新型苦参碱衍生物的合成研究

【作者】 赵利霞；

【导师】 王伟；

【作者基本信息】 陕西师范大学 ， 有机化学， 2015， 硕士

【摘要】 苦参碱的生物活性比较广泛,临床研究表明,苦参碱可用于抗炎、解热、调节免疫、治疗心律失常、脂多糖诱导的肝损伤；也可以通过增加白血细胞的数量并抑制肿瘤细胞的生长,作用于宫颈癌、肝癌和胃癌。随着对苦参碱生物碱研究的深入,一些苦参碱类似物表现出更好的生物活性,可以用于预防和治疗乙型肝炎,丙型肝炎,HIV和抗HBV。生物学评价显示,与5-氟尿嘧啶相比较,一氧化物-释放型苦参碱衍生物对体外人肝癌细胞(HepG2)具有更强的细胞毒活性。可见,对苦参碱类似物的生物活性和应用范围的研究不断的扩大,表现出良好的发展前景。本文的立题依据,首先,鉴于氮原子和硫原子在有机体的组成、生理活性和药物代谢等方面都有重要作用,通过二硫代的方式,在13位碳原子上引入含氮基团；其次,苦参碱的水溶性不理想,这样的特点不利于它在药物研发领域的广泛应用,所以设计合成了一系列水溶性良好的苦参碱类似物；最后,选择三种典型的肿瘤细胞作为受试细胞,对部分目标化合物进行初步的抗肿瘤活性研究。本文以槐果碱为底物,通过经典的Michael加成反应合成了13种新颖的苦参碱类似物,目标产物的结构通过1HNMR、13C NMR和HRMS表征,同时成功培养出三种新化合物的单晶结构,经X-ray单晶衍射表征得到精确的晶体结构数据,不仅给出了化合物精确的分子结构,还分析得出多环化合物的空间排布情况和手性化合物的绝对构型,部分单晶结构存在分子间氢键,这些氢键在单晶的成长过程中起着重要的作用。反应过程中避免了使用毒性比较大的有机溶剂,也不需要金属催化剂,反应低毒、条件简单、产率高。最后,选择水溶性较好的目标化合物进行初步的活性测试研究,受体细胞为人结肠癌细胞(SW480)、肺癌细胞(A549)、表皮鳞癌细胞(A431),期望该类化合物有好的抗肿瘤药理活性。本论文工作主要包括以下五部分内容：第一章对苦参碱类衍生物的研究现状做一个简单的简绍介绍,重点阐述了苦参碱类衍生物在结构修饰方面的研究进展,并通过部分苦参碱衍生物的生物活性分析确立构效关系,提出了本论文的设计思路和研究方法。第二章以槐果碱为起始化合物,用一锅法分别合成(哌啶-1-基)二硫代甲酸-13-苦参碱酯、(吡咯烷-1-基)二硫代甲酸-13-苦参碱酯、(吗啉-4-基)二硫代甲酸-13-苦参碱酯,合成的目标化合物分别进行了1HNMR,13C NMR、HRMS和X-ray单晶衍射结构表征,尤其通过X-ray单晶衍射得到(哌啶-1-基)二硫代甲酸-13-苦参碱酯和(吗啉-4-基)二硫代甲酸-13-苦参碱酯苦参碱酯的单晶结构,证明了是我们需要的化合物,最后对这三种化合物进行了生物活性测试。第三章以槐果碱为起始原料,在水相中合成含氮杂环苦参碱衍生物,合成方法简单,产率高,避免使用甲醇等有机溶剂。成功的合成了六种13-含氮杂环苦参碱衍生物,产物水溶性较强。对产物进行了结构表征,尤其是13-哌啶基苦参碱进行单晶分析,通过X-ray得到的数据分析其结构,为确定它们结构中手性碳原子的立体构型提供有力的数据。第四章以槐果碱为起始原料,合成另外四种胺类苦参碱衍生物,新的化合物水溶性与苦参碱相比有了明显的提高,并且引入羟基这一亲水基团,期望这类化合物有较强的药理作用。第五章对全文新化合物合成、表征及初步活性测试进行总结,展望后期工作。更多还原

