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1、湖南大学 硕士学位论文 类维生素A酸黄酮、茄尼胺、糖基衍生物的合成研究 姓名：陈静 申请学位级别：硕士 专业： 指导教师：向建南 20071202 硕士学位论文 摘 要 类维生素 A 是指天然维生素 A 及其在体内代谢后的衍生物视黄醛、视黄酸以 及所有与它相似的人工合成产物。其在调节和控制多种正常组织和上皮细胞的增 殖分化、生长发育、视觉、代谢和内环境的稳定平衡等方面具有广泛的生物学活 性。同时将其应用于肿瘤的预防和治疗也成为近年来医药领域的热点。类维 A 酸 受体(RAR)和类维 A 酸 X 受体(RXR)是配体依赖的转录因子，研究表明类维 A 酸 是通过与之结合并激活受体而表现活性并发挥作
2、用的。遗憾的是，类维 A 酸在高 剂量使用时毒性太强，难以发挥其在高级哺乳动物癌症预防方面的实际价值。因 而寻找具有更好治疗效果的类维 A 酸衍生物引起化学家的极大兴趣。 黄酮类化合物是一类具有多种生理活性的天然有机化合物，是许多中草药的 有效成分。茄尼醇是一种附加值较高的药用有效成分，具有抗菌、消炎和止血等 药理作用，而氮芥又是一种无结构专一性的抗肿瘤基团，无论是游离的还是与各 种母体相连，都具有抗肿瘤作用。糖类是自然界广泛存在的一大类具有生物活性 的分子，它们参与了许多重要的生理和病理等过程。为降低类维 A 酸的毒性、提 高其药物活性，寻找有更好治疗效果和选择性的类维 A 酸衍生物, 本工
3、作做了以 下研究： 第一、利用改良的 Baker-Venkatarama 重排法, 合成了 7-羟基黄酮，以类维 A 酸为原料，二环己基碳酰亚胺(DCC)为脱水剂，4-二甲氨基吡啶 (DMAP)为催化剂 合成了两种单酯化合物，实验方法简便、重现性好，收率高，具有较大实用价值。 第二、通过引入茄尼胺基进行结构修饰，从废次烟叶中提取茄尼醇，引入活 性基团对氨基苯酚作为一个桥联，得到新型茄尼基胺氮芥化合物。同时，将异维 A 酸经保护、氧化、脱保护得到人体内的代谢产物。并以此为母体设计合成出含 有抗肿瘤活性基团的目标化合物 4-羰异维 A 酸(4-N-茄尼基氨基苯酚)酯。 第三、以异维 A 酸为母体，
4、对苯二酚为桥联，采用相转移催化法合成了糖苷。 并探索了一种中性条件下将乙酰保护基脱去的方法，即以二丁基氧化锡作催化剂， 无水甲醇回流下将其脱去，该方法具有反应条件温和，后处理简单和立体选择性 强等优点。 本论文共合成化合物 22 个，其中新化合物 10 个。用核磁氢谱(1H NMR)、碳 谱(13C NMR)、红外光谱(IR)和质谱(MS)对所合成的物质进行了结构表征与确认， 并对其结构基团进行了归属。 关键词： 类维生素 A；类维 A 酸；黄酮；糖酯；茄尼醇；合成；生物活性 类维生素 A 酸黄酮、茄尼胺、糖基衍生物的合成研究 Abstract Retinoids contain natura
5、l vitamine A, their metabolites and all synthesized analogues. Study found that retinoids play an essential role in vertebrate growth and development, vision, supporting cell differentiation and embryonic development. Furthermore, it has been evaluated for their possible beneficial effects in severa
6、l cancerous conditions.The actions of retinoids are mediated through binding and activation of the retinoic acid receptors (RARs) or retinoid X receptors (RXRs), which function as ligand-dependent transcription factors. Unfortunately, Retinoids, including retinoic acids, have been found to be too to
7、xic at high dosage levels to be of practical value for cancer prevention in higher mammals. Therefore development of retinoid analogues possessing a higher therapeutic index is of interest. Flavonoids are a kind of natural organic compounds with potential physiological activities and effective compo
8、nents of Chinese Herbs. Solanesol is a high added value product which has remarkable medical effects such as diminishing inflammation, hemostaria and antibacterial. Nitrogen mustard is not a single-structure anti-tumour group, the dissociated and the conjugation with other compounds are both antican
9、cer prodrugs. Carbohydrates are a large group of biomolecules which are distributed widely in nature and involved in a great variety of physiological and pathological processes. In order to decrease toxicities of retinods and enhance pharmacal effects and gain the relative derivatives with better cu
10、ring effect and selectivity. The work we have done are displayed: First, Synthesized 7-Hydroxy- Flavonoe by improved Bake-Venkatarama method. Retinoic acid was modified by changing the polar group, After investigating various reaction conditions, a new synthetic method with mild reaction conditions
11、was built up to synthesize retinoates. With dicyclohexylcarbodiimide (DCC) as reagent and 4-dimethylaminopyridine (DMAP) as catalyst, a series of retinoates were synthesized from all-trans-retinoic acid and 13-cis-retinoic acid. The method was proved to be relatively simple and stable with high yiel
12、ds and superior practical value. Second, Retinoic acid was modified by using solanesolamine group. In order to improve the therapeutic efficacy of retinoid carboxylic acids, a novel retinoate was designed and synthesized with 4-aminophenol as a linker from solanesol and 4-Carbonyl-13-cis-retinoic ac
13、id. Which is one of much polar metabolites of 13-cis-retinoic acid in plasma. 硕士学位论文 Third, Retinoic acid was modified by use of sugar, and hydroquinone as bridge. A mild selective method for deacetylation has been developed. Its application to deacetylation of glucosides was studied using catalytic
14、 amount of dibutyltin oxide ascatalyst and methanol as solvent. The mechanism of the deprotection reaction have been discussed. The present results showed that the method is suitable for deactylation of glycoesters. The method has advantages of mild reaction conditions, easy seperation of products a
15、nd high stereospecificity. We have synthesized 22 compounds and 10 of them were not reported in literatures until now. Their structures were characterized and confirmed by IR, 1H NMR, 13C NMR and MS spectra. Key words: Retinoids; 13-cis-Retinoic acid; Flavonoe; Glucoesters; Solanesol; Synthesis; Bio
16、logical activity 类维生素 A 酸黄酮、茄尼胺、糖基衍生物的合成研究 插图索引 图 1.1 视黄醇、全反式维 A 酸、13-顺-维 A 酸、9-顺-维 A 酸、阿维 A 酸和阿达 帕林的化学结构3 图 1.2 类维 A 酸的两种受体 RAR 和 RXR6 图 2.1 黄酮和异黄酮的分子结构14 图 2.2 7-羟基黄酮类维 A 酸酯的合成路线19 图 2.3 DCC-DMAP 法的反应机理23 图 3.1 异维 A 酸在人体内的新陈代谢示意图 28 图 3.2 废次烟草中茄尼醇的提取29 图 3.3 4-羰基异维 A 酸（4-N-茄尼基氨基苯酚）酯的合成路线29 图 4.1 -熊果苷异维 A 酸糖酯的合成路线39 图 4.2 羧酸酯的软硬电子中心
