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 language | English |
|---|---|
| Pages (from-to) | 377-381 |
| Number of pages | 5 |
| Journal | ChemMedChem |
| Volume | 11 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2016 Feb 17 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
- Pharmacology
- Drug Discovery
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry
Cite this
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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 journal › Article
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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U2 - 10.1002/cmdc.201500546
DO - 10.1002/cmdc.201500546
M3 - Article
VL - 11
SP - 377
EP - 381
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 4
ER -