本文選題：活性　切入點：鹵酚　出處：《山西醫(yī)科大學》2014年碩士論文　論文類型：學位論文

【摘要】：目的 以LM49為先導化合物,設計并合成系列氯代多羥基二苯甲酮類化合物,尋找新的候選化合物。對目標化合物進行體外活性研究,選擇活性較高且易制備的化合物,分別考察其與LM49在大鼠體內的腸吸收特性,為闡明化合物腸吸收與生物利用度的關系提供合理的依據(jù)。 方法與結果 以甲氧基和鹵素取代的苯甲酸為起始原料,經過羧酸酰基化、傅克酰基化、芳香環(huán)鹵代、脫甲基等反應合成了系列氯酚類化合物,并通過質譜、高分辨質譜、氫譜和碳譜確證結構。對目標化合物進行了血管內皮細胞過氧化氫損傷保護、蛋白酪氨酸激酶抑制、體外抗腫瘤活性等多種體外生物活性的篩選。 本研究合成了12個未見文獻報道的化合物,其中包括8個目標化合物�；钚院Y選結果表明,系列氯酚化合物表現(xiàn)出顯著的細胞保護活性,其中兩個氯酚化合物2',3,4-三羥基-2,5,5'-三氯二苯甲酮(2b')和4,5,5'-三羥基-2,5'-二氯二苯甲酮(9a')對H202誘導的人臍靜脈內皮細胞損傷具有較強的保護活性,其EC50分別為5.2μM和6.2μM,對照品槲皮素與LM49分別為5.8μM和3.5μM。另外,化合物2b'還表現(xiàn)出較好的蛋白酪氨酸激酶抑制活性,其IC50為3.1μM,優(yōu)于陽性對照金雀異黃素13.6gM。 采用大鼠在體單向腸灌流法研究3個劑量組(20.00,40.00,80.00μg.mL-1)的LM49在大鼠十二指腸、空腸、回腸及結腸的吸收情況,同時選取了一個具有較高內皮細胞保護活性且較易制備的衍生物9a'與LM49在整體腸道水平進行了吸收對比,所選灌流液濃度為40.00μ.g.mL-1。 結果表明,9a'與LM49在全腸道吸收良好,并且LM49無特定吸收部位。 結論 本研究發(fā)現(xiàn)了2個具有較強細胞保護活性的新候選化合物,為接下來的工作提供了新的物質基礎；LM49在腸道吸收較好,說明了腸吸收不是導致其生物利用度偏低的原因,可能受肝臟首過影響較大,為我們下一步的研究提供了新的依據(jù)。
[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.
【學位授予單位】：山西醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914;R969.1

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