本文選題：異戊烯基黃酮類(lèi)　切入點(diǎn)：全合成　出處：《湖南大學(xué)》2015年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：黃酮類(lèi)是一類(lèi)廣泛分布于植物界的酚類(lèi)次級(jí)代謝產(chǎn)物,是天然產(chǎn)物的重要組成部分。這類(lèi)化合物具有多種生物活性和有效的醫(yī)療應(yīng)用,如抗癌和抗腫瘤活性、抗炎和抗病毒活性、抗菌和抗真菌活性、抗心血管疾病、酶抑制活性、抗自由基和抗氧化活性。異戊烯黃酮是一類(lèi)獨(dú)特的天然黃酮類(lèi)化合物,其特征是在黃酮骨架上存在著異戊烯基側(cè)鏈。C-異戊烯化的黃酮可以增強(qiáng)其對(duì)p-糖蛋白的親和力和對(duì)細(xì)胞膜的通透性,可以顯著提高黃酮類(lèi)化合物的生物活性。具有顯著抗癌活性的天然異戊烯基黃酮類(lèi),可以作為日益增長(zhǎng)的保健食品的先導(dǎo)化合物和人類(lèi)疾病治療新的藥物來(lái)源。然而,黃酮類(lèi)和異戊烯基類(lèi)黃酮在自然界植物中的含量低且來(lái)源有限,這些因素嚴(yán)重影響其生物活性?xún)r(jià)值的開(kāi)發(fā)和利用。因此,黃酮類(lèi)和異戊烯基類(lèi)黃酮的化學(xué)合成將解決其實(shí)用性難題。另一方面,黃酮類(lèi)化合物在藥物研發(fā)中存在著溶解性差、生物利用度低等缺點(diǎn),限制了它們的應(yīng)用。Mannich反應(yīng)是合成β-胺基酮和鄰胺基酚類(lèi)等含氮有機(jī)化合物的有效方法,被廣泛應(yīng)用于天然產(chǎn)物和有機(jī)藥物分子的合成。含氮的Mannich堿結(jié)構(gòu)單元是一類(lèi)重要的藥理活性基團(tuán),它可以有效提高化合物的生物活性、生物利用度和水溶性。因此進(jìn)行黃酮Mannich堿衍生物的合成與生物活性研究具有重要意義。本論文圍繞異戊烯基黃酮類(lèi)和黃酮Mannich堿衍生物的合成與生物活性進(jìn)行了系列研究。1、淫羊藿素(1a)的全合成。本論文以2,4,6-三羥基苯乙酮和4-羥基苯甲酸為原料,通過(guò)Baker-Venkatarama反應(yīng)、選擇性芐基或甲氧基甲基保護(hù)、二甲基過(guò)氧丙酮(DMDO)氧化、O-異戊烯基化反應(yīng)、微波促進(jìn)的Claisen重排和脫保護(hù)基等8步反應(yīng),以23%的總產(chǎn)率合成了具有重要意義的生物活性物質(zhì)8-異戊烯基類(lèi)黃酮淫羊藿素。對(duì)該合成的關(guān)鍵反應(yīng)步驟微波促進(jìn)的Claisen重排進(jìn)行了探討。2、首次全合成了Sophoflavescenol(1b)、Flavenochromane C(2b)和Citrusinol(3b)等三種有良好藥理活性如細(xì)胞毒性、抗癌和治療性功能勃起障礙的天然異戊烯基黃酮類(lèi)或異戊烯基側(cè)鏈成環(huán)的黃酮類(lèi)化合物。全合成是以2,4,6-三羥基苯乙酮和取代苯甲醛為初始原料,分別通過(guò)甲氧甲基保護(hù)、羥醛縮合、環(huán)合反應(yīng)、DMDO氧化、O-異戊烯化、微波促進(jìn)的Claisen重排、脫保護(hù)基、異戊烯基環(huán)合作用和DDQ脫氫等反應(yīng)步驟。1b、2b和3b的總產(chǎn)率分別為23%,17%和16%。其中最為關(guān)鍵的步驟是從5-O-異戊烯基黃酮通過(guò)微波促進(jìn)的Claisen重排得到8-異戊烯基黃酮類(lèi)。3、異戊烯基黃酮類(lèi)淫羊藿素(1a)在微波條件下和甲酸反應(yīng)以89%的收率得到另一種天然產(chǎn)物β-去水淫羊藿黃素(2c)。以1a和2c為底物,分別與甲醛、各種仲胺在酸性醇溶液中進(jìn)行Mannich反應(yīng),合成得到18個(gè)6位胺甲基化的Mannich堿衍生物3c-11c和12c-20c。對(duì)這些化合物采用標(biāo)準(zhǔn)CCK-8法對(duì)宮頸癌Hela細(xì)胞系的細(xì)胞毒性潛力進(jìn)行了測(cè)試,以抗癌藥物順鉑為陽(yáng)性對(duì)照,結(jié)果表明絕大部分化合物對(duì)Hela細(xì)胞表現(xiàn)出中等強(qiáng)度的細(xì)胞毒性。4、山奈素(3,5,7-三羥基-4'-甲氧基黃酮,1d)是對(duì)許多人腫瘤細(xì)胞系有抗癌活性的黃酮類(lèi)天然產(chǎn)物,我們以來(lái)源豐富且廉價(jià)的柚皮苷為原料首次通過(guò)半合成得到山奈素。以山奈素與各種仲胺和甲醛進(jìn)行Mannich反應(yīng),得到9種山奈素Mannich堿衍生物2d-10d。胺甲基化的位置,優(yōu)先發(fā)生在黃酮環(huán)上的C-6和C-8位置。所有合成化合物以標(biāo)準(zhǔn)CCK-8法測(cè)試其對(duì)宮頸癌Hela細(xì)胞系的細(xì)胞毒活性,結(jié)果表明,所有的目標(biāo)化合物表現(xiàn)出對(duì)Hela細(xì)胞的中度到良好的細(xì)胞毒性(IC50值為12.48-70.52μM),化合物1d,2d,5d-9d及10d的細(xì)胞毒性效果分別為優(yōu)于或等于陽(yáng)性對(duì)照藥物順鉑。5、通過(guò)使用微波加熱方法水解黃酮苷類(lèi)化合物橙皮苷(1a),柚皮苷(1b)和蘆丁(1c)中的糖基,分別得到相應(yīng)的黃酮苷元橙皮素(2e),柚皮素(2f)和槲皮素(2g)。研究了微波加熱水解過(guò)程中的影響因素,如微波的功率,反應(yīng)溫度和照射時(shí)間的反應(yīng)產(chǎn)率的影響,優(yōu)化了反應(yīng)條件。黃酮苷元的產(chǎn)率為90-95%。研究結(jié)果表明微波可以大大加快黃酮苷的水解速率,縮短反應(yīng)時(shí)間,并提高了黃酮苷元的產(chǎn)率。優(yōu)化的反應(yīng)條件是:微波功率500-600 W,照射時(shí)間30-45分鐘,反應(yīng)溫度為80-90攝氏度。微波協(xié)助的方法具有高效省時(shí)、低碳環(huán)保、產(chǎn)品純度和產(chǎn)率更高的優(yōu)點(diǎn)。6、本論文共合成異戊烯基黃酮類(lèi)以及黃酮Mannich堿衍生物55個(gè),其中有26個(gè)是未見(jiàn)文獻(xiàn)報(bào)道的新化合物,所合成的化合物結(jié)構(gòu)已經(jīng)核磁共振氫譜(1H NMR),核磁共振碳譜(~(13)C NMR),質(zhì)譜(MS)或(HRMS),紅外光譜(IR)等波譜方法進(jìn)行了結(jié)構(gòu)表征。
