 400 compounds yielded potent hit compounds with inhibitory effects against CDC in U87-MG cells expressing human AQP4. Derivatives of the hit compounds were synthesized and evaluated for their inhibition of CDC. Of the small molecules synthesized, (E)-1-(2-((4-methoxyphenyl)sulfonyl)vinyl)-[4-[(3-trifluoromethyl)phenyl] methoxy]benzene (5 c) showed the most potent activity in both stably transfected U87-MG cells and mice-derived astrocytes. The results of this study suggest that 5 c, which targets NMO-IgG-specific CDC, may be useful as a research tool and a potential candidate for therapeutic development for the treatment of NMO.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.|Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Ju
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.|Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
authors.forename: Seul Ki
authors.initials: SK
authors.lastname: Yeon
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Neurology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Cheon
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.|Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
authors.forename: Taehwan
authors.initials: T
authors.lastname: Ha
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
authors.forename: Bo Ko
authors.initials: BK
authors.lastname: Jang
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.|Department of Biological Chemistry, University of Science and Technology, Daejeon, 34132, Republic of Korea.
authors.forename: Siwon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
authors.forename: Yong Gu
authors.initials: YG
authors.lastname: Kang
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Hwang
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Cheong
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
authors.forename: Yong Sun
authors.initials: YS
authors.lastname: Bahn
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.|Department of Biological Chemistry, University of Science and Technology, Daejeon, 34132, Republic of Korea.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.affiliation: Department of Neurology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea. sueh916@gmail.com.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea. kdpark@kist.re.kr.|Department of Biological Chemistry, University of Science and Technology, Daejeon, 34132, Republic of Korea. kdpark@kist.re.kr.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D009471:Neuromyelitis Optica / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G; D013450:Sulfones; C009873:divinyl sulfone; D003165:Complement System Proteins
keywords: NMO-specific immunoglobulin G autoantibodies; aquaporin-4; complement-dependent cytotoxicity; neuromyelitis optica; vinyl sulfones