异戊烯基黄酮类和黄酮Mannich碱衍生物的合成与生物活性研究

发布时间：2018-03-03 14:10

本文选题：异戊烯基黄酮类　切入点：全合成　出处：《湖南大学》2015年博士论文　论文类型：学位论文

【摘要】：黄酮类是一类广泛分布于植物界的酚类次级代谢产物,是天然产物的重要组成部分。这类化合物具有多种生物活性和有效的医疗应用,如抗癌和抗肿瘤活性、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。异戊烯黄酮是一类独特的天然黄酮类化合物,其特征是在黄酮骨架上存在着异戊烯基侧链。C-异戊烯化的黄酮可以增强其对p-糖蛋白的亲和力和对细胞膜的通透性,可以显著提高黄酮类化合物的生物活性。具有显著抗癌活性的天然异戊烯基黄酮类,可以作为日益增长的保健食品的先导化合物和人类疾病治疗新的药物来源。然而,黄酮类和异戊烯基类黄酮在自然界植物中的含量低且来源有限,这些因素严重影响其生物活性价值的开发和利用。因此,黄酮类和异戊烯基类黄酮的化学合成将解决其实用性难题。另一方面,黄酮类化合物在药物研发中存在着溶解性差、生物利用度低等缺点,限制了它们的应用。Mannich反应是合成β-胺基酮和邻胺基酚类等含氮有机化合物的有效方法,被广泛应用于天然产物和有机药物分子的合成。含氮的Mannich碱结构单元是一类重要的药理活性基团,它可以有效提高化合物的生物活性、生物利用度和水溶性。因此进行黄酮Mannich碱衍生物的合成与生物活性研究具有重要意义。本论文围绕异戊烯基黄酮类和黄酮Mannich碱衍生物的合成与生物活性进行了系列研究。1、淫羊藿素(1a)的全合成。本论文以2,4,6-三羟基苯乙酮和4-羟基苯甲酸为原料,通过Baker-Venkatarama反应、选择性苄基或甲氧基甲基保护、二甲基过氧丙酮(DMDO)氧化、O-异戊烯基化反应、微波促进的Claisen重排和脱保护基等8步反应,以23%的总产率合成了具有重要意义的生物活性物质8-异戊烯基类黄酮淫羊藿素。对该合成的关键反应步骤微波促进的Claisen重排进行了探讨。2、首次全合成了Sophoflavescenol(1b)、Flavenochromane C(2b)和Citrusinol(3b)等三种有良好药理活性如细胞毒性、抗癌和治疗性功能勃起障碍的天然异戊烯基黄酮类或异戊烯基侧链成环的黄酮类化合物。全合成是以2,4,6-三羟基苯乙酮和取代苯甲醛为初始原料,分别通过甲氧甲基保护、羟醛缩合、环合反应、DMDO氧化、O-异戊烯化、微波促进的Claisen重排、脱保护基、异戊烯基环合作用和DDQ脱氢等反应步骤。1b、2b和3b的总产率分别为23%,17%和16%。其中最为关键的步骤是从5-O-异戊烯基黄酮通过微波促进的Claisen重排得到8-异戊烯基黄酮类。3、异戊烯基黄酮类淫羊藿素(1a)在微波条件下和甲酸反应以89%的收率得到另一种天然产物β-去水淫羊藿黄素(2c)。以1a和2c为底物,分别与甲醛、各种仲胺在酸性醇溶液中进行Mannich反应,合成得到18个6位胺甲基化的Mannich碱衍生物3c-11c和12c-20c。对这些化合物采用标准CCK-8法对宫颈癌Hela细胞系的细胞毒性潜力进行了测试,以抗癌药物顺铂为阳性对照,结果表明绝大部分化合物对Hela细胞表现出中等强度的细胞毒性。4、山奈素(3,5,7-三羟基-4'-甲氧基黄酮,1d)是对许多人肿瘤细胞系有抗癌活性的黄酮类天然产物,我们以来源丰富且廉价的柚皮苷为原料首次通过半合成得到山奈素。以山奈素与各种仲胺和甲醛进行Mannich反应,得到9种山奈素Mannich碱衍生物2d-10d。胺甲基化的位置,优先发生在黄酮环上的C-6和C-8位置。所有合成化合物以标准CCK-8法测试其对宫颈癌Hela细胞系的细胞毒活性,结果表明,所有的目标化合物表现出对Hela细胞的中度到良好的细胞毒性(IC50值为12.48-70.52μM),化合物1d,2d,5d-9d及10d的细胞毒性效果分别为优于或等于阳性对照药物顺铂。5、通过使用微波加热方法水解黄酮苷类化合物橙皮苷(1a),柚皮苷(1b)和芦丁(1c)中的糖基,分别得到相应的黄酮苷元橙皮素(2e),柚皮素(2f)和槲皮素(2g)。研究了微波加热水解过程中的影响因素,如微波的功率,反应温度和照射时间的反应产率的影响,优化了反应条件。黄酮苷元的产率为90-95%。研究结果表明微波可以大大加快黄酮苷的水解速率,缩短反应时间,并提高了黄酮苷元的产率。优化的反应条件是:微波功率500-600 W,照射时间30-45分钟,反应温度为80-90摄氏度。微波协助的方法具有高效省时、低碳环保、产品纯度和产率更高的优点。6、本论文共合成异戊烯基黄酮类以及黄酮Mannich碱衍生物55个,其中有26个是未见文献报道的新化合物,所合成的化合物结构已经核磁共振氢谱(1H NMR),核磁共振碳谱(~(13)C NMR),质谱(MS)或(HRMS),红外光谱(IR)等波谱方法进行了结构表征。
[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.

【学位授予单位】：湖南大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R914;O621.3

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