【Abstract】 Matrine is one of the major active alkaloids isolated from the sophora alopecuroides. Matrine possesses good biological activities. For example, matrine has been used for the treatment of anti- inflammatory, antipyretic, immune, cardiac arrhythmia treatment, LPS-induced liver injury; Matrine also could increase the number of white blood cells and inhibit the growth of tumor cells and further effect on cervical, hepatic and gastric carcinomas. With the in-depth study of matrine alkaloids, the matrine alkaloids have been used in the prevention and treatment of viral diseases of hepatitis B, hepatitis C, HIV and anti- HBV with greater inhibitory activity than both matrine and sophocarpine. The biological evaluation showed that nitric oxide-releasing matrine derivatives had stronger cytotoxic activities than 5-fluorouracil against human hepatoma cells (HepG2) in vitro. Therefore, the study of biological activity and application of matrine analogues is continuing to expand, showing a good development prospects. The purpose of this paper consists of three parts. Firstly, introducting of the nitrogen-containing groups at the 13 position by dithiophosphate in view of the nitrogen atom and the sulfur atom play an important role in the organism of the composition, and aspects of the physiologically active drug metabolism. Secondly, the widespread use of matrine is limited because its water-solubility is not really ideal. We designed and synthesized a number of water-soluble matrine derivatives. Finally, part of the target compounds were preliminary antitumor activity experiments on three typical tumor cells.In the synthesis process, sophocarpine was used as the starting material via the classic Michael addition reaction matrine and we have designed and synthesized of 13 novel matrine derivatives. We also have successfully cultured three new compound single crystal structure and obtained accurate data of the crystal structure. The chemical structures of them were further confirmed by 1HNMR,13CNMR and HRMS. Particularly, the structures of some compound were characterized by X-diffraction and partly crystalline structure exists intermolecular hydrogen bonds which are play an important role in the single crystal growth process. The methods of synthesis target compounds are simple, easy and organic solvents, expensive catalysts are not needed by generated a new chiral carbon atom. Finally, water-soluble target compounds are evaluated for their activity on human colon cancer cells (SW480), lung cancer cells (A549) and epidermal squamous cells (A431). We expect these compounds will have good pharmacological activity. This thesis is comprised of five parts as follows:In the chapter one:We described the status of research matrine derivatives mainly tends to progress of matrine derivatives modified structure. The biologically active portion of matrine derivatives were introduced. Based on structure-activity relationships, this paper design ideas and research methods have been proposed.In the chapter two:The 13-position of sophocarpine was introduced three kinds of nitrogen-containing heterocyclic compounds by the Michael addition reaction. The three kinds of matrine derivatives were successfully obtained. The method was confirmed to be novel for one-pot preparation of matrine derivatives. The target compound were characterized by 1H NMR,13C NMR,HR-MS and X-ray. At last, these three compounds were made bioassay experiments.In the chapter three:As sophocarpine with the starting material, several nitrogen-containing heterocyclic derivative of matrine were designed and synthesized in the aqueous phase. Synthesis method is simple, high yield and avoidinguse of methanol and other organic solvent. We successfully synthesized five novel nitrogen-containing heterocyclic group matrine derivative and the structure of products were characterized, especially 13-piperidine derivatives matrine crystal analysis, analysis of its structure by X-ray.In the chapter four:A series of amine derivatives matrine were synthesized and new compounds have good solubility in water compared with matrine. Some strong activity group is introduced during the synthesis. We designed and synthesized a number of water-soluble matrine derivatives.In the chapter fifth:We make a summary of the full text of the new compound synthesis, characterization and preliminary activity tests, outlook late work.更多还原