國家衛生研究院 NHRI:Item 3990099045/16036
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    题名: Synthesis of electrophilic cyclopent-2-enone conjugates with modulatory effects on inflammatory responses mediated by Nrf2/Keap1, NF-κB and IL-6
    作者: Neri, GLL;Chen, YS;Arturo, HCP;Quimque, MTJ;Vidar, WS;Keum, YS;Liao, CC;Yen, CH;Macabeo, APG
    贡献者: NHRI Graduate Student Program
    摘要: Cyclopent-2-enone bearing natural products possess anti-inflammatory, cytotoxic, antiproliferative, and antimicrobial activities attributed to the presence of a Michael acceptor enone group acting as a bait for protein targets. To explore the biological activity of synthetic small molecules bearing the cyclopent-2-enone moiety, a collection of 4-substituted cyclopent-2-enones (3 a-3 i) was prepared synthetically using Lewis acid-catalyzed Mukaiyama-Michael reaction (MMR) in modest to high yields. These derivatives were screened for their effect on inflammatory response mediators, namely Nrf2, NF-kappa B, and IL-6 through cell-based reporter assays. The results show that 5-(4-oxocyclopent-2-en-1-yl)furan-2(5H)-one (3 g) is a potent Nrf2 activator in HaCaT cells. The mechanism of Nrf2 activation by 3 g was investigated through an MS/MS-directed proteomic analysis and have shown the formation of a Michael adduct via cysteine-613 on Keap1, an inhibitor of Nrf2. Density functional theory calculations show favorable Michael adduct formation between 3 g and the truncated Keap1 tripeptide Pro-Cys613-Ala at the beta-carbon of the cyclopent-2-enone moiety. On the other hand, the derivative 4-(2-oxo-2-phenylethyl)cyclopent-2-en-1-one (3 a) exhibited selective Nrf2 inhibition in the cancer cell line Huh7, and inhibitory activity along with 3 g against NF-kappa B, and IL-6 in RAW 264.7 cells. This points to the cyclopent-2-enone group being an effective scaffold for anti-inflammatory drug designs.
    日期: 2024-08-12
    關聯: Chemistryselect. 2024 Aug 12;9(30):Article number e202401507.
    Link to: http://dx.doi.org/10.1002/slct.202401507
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2365-6549&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001284864600001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85200696260
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