Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator

Ji Won Choi; Su Jeong Shin; Hyeon Ji Kim; Jong Hyun Park; Hyeon Jeong Kim; Elijah Hwejin Lee; Ae Nim Pae; Yong Sun Bahn; Ki Duk Park

doi:10.1021/acsmedchemlett.9b00163

Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator

Ji Won Choi, Su Jeong Shin, Hyeon Ji Kim, Jong Hyun Park, Hyeon Jeong Kim, Elijah Hwejin Lee, Ae Nim Pae, Yong Sun Bahn, Ki Duk Park

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone (1) as an Nrf2 activator with therapeutic potential for Parkinson's disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, 3c exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.

Original language	English
Pages (from-to)	1061-1067
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00163
Publication status	Published - 2019 Jul 11

Bibliographical note

Funding Information:
This study was supported by a National Research Council of Science & Technology grant by the South Korean government (MSIP, No. CRC-15-04-KIST) and the National Research Foundation of Korea (NRF-2018M3A9C8016849).

Publisher Copyright:
© 2019 American Chemical Society.

All Science Journal Classification (ASJC) codes

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.9b00163

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title = "Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator",

abstract = "The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone (1) as an Nrf2 activator with therapeutic potential for Parkinson's disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, 3c exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.",

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AU - Kim, Hyeon Jeong

AU - Lee, Elijah Hwejin

AU - Pae, Ae Nim

AU - Bahn, Yong Sun

AU - Park, Ki Duk

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PY - 2019/7/11

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N2 - The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone (1) as an Nrf2 activator with therapeutic potential for Parkinson's disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, 3c exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.

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Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator

Abstract

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