具有干预脂肪细胞分化活性天然产物Nigrasin Ⅰ的全合成及构效关系研究

发布时间：2018-01-26 16:09

本文关键词： 异戊烯基黄酮类化合物 Nigrasin I Kuwanon C 全合成促进脂肪细胞分化胰脂肪酶抑制剂　出处：《复旦大学》2014年硕士论文　论文类型：学位论文

【摘要】：Nigrasin I (1)是课题组前期从我国的桑科植物黑桑(Morus nigra Linn)中分离得到的异戊烯基黄酮类化合物。前期的体外药理活性研究显示,该化合物具有显著的促进脂肪细胞分化、增加Glut 4蛋白表达量而增加胰岛素敏感性和促进葡萄糖转运的作用,同时还具有抑制胰脂肪酶的活性,作为双靶标活性化合物,极具潜力发展成为抗2型糖尿病并具有减肥作用的候选药物。Nigrasin I在黑桑中含量极少(仅为10-6),这给后期的生物活性研究带来困难。经查阅文献,未见其全合成的相关报道。因此,本论文拟开展Nigrasin I的全合成及其类似物的合成研究。一方面为Nigrasin I生物活性的进一步研究奠定物质基础、解决Nigrasin I的资源问题,另一方面通过其类似物的合成可初步探讨构效关系规律,因此本课题的研究不仅对发展异戊烯基黄酮类天然产物的合成方法学、而且对寻找具有多靶标作用的抗代谢性疾病药物具有重要的学术意义和研究价值。通过三条合成路线的摸索,最终以廉价易得的2,4,6-三羟基苯乙酮为原料,经过11步反应,首次建立了Nigrasin I的全合成路线,总收率为22%。与此同时,利用该路线的关键中间体,以21%的总收率首次建立了另一生物活性天然产物Kuwanon C的全合成路线。在合成研究过程中,改进并建立了一些反应如Claisen重排和脱苄基全新条件,从而大大提高了合成的效率。这些工作对于天然异戊烯基黄酮类化合物的开发和利用具有重要价值。全文共合成未见文献报道的新化合物42个,均经波谱鉴定结构,其中目标化合物的类似物36个,可供生物活性测定。在探索Nigrasin I合成路线过程中,早期获得的一些关键中间体和结构类似物的部分生物活性数据已返回,包括对蛋白酪氨酸磷酸酶PTP1B抑制活性及NF-κB信号途径抑制活性。对蛋白酪氨酸磷酸酶PTP 1B抑制活性的测试结果显示,该批化合物均表现出了与阳性药齐墩果酸相当或更好的抑制活性。通过比较得出以下初步构效关系信息：(1)黄酮母核8-位2-甲基-3-丁烯-2-基侧链的存在对活性的提高是有利的。(2)黄酮母核3-位3-甲基-2-丁烯-1-基侧链的存在与否,对活性影响不大。(3)黄酮母核7-位羟基裸露时对活性的提高更为有利。(4)黄酮母核B环上两个羟基被保护时对抑制活性的提高是有利的,并且大基团(如苄基、苯甲酰基)比小基团(如甲基、乙酰基)对活性的提高更为有利。对NF--κB信号途径抑制活性的测试结果显示,只有化合物91和64表现出了一定的活性,其余化合物均无明显的抑制活性。据此可以得出以下初步构效关系信息：黄酮母核7-位羟基上的异戊烯基边链是化合物表现出活性所必须的,8-位和3-位侧链的存在与否对活性没有影响。另外,对于促进脂肪细胞分化活性和胰脂肪酶抑制活性的测试还在进行中。以上构效关系结果对该系列化合物的进一步研究具有一定的指导意义。
[Abstract]:Nigrasin I ~ (1) is a study group from Morus nigra Linn, a mulberry plant in China. Isopentenyl flavonoids isolated in vitro. Previous studies on pharmacological activities in vitro showed that isopentenyl flavonoids were isolated. The compound can significantly promote adipocyte differentiation, increase the expression of Glut 4 protein, increase insulin sensitivity and glucose transport, and inhibit the activity of pancreatic lipase. As a double target active compound, Nigrasin I has a great potential to be a candidate drug for anti-type 2 diabetes mellitus and has the effect of reducing weight. The content of Nigrasin I in black mulberry is very low (10-6 only). This brings difficulties to the study of biological activity in the later stage. After consulting the literature, there is no related report on its total synthesis. In this thesis, the total synthesis of Nigrasin I and the synthesis of its analogues will be carried out. On the one hand, it will lay a solid foundation for the further study of the biological activity of Nigrasin I. To solve the resource problem of Nigrasin I, on the other hand, through the synthesis of its analogues, we can preliminarily discuss the law of structure-activity relationship. Therefore, the study of this topic not only for the development of isopentenyl flavonoids natural products synthesis methodology. Moreover, it has important academic significance and research value to search for multi-target anti-metabolic disease drugs. Through the exploration of three synthetic routes, the cheap and easy to obtain 2O4 was finally adopted. 6-trihydroxyacetophenone was used as raw material, after 11 steps of reaction, the total synthesis route of Nigrasin I was established for the first time, the overall yield was 22%. At the same time, the key intermediate of this route was used. Another bioactive natural product, Kuwanon C, was synthesized with the total yield of 21% for the first time. Some new conditions for reaction such as Claisen rearrangement and debenzylation were improved and established. These works are of great value for the development and utilization of natural isopentenyl flavonoids. 42 new compounds have not been reported in the literature. All of them were identified by spectroscopic analysis, of which 36 of the target compounds could be used for the determination of biological activity. In the process of exploring the synthetic route of Nigrasin I. Some of the early bioactivity data for key intermediates and structural analogues have been returned. The inhibitory activity of protein tyrosine phosphatase (PTP1B) and NF- 魏 B signaling pathway (NF- 魏 B) was also studied. The results of PTP1B inhibitory activity of protein tyrosine phosphatase showed. All of the compounds showed inhibitory activity comparable to or better than the positive drug oleanolic acid. The following preliminary structure-activity relationship information: 1) was obtained by comparing with the positive drug oleanolic acid (Oleanolic acid). The existence of 8-methyl-3-butene-2-yl side chain in the parent nucleus of flavonoids was beneficial to the improvement of the activity.) the existence of the 3-methyl-2-butene-1-yl side chain in the mother nucleus of flavonoids. It is more favorable to increase the activity when the 7-position hydroxyl group of flavonoid mother nucleus is exposed. 4) the two hydroxyl groups on the B ring of the flavonoid mother nucleus are protected to increase the inhibitory activity. And large groups (such as benzyl, benzoyl) are more favorable than small groups (such as methyl, acetyl) on the increase of activity. The results of NF- 魏 B signaling pathway inhibition results show. Only compounds 91 and 64 showed some activity. The other compounds had no obvious inhibitory activity, and the following preliminary structure-activity relationship information could be obtained: the isopentenyl side chain on the 7-position hydroxyl group of flavonoid mother nucleus was necessary for the compound to exhibit activity. The presence of 8-site and 3-position side chains had no effect on the activity. The results of the structure-activity relationship are instructive for the further study of this series of compounds, which are still in progress in promoting adipocyte differentiation activity and pancreatic lipase inhibitory activity.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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