1. Academic Validation
  2. Design, synthesis, and biological evaluation of novel sesquiterpene lactone derivatives as PKM2 activators with potent anti-ulcerative colitis activities

Design, synthesis, and biological evaluation of novel sesquiterpene lactone derivatives as PKM2 activators with potent anti-ulcerative colitis activities

  • Eur J Med Chem. 2024 Jun 5:272:116426. doi: 10.1016/j.ejmech.2024.116426.
Lingyu Ma 1 Mengting Li 1 Jiahao Lv 1 Qingxin Yuan 1 Xunkai Yin 1 Wenyu Lu 2 Weijiang Lin 1 Ping Wang 1 Jian Cui 1 Qi Lv 3 Jian Liu 4 Lihong Hu 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: qilv@njucm.edu.cn.
  • 4 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: liujian623@njucm.edu.cn.
  • 5 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: lhhu@njucm.edu.cn.
Abstract

Pyruvate Kinase isoform 2 (PKM2) is closely related to the regulation of Th17/Treg balance, which is considered to be an effective strategy for UC therapy. Parthenolide (PTL), a natural product, only possesses moderate PKM2-activating activity. Thus, five series of PTL derivatives are designed and synthesized to improve PKM2-activated activities and anti-UC abilities. Through detailed structure optimization, B4 demonstrates potent T-cell anti-proliferation activity (IC50 = 0.43 μM) and excellent PKM2-activated ability (AC50 = 0.144 μM). Subsequently, through mass spectrometry analysis, B4 is identified to interact with Cys423 of PKM2 via covalent-bond. Molecular docking and molecular dynamic simulation results reveal that the trifluoromethoxy of B4 forms a stronger hydrophobic interaction with Ala401, Pro402, and Ile403. In addition, B4 has a significant effect only on Th17 cell differentiation, thereby regulating the Th17/Treg balance. The effect of B4 on Th17/Treg imbalance can be attributed to inhibition of PKM2 dimer translocation and suppression of glucose metabolism. Finally, B4 can notably ameliorate the symptoms of dextran sulfate sodium (DSS)-induced colitis in mouse model in vivo. Thus, B4 is confirmed as a potent PKM2 activator, and has the potential to develop as a novel anti-UC agent.

Keywords

PKM2 activators; Parthenolide; Parthenolide derivatives; Th17/treg balance; Ulcerative colitis.

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