[Abstract]:Flavonoids are phenolic secondary metabolites widely distributed in plants, is an important part of natural products. These compounds have many biological activities and effective medical applications, such as anticancer and antitumor activity, anti-inflammatory and antiviral, antibacterial and antifungal activity, anti cardiovascular disease, enzyme activity, anti free radical and antioxidant activity. The isopentenyl flavonoids is a kind of unique natural flavonoid compounds, and is characterized in that the flavone skeleton exists from the isoprenoid side chain.C- prenylation can enhance the affinity of p- glycoprotein and on cell membrane permeability, can significantly improve the flavonoids compound biological activity has significant anticancer activity. The natural prenylflavonoid, can be used as a health food growing lead compounds and new sources of human disease drug treatment. However, flavonoids and ISO Prenylated flavonoids in natural plant base in low and limited sources, these factors seriously affect the development of the biological activity of value and use. Therefore, chemical synthesis of flavonoids and prenylated flavonoids will solve the practical problems. On the other hand, flavonoid compounds in drug development has poor solubility and its bioavailability is low, which limits the application of.Mannich reaction is an effective method for the synthesis of beta amino ketones and adjacent amino phenols of nitrogen-containing organic compounds, is widely used in the synthesis of natural products and organic molecules. The structure of Mannich base unit of nitrogen is a kind of important pharmacological active groups and it can effectively improve the bioactivity of compounds, bioavailability and water solubility. Therefore it is of great significance to the total synthesis of Mannich base derivatives and biological activity research. This paper focuses on the isopentenyl yellow Synthesis and biological activity of ketone and flavonoids of Mannich base derivatives were studied in the.1, icariin (1a). In this paper, the total synthesis of 2,4,6- three hydroxy acetophenone and 4- hydroxy benzoic acid as raw materials, through Baker-Venkatarama reaction, selective methyl or methoxy benzyl protection, two methyl acetone peroxide (DMDO) O- oxidation, prenylation reaction, Claisen rearrangement and microwave promoted deprotection of 8 step reaction, with an overall yield of 23% was synthesized with important biological active substances 8- prenylated flavonoids. Icaritin on Claisen rearrangement reaction steps of microwave synthesis of the key to promote the.2 is discussed. The first total synthesis of Sophoflavescenol (1b), Flavenochromane C (2b) and Citrusinol (3b) three has good pharmacological activity such as cytotoxic, antitumor and treatment of erectile dysfunction in natural prenylflavonoid or isopentenyl The side chain into flavone ring. The total synthesis is 2,4,6- three hydroxy acetophenone and substituted benzaldehyde as the starting materials, respectively by methoxy methyl protection, aldol condensation, cyclization, oxidation of DMDO, O- prenylation, Claisen rearrangement of microwave irradiation, deprotection reaction