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
复制标题
苯并氧杂环庚烷衍生物作为缺血性中风潜在抗神经炎症药物的合成和靶点鉴定
DOI：
10.1002/anie.201912489
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发表时间：
2019-12-27
影响因子：
16.6
通讯作者：
Li, Xu-Wen
中科院分区：
文献类型：
--
作者：
Gao, Cheng-Long;Hou, Gui-Ge;Li, Xu-Wen
设计并合成了苯并氧杂卓衍生物，其中一种命中化合物在体外表现出有效性且毒性较低。在体内，该命中化合物通过在脂多糖诱导的神经炎症小鼠模型中发挥抗炎作用改善了疾病行为，并且通过在大脑中动脉短暂闭塞的大鼠中发挥抗神经炎症作用减轻了脑缺血损伤。利用光亲和探针对命中化合物进行靶点捕捞，确定丙酮酸激酶M2（PKM2）是负责该命中化合物抗炎作用的靶蛋白。此外，该命中化合物通过抑制PKM2介导的糖酵解和NLRP3激活，在体外和体内均表现出抗神经炎症作用，表明PKM2是神经炎症及其相关脑部疾病的一个新靶点。与已报道的PKM2抑制剂紫草素相比，该命中化合物具有更好的安全性，这使其成为针对PKM2治疗炎症相关疾病的先导化合物。
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.