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

doi:10.1002/cmdc.201500546

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 journal › Article › peer-review

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 language	English
Pages (from-to)	377-381
Number of pages	5
Journal	ChemMedChem
Volume	11
Issue number	4
DOIs	https://doi.org/10.1002/cmdc.201500546
Publication status	Published - 2016 Feb 17

Bibliographical note

Funding Information:
Funding for this study was provided by supporting grants from the Korea Health Technology R&D Project, the Korean Ministry of Health and Welfare (HI12C1022), and the Korea Institute of Science and Technology (KIST, 2E25240).

Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

All Science Journal Classification (ASJC) codes

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

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10.1002/cmdc.201500546

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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

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.

@article{b42f165e13754f699f207cb532f7f2a6,

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.",

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

note = "Funding Information: Funding for this study was provided by supporting grants from the Korea Health Technology R&D Project, the Korean Ministry of Health and Welfare (HI12C1022), and the Korea Institute of Science and Technology (KIST, 2E25240). Publisher Copyright: {\textcopyright} 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2016",

month = feb,

day = "17",

doi = "10.1002/cmdc.201500546",

language = "English",

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journal = "ChemMedChem",

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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, YS, 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 journal › Article › peer-review

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

N1 - Funding Information: Funding for this study was provided by supporting grants from the Korea Health Technology R&D Project, the Korean Ministry of Health and Welfare (HI12C1022), and the Korea Institute of Science and Technology (KIST, 2E25240). Publisher Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Abstract

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