Synthesis and bioevaluation of Scutellarein-Tertramethylpyrazine hybrid molecules for the treatment of ischemic stroke
Synthesis and bioevaluation of Scutellarein-Tertramethylpyrazine hybrid molecules for the treatment of ischemic stroke
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DOI：
10.1016/j.bioorg.2023.106978
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发表时间：
2023-11-18
影响因子：
5.1
通讯作者：
Xu，Jianwei
中科院分区：
文献类型：
--
作者：
Dong，Yongxi;Wang，Fang;Xu，Jianwei
脑供血不足引起的缺血性中风可能会产生一系列级联反应，导致氧化应激，最终诱导神经细胞损伤。因此，具有多重治疗作用的杂合分子对于缺血性脑卒中的治疗具有不可替代的优势。本文在前人工作的基础上，根据PepT 1设计合成了两种野黄芩素和四甲基吡嗪杂合分子。经系统研究，合成的杂合分子均表现出较原药物更好的神经保护作用和抗血小板活性。其中，筛选出的具有上级神经保护和抗血小板作用的化合物1 e能显著增强Caco-2细胞单层膜的通透性，抑制Caco-2细胞对Gly-Sar的摄取。同时，肠灌注结果也证实了所选化合物1 e的吸收确实增加。此外，所选化合物1显著减少大脑中动脉闭塞/再灌注大鼠的脑梗死体积。尤其是高剂量组脑梗死体积缩小至模型组的1/4。同时，苏木精-伊红染色的结果也表明，用化合物1 e处理后，海马CA 1区的损伤显著减轻。因此，分子杂交策略是提高单靶向药物治疗效果的简单可行的方法之一。
Ischemic stroke caused by insufficient blood supply to the brain may produce a sequence of cascade reactions, leading to oxidative stress and ultimately inducing nerve cell damage. Therefore, hybrid molecules with multiple therapeutic effects have irreplaceable advantages for the treatment of ischemic stroke. Based on the previous works, two types of Scutellarein and Tertramethylpyrazine hybrid molecules were designed and synthesized according to the PepT 1-based design. After systematic research, all synthesized hybrid molecules exhibited more excellent neuroprotective effect and antiplatelet activity compared to the original drugs. Among them, the selected compound1ewith superior neuroprotective and antiplatelet effects could significantly enhance the permeability on the Caco-2 monolayer membrane and inhibit the Gly-Sar uptake on Caco-2 cells. Meanwhile, the result of intestinal perfusion has also confirmed that the absorption of the selected compound1eis indeed increased. Further, the selected compound1esignificantly reduce the cerebral infarction volume of middle cerebral artery occlusion/reperfusion rats. Especially, the cerebral infarction volume of the high-dose1egroup reduced to one fourth of the model group. Meanwhile, results of hematoxylin-eosin staining also indicated that the damage in the hippocampus CA1 region was significantly alleviated after treatment with the compound1e. Accordingly, molecular hybridization strategy is one of the simple and feasible ways to improve the therapeutic effect of single targeted drug.