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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

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Complement Inactivating Agents
Neuromyelitis Optica
Cytotoxicity
Screening
Aquaporin 4
Immunoglobulin G
Astrocytes
Aquaporins
Benzene
Optics
Cells
Demyelinating Diseases
Optic Nerve
Derivatives
Autoimmune Diseases
Molecules
divinyl sulfone
In Vitro Techniques
Antibodies
Spinal Cord

All Science Journal Classification (ASJC) codes

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

Cite this

Ju, Eun Ji ; Yeon, Seul Ki ; Park, Jong Hyun ; Cheon, So Young ; Choi, Ji Won ; Ha, Taehwan ; Jang, Bo Ko ; Kim, Siwon ; Kang, Yong Gu ; Hwang, Hayoung ; Cho, Sung Jin ; Cheong, Eunji ; Bahn, Yong-Sun ; Pae, Ae Nim ; Kim, Sung Min ; Park, Ki Duk. / Screening, Synthesis, and in Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica. In: ChemMedChem. 2016 ; Vol. 11, No. 4. pp. 377-381.
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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.",
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Ju, EJ, Yeon, SK, Park, JH, Cheon, SY, Choi, JW, Ha, T, Jang, BK, Kim, S, Kang, YG, Hwang, H, Cho, SJ, Cheong, E, Bahn, Y-S, Pae, AN, Kim, SM & Park, KD 2016, 'Screening, Synthesis, and in Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica', ChemMedChem, vol. 11, no. 4, pp. 377-381. https://doi.org/10.1002/cmdc.201500546

Screening, Synthesis, and in Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica. / Ju, Eun Ji; Yeon, Seul Ki; Park, Jong Hyun; Cheon, So Young; Choi, Ji Won; Ha, Taehwan; Jang, Bo Ko; Kim, Siwon; Kang, Yong Gu; Hwang, Hayoung; Cho, Sung Jin; Cheong, Eunji; Bahn, Yong-Sun; Pae, Ae Nim; Kim, Sung Min; Park, Ki Duk.

In: ChemMedChem, Vol. 11, No. 4, 17.02.2016, p. 377-381.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Screening, Synthesis, and in Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica

AU - Ju, Eun Ji

AU - Yeon, Seul Ki

AU - Park, Jong Hyun

AU - Cheon, So Young

AU - Choi, Ji Won

AU - Ha, Taehwan

AU - Jang, Bo Ko

AU - Kim, Siwon

AU - Kang, Yong Gu

AU - Hwang, Hayoung

AU - Cho, Sung Jin

AU - Cheong, Eunji

AU - Bahn, Yong-Sun

AU - Pae, Ae Nim

AU - Kim, Sung Min

AU - Park, Ki Duk

PY - 2016/2/17

Y1 - 2016/2/17

N2 - 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.

AB - 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.

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