活性卤酚化合物LM49的结构优化及肠吸收评价

发布时间：2018-03-07 11:58

本文选题：活性　切入点：卤酚　出处：《山西医科大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的以LM49为先导化合物,设计并合成系列氯代多羟基二苯甲酮类化合物,寻找新的候选化合物。对目标化合物进行体外活性研究,选择活性较高且易制备的化合物,分别考察其与LM49在大鼠体内的肠吸收特性,为阐明化合物肠吸收与生物利用度的关系提供合理的依据。方法与结果以甲氧基和卤素取代的苯甲酸为起始原料,经过羧酸酰基化、傅克酰基化、芳香环卤代、脱甲基等反应合成了系列氯酚类化合物,并通过质谱、高分辨质谱、氢谱和碳谱确证结构。对目标化合物进行了血管内皮细胞过氧化氢损伤保护、蛋白酪氨酸激酶抑制、体外抗肿瘤活性等多种体外生物活性的筛选。本研究合成了12个未见文献报道的化合物,其中包括8个目标化合物。活性筛选结果表明,系列氯酚化合物表现出显著的细胞保护活性,其中两个氯酚化合物2',3,4-三羟基-2,5,5'-三氯二苯甲酮(2b')和4,5,5'-三羟基-2,5'-二氯二苯甲酮(9a')对H202诱导的人脐静脉内皮细胞损伤具有较强的保护活性,其EC50分别为5.2μM和6.2μM,对照品槲皮素与LM49分别为5.8μM和3.5μM。另外,化合物2b'还表现出较好的蛋白酪氨酸激酶抑制活性,其IC50为3.1μM,优于阳性对照金雀异黄素13.6gM。采用大鼠在体单向肠灌流法研究3个剂量组(20.00,40.00,80.00μg.mL-1)的LM49在大鼠十二指肠、空肠、回肠及结肠的吸收情况,同时选取了一个具有较高内皮细胞保护活性且较易制备的衍生物9a'与LM49在整体肠道水平进行了吸收对比,所选灌流液浓度为40.00μ.g.mL-1。结果表明,9a'与LM49在全肠道吸收良好,并且LM49无特定吸收部位。结论本研究发现了2个具有较强细胞保护活性的新候选化合物,为接下来的工作提供了新的物质基础；LM49在肠道吸收较好,说明了肠吸收不是导致其生物利用度偏低的原因,可能受肝脏首过影响较大,为我们下一步的研究提供了新的依据。
[Abstract]:Purpose. A series of chlorinated polyhydroxybenzophenone compounds were designed and synthesized with LM49 as the lead compound to search for new candidate compounds. In order to clarify the relationship between intestinal absorption and bioavailability of compound, the characteristics of intestinal absorption and LM49 in rats were investigated respectively in order to provide a reasonable basis for elucidating the relationship between intestinal absorption and bioavailability. Methods and results. A series of chlorophenols were synthesized from methoxy and halogen-substituted benzoic acid by carboxylic acylation, Fourier acylation, aromatic cyclic halogenation and demethylation. Hydrogen and carbon spectra were used to confirm the structure of the target compounds. The target compounds were screened for hydrogen peroxide damage, inhibition of protein tyrosine kinase and antitumor activity in vitro. In this study, 12 unreported compounds were synthesized, including 8 target compounds. The screening results showed that the series of chlorophenols exhibited significant cytoprotective activity. Among them, two chlorophenol compounds, 2O3H3H3H2O5O5C2K2BX and 4C5O5H2H2H2K2) have strong protective activity against H202 induced injury of human umbilical vein endothelial cells (H202), and the two compounds have a strong protective activity against human umbilical vein endothelial cell injury induced by H202, and the two compounds have strong protective activity against human umbilical vein endothelial cell injury induced by H202, and the two compounds have strong protective effects on human umbilical vein endothelial cells induced by H202. Their EC50 were 5.2 渭 M and 6.2 渭 M, and those of quercetin and LM49 were 5.8 渭 M and 3.5 渭 M. in addition, 2b'also showed a good inhibitory activity of protein tyrosine kinase, its IC50 was 3.1 渭 M, which was better than that of genistein (13.6 g / m). The absorption of LM49 from the duodenum, jejunum, ileum and colon of rats in three dose groups was studied by unilateral intestinal perfusion in vivo, and the absorption of LM49 in the duodenum, jejunum, ileum and colon of three dose groups was studied. At the same time, a derivative 9a', which has high endothelial cell protective activity and is easy to be prepared, was selected for absorption comparison with LM49 at the whole intestinal level. The concentration of perfusion fluid was 40.00 渭 .g.mL-1. The results showed that 9 'and LM49 absorbed well in the whole intestine, and there was no specific absorption site in LM49. Conclusion. In this study, two new candidate compounds with strong cytoprotective activity were found, which provided a new material basis for the following work: LM49 was well absorbed in the intestine, indicating that intestinal absorption is not the cause of its low bioavailability. May be greatly affected by liver first pass, which provides a new basis for our next research.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914;R969.1

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