白藜芦醇衍生物的合成及抗炎活性评价

发布时间：2018-12-18 20:19

【摘要】：目前,非甾体抗炎药是全世界范围内处方量最大的药物之一,仅次于抗感染药。然而,长期大剂量使用非甾体抗炎药会产生胃肠道和肾脏等不良反应。因此,开发高效低毒的新型抗炎药物具有重大意义。有研究表明,白藜芦醇具有广泛而有效的抗炎作用。基于课题组前期关于白藜芦醇药理作用的探索和构效关系的研究,期望合成出新型白藜芦醇衍生物,并对体外抗炎活性进行评价。在此基础上,对活性较好的化合物的进行作用机制的研究,为开发高效低毒的抗炎药物提供科学依据。本课题以(E)-1,3-二甲氧基-5-(4-甲氧基苯乙烯基)苯为起始原料,合成了白藜芦醇丙烯酸酯类衍生物系列(23个化合物)和白藜芦醇类黄酮衍生物系列(30个化合物)。通过合成路线筛选,工艺优化,使得原料易得,反应操作简便,收率较高。所合成的化合物通过1H NMR、13C NMR和MS、单晶衍射确定结构和构型。以LPS刺激的RAW 264.7细胞为炎症细胞模型,对白藜芦醇丙烯酸酯类衍生物进行抗炎活性评价。采用Griess法测定细胞上清液中NO含量,检测了白藜芦醇丙烯酸酯类衍生物对RAW 264.7细胞释放NO的影响。结果表明,大多数白藜芦醇丙烯酸酯衍生物能够不同程度抑制NO的释放。其中,化合物D15抑制能力最强,且一定范围内,随着药物浓度的升高其抑制NO释放的程度越高。采用Western blot法分析D15对RAW 264.7细胞NF-κB信号通路中IκB、p65蛋白的磷酸化水平的影响,结果表明,化合物D15能够抑制RAW 264.7细胞内IκB、p65蛋白的磷酸化,其能通过阻断NF-κB信号通路发挥抗炎活性。
[Abstract]:At present, non-steroidal anti-inflammatory drugs are one of the largest prescriptions in the world, second only to anti-infective drugs. However, long-term high-dose non-steroidal anti-inflammatory drugs can produce adverse effects such as gastrointestinal and kidney reactions. Therefore, it is of great significance to develop new anti-inflammatory drugs with high efficiency and low toxicity. Some studies have shown that resveratrol has extensive and effective anti-inflammatory effects. Based on the previous research on the pharmacological action and structure-activity relationship of resveratrol, a new type of resveratrol derivative is expected to be synthesized and its anti-inflammatory activity is evaluated in vitro. On this basis, the study on the mechanism of action of the active compounds provides scientific basis for the development of high efficiency and low toxicity anti-inflammatory drugs. In this paper, the starting material of (E) 1 (3-dimethoxy-5- (4-methoxystyreneyl) benzene) was used as the starting material. Resveratrol acrylate derivatives (23 compounds) and resveratrol flavonoids derivatives (30 compounds) were synthesized. By screening the synthetic route and optimizing the process, the raw materials are easily obtained, the reaction is easy to operate and the yield is high. The structure and configuration of the synthesized compounds were determined by 1H NMR,13C NMR and MS, single crystal diffraction. The anti-inflammatory activity of resveratrol acrylate derivatives was evaluated by using RAW 264.7 cells stimulated by LPS as inflammatory cell model. The effect of resveratrol acrylate derivatives on the release of NO from RAW 264.7 cells was determined by Griess assay. The results showed that most of the resveratrol acrylate derivatives could inhibit the release of NO to varying degrees. Among them, compound D15 has the strongest inhibitory ability, and in a certain range, with the increase of drug concentration, the degree of inhibition of NO release is higher. The effect of D15 on the phosphorylation of I 魏 B p65 protein in NF- 魏 B signaling pathway of RAW 264.7 cells was analyzed by Western blot assay. The results showed that D15 could inhibit the phosphorylation of I 魏 B p65 protein in RAW 264.7 cells. It can play an anti-inflammatory activity by blocking NF- 魏 B signaling pathway.
【学位授予单位】：合肥工业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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