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目的设计合成一系列黄酮醇类衍生物,并评价其抗神经炎症活性。方法以间苯三酚为原料,经傅克酰基化、缩合、Algar-Flynn-Oyamada和Claisen重排等反应合成目标化合物。采用CCK-8法检测化合物对小鼠小胶质细胞(BV2细胞)的无毒剂量范围。应用脂多糖(LPS)和干扰素γ(IFN-γ)与BV2细胞孵育24 h建立神经炎症细胞模型,用Griess法检测BV2细胞释放的一氧化氮(NO)含量。结果合成了8个黄酮醇类化合物,其中4个具有异戊烯基,目标化合物的结构经质谱、核磁共振氢谱确定。化合物6a~6d和10a~10d在1~100μmol·L-1的剂量范围内均未显示细胞毒性。化合物6a和10a(10μmol·L-1)与BV2细胞预孵育24 h能够明显抑制LPS/IFN-γ诱导的炎性介质NO过度产生和释放。结论合成的黄酮醇类化合物6a和10a具有抗神经炎症的活性。
Objective To design and synthesize a series of flavonol derivatives and evaluate their anti-neuroinflammatory activity. Methods The target compounds were synthesized from phloroglucinol by Friedel-Crafts acylation, condensation, Algar-Flynn-Oyamada and Claisen rearrangement. The non-toxic dose range of compound to mouse microglial cells (BV2 cells) was tested by CCK-8 method. Neuronal inflammatory cell model was established by incubating BV2 cells with lipopolysaccharide (LPS) and interferon gamma (IFN-γ) for 24 hours. The content of nitric oxide (NO) released from BV2 cells was detected by Griess method. Results Eight flavonol compounds were synthesized, of which four had isopentenyl groups. The structure of target compounds was confirmed by MS and 1H NMR. Compounds 6a to 6d and 10a to 10d did not show cytotoxicity in the dose range of 1 to 100 μmol·L -1. The preincubation of compounds 6a and 10a (10 μmol·L-1) with BV2 cells for 24 h significantly inhibited NO production and release induced by LPS / IFN-γ in inflammatory mediators. Conclusion The synthetic flavonols 6a and 10a have anti-neuroinflammatory activity.