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  2. The in vitro and in vivo study of oleanolic acid indole derivatives as novel anti-inflammatory agents: Synthesis, biological evaluation, and mechanistic analysis

The in vitro and in vivo study of oleanolic acid indole derivatives as novel anti-inflammatory agents: Synthesis, biological evaluation, and mechanistic analysis

  • Bioorg Chem. 2021 Aug;113:104981. doi: 10.1016/j.bioorg.2021.104981.
Jingwei Jin 1 Hao He 1 Xinyue Zhang 1 Rihui Wu 1 Lishe Gan 1 Dongli Li 1 Yujing Lu 2 Panpan Wu 3 Wing-Leung Wong 4 Kun Zhang 5
Affiliations

Affiliations

  • 1 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, PR China.
  • 2 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: luyj@gdut.edu.cn.
  • 3 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, PR China. Electronic address: wyuchemwpp@126.com.
  • 4 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, PR China. Electronic address: wleungwong@outlook.com.
  • 5 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, PR China; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: kzhang@gdut.edu.cn.
Abstract

Oleanolic acid (OA) is a well-known natural product possessing many important pharmacological activities; however, its weak bioactivities significantly restrict the potential application in drug development. The structural modification of oleanolic acid is an effective mean to enhance its bioactivity with lower toxicity but it is challenging. In the present study, we systematically synthesized a series of new 11-oxooleanolic acid derivatives and evaluated their anti-inflammatory activities with a LPS induced BV2 cells inflammation model and a 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced ear inflammation mice model. It was found that compounds 8 and 9 show more potent anti-inflammatory effects than OA and exhibit a low cytotoxicity. The possible mechanism of action was also investigated. The in vitro and in vivo results revealed that these two new 11-oxooleanolic acid derivatives may exert anti-inflammatory activities through the inhibition of NO, pro-inflammatory cytokines and chemokines (IL-1β, IL-6, IL-12, TNF-α, MCP-1 and MIP-1α) and upregulation of anti-inflammatory cytokines (IL-10), which may be caused by inhibiting the activation of NF-κB, MAPKs and PI3K/Akt related inflammatory signaling pathways and the activation of Nrf2/HO-1 signaling pathway. The results suggest that these two 11-oxooleanolic acid derivatives may be potential candidates for further anti-inflammatory drug development and our study demonstrated an important and practical strategy for drug discovery through the rational modification of Natural Products.

Keywords

11-Oxooleanolic acid; Anti-inflammatory; Derivatives; Mechanism; Synthesis.

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