steps, isoamyl alkenyl cyclization and DDQ dehydrogenation of.1b, the total yield of 2B and 3b were 23%, 17% and 16%., one of the most critical steps from 5-O- prenylated flavonoids by Claisen rearrangement under microwave irradiation 8- prenylflavonoid.3 prenylflavonoid icariin (1a) under the condition of microwave radiation and benzoic acid in 89% yield by another natural product beta anhydroicaritin (2C). With 1a and 2C as the substrate, respectively, and formaldehyde, various secondary amine Mannich reaction in acid alcohol solution, obtained 18 6 amino methylated Mannich base derivatives of 3c-11c and 12c-2 0C. of these compounds using standard CCK-8 cytotoxic potential on cervical carcinoma cell line Hela was tested with the anticancer drug cisplatin as positive control. The results showed that most compounds on Hela cells showed moderate cytotoxic.4, Yama Nasu (3,5,7- three hydroxy -4'- methoxy flavone, 1D) is a flavonoid natural products have anticancer activity on many human tumor cell lines, we used naringin source is abundant and cheap raw materials for the first time through the semi synthesized kaempferol. With kaempferol and various secondary amine and formaldehyde by Mannich reaction, 9 kaempferol Mannich base derivatives of 2d-10d. amine methylation sites, preferentially occurs in flavonoids the ring on the C-6 and C-8 position. All compounds in the standard CCK-8 test method on cervical carcinoma cell line Hela cytotoxic activity, results showed that all the compounds exhibited on Hela fine Moderate to good cell cytotoxicity (IC50 = 12.48-70.52, M) compounds 1D, 2D, 5d-9d and 10d cell toxic effects were better than or equal to the positive control drug cisplatin.5, by using the microwave heating method of hydrolysis of flavonoid glycosides of hesperidin (1a), grapefruit (1b) hesperidin and rutin (1c) sugar in the medium were obtained flavonoid aglycone hesperetin, naringenin (2e) (2f) and quercetin (2G). To study the influencing factors of microwave heating in the hydrolysis process, such as microwave power, influence the yield of reaction reaction temperature and irradiation time, the reaction conditions were optimized. The yield of flavone glycosides was 90-95%. the results of the study show that microwave can greatly accelerate the hydrolysis rate of flavone glycosides, shorten the reaction time, and improve the yield of flavonoid aglycones. The optimized reaction conditions are: microwave power 500-600 W, irradiation time of 30-45 minutes, the reaction temperature is 80-90 degrees Celsius. Assist with wave time efficient, low carbon environmental protection products,.6 has the advantages of higher purity and yield, the total synthesis of prenylated flavonoids and flavonoids of Mannich base derivatives of 55, of which 26 are new compounds, all of the synthesized compounds have NMR (1H NMR), 13C NMR (~ (13) C NMR), mass spectrometry (MS) or (HRMS), infrared spectroscopy (IR) spectra were characterized.

【學(xué)位授予單位】：湖南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R914;O621.3

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