本文關(guān)鍵詞： 異戊烯基黃酮類化合物 Nigrasin I Kuwanon C 全合成 促進(jìn)脂肪細(xì)胞分化 胰脂肪酶抑制劑　出處：《復(fù)旦大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：Nigrasin I (1)是課題組前期從我國的�？浦参锖谏�(Morus nigra Linn)中分離得到的異戊烯基黃酮類化合物。前期的體外藥理活性研究顯示,該化合物具有顯著的促進(jìn)脂肪細(xì)胞分化、增加Glut 4蛋白表達(dá)量而增加胰島素敏感性和促進(jìn)葡萄糖轉(zhuǎn)運(yùn)的作用,同時(shí)還具有抑制胰脂肪酶的活性,作為雙靶標(biāo)活性化合物,極具潛力發(fā)展成為抗2型糖尿病并具有減肥作用的候選藥物。Nigrasin I在黑桑中含量極少(僅為10-6),這給后期的生物活性研究帶來困難。經(jīng)查閱文獻(xiàn),未見其全合成的相關(guān)報(bào)道。因此,本論文擬開展Nigrasin I的全合成及其類似物的合成研究。一方面為Nigrasin I生物活性的進(jìn)一步研究奠定物質(zhì)基礎(chǔ)、解決Nigrasin I的資源問題,另一方面通過其類似物的合成可初步探討構(gòu)效關(guān)系規(guī)律,因此本課題的研究不僅對(duì)發(fā)展異戊烯基黃酮類天然產(chǎn)物的合成方法學(xué)、而且對(duì)尋找具有多靶標(biāo)作用的抗代謝性疾病藥物具有重要的學(xué)術(shù)意義和研究價(jià)值。通過三條合成路線的摸索,最終以廉價(jià)易得的2,4,6-三羥基苯乙酮為原料,經(jīng)過11步反應(yīng),首次建立了Nigrasin I的全合成路線,總收率為22%。與此同時(shí),利用該路線的關(guān)鍵中間體,以21%的總收率首次建立了另一生物活性天然產(chǎn)物Kuwanon C的全合成路線。在合成研究過程中,改進(jìn)并建立了一些反應(yīng)如Claisen重排和脫芐基全新條件,從而大大提高了合成的效率。這些工作對(duì)于天然異戊烯基黃酮類化合物的開發(fā)和利用具有重要價(jià)值。全文共合成未見文獻(xiàn)報(bào)道的新化合物42個(gè),均經(jīng)波譜鑒定結(jié)構(gòu),其中目標(biāo)化合物的類似物36個(gè),可供生物活性測(cè)定。在探索Nigrasin I合成路線過程中,早期獲得的一些關(guān)鍵中間體和結(jié)構(gòu)類似物的部分生物活性數(shù)據(jù)已返回,包括對(duì)蛋白酪氨酸磷酸酶PTP1B抑制活性及NF-κB信號(hào)途徑抑制活性。對(duì)蛋白酪氨酸磷酸酶PTP 1B抑制活性的測(cè)試結(jié)果顯示,該批化合物均表現(xiàn)出了與陽性藥齊墩果酸相當(dāng)或更好的抑制活性。通過比較得出以下初步構(gòu)效關(guān)系信息：(1)黃酮母核8-位2-甲基-3-丁烯-2-基側(cè)鏈的存在對(duì)活性的提高是有利的。(2)黃酮母核3-位3-甲基-2-丁烯-1-基側(cè)鏈的存在與否,對(duì)活性影響不大。(3)黃酮母核7-位羥基裸露時(shí)對(duì)活性的提高更為有利。(4)黃酮母核B環(huán)上兩個(gè)羥基被保護(hù)時(shí)對(duì)抑制活性的提高是有利的,并且大基團(tuán)(如芐基、苯甲�；�)比小基團(tuán)(如甲基、乙�；�)對(duì)活性的提高更為有利。對(duì)NF--κB信號(hào)途徑抑制活性的測(cè)試結(jié)果顯示,只有化合物91和64表現(xiàn)出了一定的活性,其余化合物均無明顯的抑制活性。據(jù)此可以得出以下初步構(gòu)效關(guān)系信息：黃酮母核7-位羥基上的異戊烯基邊鏈?zhǔn)腔衔锉憩F(xiàn)出活性所必須的,8-位和3-位側(cè)鏈的存在與否對(duì)活性沒有影響。另外,對(duì)于促進(jìn)脂肪細(xì)胞分化活性和胰脂肪酶抑制活性的測(cè)試還在進(jìn)行中。以上構(gòu)效關(guān)系結(jié)果對(duì)該系列化合物的進(jìn)一步研究具有一定的指導(dǎo)意義。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914

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