2. Academic Validation
  3. Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke

Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke

  • Angew Chem Int Ed Engl. 2020 Feb 3;59(6):2429-2439. doi: 10.1002/anie.201912489.
Cheng-Long Gao 1 2,  Gui-Ge Hou 1 3,  Jin Liu 1,  Tong Ru 1,  Ya-Zhou Xu 2,  Shun-Yi Zhao 2,  Hui Ye 2,  Lu-Yong Zhang 2,  Kai-Xian Chen 1 4,  Yue-Wei Guo 1 4,  Tao Pang 2,  Xu-Wen Li 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, China.
  • 3 School of Pharmacy, The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, China.
  • 4 Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China.
PMID: 31782597 DOI: 10.1002/anie.201912489
Abstract

Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti-inflammation in LPS-induced neuroinflammatory mice model and cerebral ischemic injury through anti-neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti-inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti-neuroinflammatory effect in vitro and in vivo by inhibiting PKM2-mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation-related diseases.

Keywords

anti-inflammatory; drug discovery; heterocycles; photoaffinity labeling; proteins.

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