Screening, Synthesis, and in Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica

Eun Ji Ju, Seul Ki Yeon, Jong Hyun Park, So Young Cheon, Ji Won Choi, Taehwan Ha, Bo Ko Jang, Siwon Kim, Yong Gu Kang, Hayoung Hwang, Sung Jin Cho, Eunji Cheong, Yong Sun Bahn, Ae Nim Pae, Sung Min Kim, Ki Duk Park

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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.

Original languageEnglish
Pages (from-to)377-381
Number of pages5
JournalChemMedChem
Volume11
Issue number4
DOIs
Publication statusPublished - 2016 Feb 17

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Ju, E. J., Yeon, S. K., Park, J. H., Cheon, S. Y., Choi, J. W., Ha, T., Jang, B. K., Kim, S., Kang, Y. G., Hwang, H., Cho, S. J., Cheong, E., Bahn, Y. S., Pae, A. N., Kim, S. M., & Park, K. D. (2016). Screening, Synthesis, and in Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica. ChemMedChem, 11(4), 377-381. https://doi.org/10.1002/cmdc.201500546