TY - JOUR
T1 - The in vitro and in vivo study of oleanolic acid indole derivatives as novel anti-inflammatory agents
T2 - Synthesis, biological evaluation, and mechanistic analysis
AU - Jin, Jingwei
AU - He, Hao
AU - Zhang, Xinyue
AU - Wu, Rihui
AU - Gan, Lishe
AU - Li, Dongli
AU - Lu, Yujing
AU - Wu, Panpan
AU - Wong, Wing Leung
AU - Zhang, Kun
N1 - Funding Information:
The authors gratefully acknowledge the support received from the National Natural Science Foundation of China (Grant: 81901678, 81803390, 22077020 and 22077111). Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515010221), Science Foundation for Young Teachers (2019td04) of Wuyi University. Special Fund Project of Science and Technology Innovation Strategy of Guangdong Province 2018 and 2020 [No. Jiangke (2018)352 and Jiangke (2020)182], the project of Jiangmen city social welfare innovation platform construction (No. 2016350100170008351, 2018090103460022105). The authors are also grateful to the foundation of Department of Education of Guangdong Province (No. 2020KZDZX1202, 2018KTSCX236, 2017KSYS010 and 2016KCXTD005) and Jiangmen Program for Innovative Research Team (No. 2018630100180019806).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - 11-Oxooleanolic acid
KW - Anti-inflammatory
KW - Derivatives
KW - Mechanism
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=85106221393&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2021.104981
DO - 10.1016/j.bioorg.2021.104981
M3 - Journal article
C2 - 34020279
AN - SCOPUS:85106221393
VL - 113
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
SN - 0045-2068
M1 - 104981
ER -