2. Academic Validation
  3. Design and synthesis of adamantyl-substituted flavonoid derivatives as anti-inflammatory Nur77 modulators: Compound B7 targets Nur77 and improves LPS-induced inflammation in vitro and in vivo

Design and synthesis of adamantyl-substituted flavonoid derivatives as anti-inflammatory Nur77 modulators: Compound B7 targets Nur77 and improves LPS-induced inflammation in vitro and in vivo

  • Bioorg Chem. 2022 Mar;120:105645. doi: 10.1016/j.bioorg.2022.105645.
Mingtao Ao 1,  Jianyu Zhang 2,  Yuqing Qian 3,  Boqun Li 3,  Xiumei Wang 3,  Jun Chen 3,  Yuxiang Zhang 3,  Yin Cao 3,  Yingkun Qiu 3,  Yang Xu 4,  Zhen Wu 5,  Meijuan Fang 6
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China; School of Pharmacy, Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, Hubei 437100 China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
  • 3 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China.
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China. Electronic address: [email protected].
  • 5 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China. Electronic address: [email protected].
  • 6 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Chemistry and Chemical Engineering, Xiamen University, South Xiang-An Road, Xiamen 361102, China. Electronic address: [email protected].
PMID: 35121551 DOI: 10.1016/j.bioorg.2022.105645
Abstract

In continuing our study on discovering new Nur77-targeting anti-inflammatory agents with natural skeletons, we combined adamantyl group and hydroxamic acid moiety with flavonoid nucleus, synthesized three series of flavonoid derivatives with a similar structure like CD437, and evaluated their activities against LPS-induced inflammation. Compound B7 was found to be an excellent Nur77 binder (Kd = 3.55 × 10-7 M) and a potent inhibitor of inflammation, which significantly decreased the production of cytokines in vitro, such as NO, IL-6, IL-1β, and TNF-α, at concentrations of 1.25, 2.5, and 5 μM. Mechanistically, B7 modulated the colocalization of Nur77 at mitochondria and inhibited the lipopolysaccharides (LPS)-induced inflammation via the blockade of NF-κB activation in a Nur77-dependent manner. Additionally, B7 showed in vivo anti-inflammatory activity in the LPS-induced mice model of acute lung injury (ALI). These data suggest that the Nur77-targeting flavonoid derivatives can be particularly useful for further pharmaceutical development for the treatment of inflammatory diseases such as ALI.

Keywords

Acute lung injury; Anti-inflammation; Flavonoid derivatives; Nur77.

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