【摘要】：目前,非甾體抗炎藥是全世界范圍內(nèi)處方量最大的藥物之一,僅次于抗感染藥。然而,長(zhǎng)期大劑量使用非甾體抗炎藥會(huì)產(chǎn)生胃腸道和腎臟等不良反應(yīng)。因此,開發(fā)高效低毒的新型抗炎藥物具有重大意義。有研究表明,白藜蘆醇具有廣泛而有效的抗炎作用�；谡n題組前期關(guān)于白藜蘆醇藥理作用的探索和構(gòu)效關(guān)系的研究,期望合成出新型白藜蘆醇衍生物,并對(duì)體外抗炎活性進(jìn)行評(píng)價(jià)。在此基礎(chǔ)上,對(duì)活性較好的化合物的進(jìn)行作用機(jī)制的研究,為開發(fā)高效低毒的抗炎藥物提供科學(xué)依據(jù)。本課題以(E)-1,3-二甲氧基-5-(4-甲氧基苯乙烯基)苯為起始原料,合成了白藜蘆醇丙烯酸酯類衍生物系列(23個(gè)化合物)和白藜蘆醇類黃酮衍生物系列(30個(gè)化合物)。通過(guò)合成路線篩選,工藝優(yōu)化,使得原料易得,反應(yīng)操作簡(jiǎn)便,收率較高。所合成的化合物通過(guò)1H NMR、13C NMR和MS、單晶衍射確定結(jié)構(gòu)和構(gòu)型。以LPS刺激的RAW 264.7細(xì)胞為炎癥細(xì)胞模型,對(duì)白藜蘆醇丙烯酸酯類衍生物進(jìn)行抗炎活性評(píng)價(jià)。采用Griess法測(cè)定細(xì)胞上清液中NO含量,檢測(cè)了白藜蘆醇丙烯酸酯類衍生物對(duì)RAW 264.7細(xì)胞釋放NO的影響。結(jié)果表明,大多數(shù)白藜蘆醇丙烯酸酯衍生物能夠不同程度抑制NO的釋放。其中,化合物D15抑制能力最強(qiáng),且一定范圍內(nèi),隨著藥物濃度的升高其抑制NO釋放的程度越高。采用Western blot法分析D15對(duì)RAW 264.7細(xì)胞NF-κB信號(hào)通路中IκB、p65蛋白的磷酸化水平的影響,結(jié)果表明,化合物D15能夠抑制RAW 264.7細(xì)胞內(nèi)IκB、p65蛋白的磷酸化,其能通過(guò)阻斷NF-κB信號(hào)通路發(fā)揮抗炎活性。
[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.
【學(xué)位授予單位】：合肥工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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本文編號(hào)：2386443