苦参碱类化合物的设计、合成及抗柯萨奇B3病毒活性研究

发布时间：2018-01-30 23:12

本文关键词： 苦参碱柯萨奇病毒构效关系类药五原则病毒性心肌炎　出处：《青岛科技大学》2015年硕士论文　论文类型：学位论文

【摘要】：柯萨奇病毒是一类传播途径较广,且致病性极强的肠道病毒,其中又以B3型(CVB3)亚种致病性最强,危害性最大。CVB3病毒的感染会导致心肌细胞的凋亡,进而导致病毒性心肌炎的发作。根据数据显示,约有50%的病毒性心肌炎(VMC)的发病与CVB3病毒的感染相关。此外CVB3病毒还可以引起心包炎、流行性胸痛、胰腺炎、脑膜炎甚至手足口病等多种极其严重的疾病。苦参提取物(槐果碱注射液)是已经被应用于治疗由柯萨奇病毒B3引起的病毒性心肌炎等疾病的药物,其安全性与疗效得到了普遍认可。但是由于其对CVB3病毒的抑制活性有限,导致其在临床应用剂量较大,且治疗周期较长,因此对苦参类药物的结构进行修饰以提高其病毒的活性具有重要的意义。本课题组对此类化合物抗CVB3病毒的活性有了初步的构效关系总结：头期构效关系表明12-N-苯磺酰基取代是活性必需基团,当苯磺酰基的苯磺上连有吸电子基团时,化合物活性较好；C11侧链为非活性必需基团,但可以通过改变其脂溶性等参数来调节目标化合物的溶解度以及药代参数来提高化合物的成药性。为了进一步提高药物的活性以及成药性,并降低研发成本及时间。本课题以其构效关系为基础,参照类药五原则,并采用计算机对预合成化合物的C1ogP以及tPSA等药代参数进行了计算以使其符合高成药性的标准,进而指导后续的合成工作。本课题以苦参碱为原料,经过开环,酯化,水解,还原胺化,斯文氧化,四氢铝锂还原,成醚,酸胺缩合等一系列化学合成手段,累计合成了34个未见文献报道的目标化合物,结果均经1H-NMR, 13C-NMR, MS和HRMS确证。其中的苦参酰胺类,苦参丁烷类以及苦参醚类化合物都取得了较好的活性数据。此外还对以前的构效关系进行了进一步验证及修改。其中进一步验证了12-N上的苯磺酰基上只有连有强吸电子基团时才具有最良好的活性与治疗窗口。另外,本文通过大量的实验数据,认为11位侧链基团也是活性必需基团,侧链的PKa值会直接影响化合物的抗CVB活性。苦参酰胺化合物21c-d,21j以及苦参丁烷类化合物ks-dw-1,ks-dw-3都体现出了非常好的抗CVB3活性以及治疗窗口指数,已经被用来做下一步的研究。
[Abstract]:Coxsackie virus (Coxsackie virus) is a kind of enteroviruses with wide transmission route and strong pathogenicity, among which B3 type CVB3 subspecies are the most pathogenic. The most harmful. CVB3 virus infection will lead to cardiomyocyte apoptosis, and then lead to the outbreak of viral myocarditis. According to the data show. About 50% of viral myocarditis (VMC) is associated with the infection of CVB3 virus. In addition, CVB3 virus can also cause pericarditis, epidemic chest pain, pancreatitis. The extract of Sophora flavescens (Sophora flavescens injection) has been used in the treatment of viral myocarditis caused by Coxsackie virus B3 and other diseases. Its safety and efficacy have been generally accepted, but because of its limited inhibitory activity against CVB3 virus, it has a large dose in clinical use and a long treatment period. Therefore, it is of great significance to modify the structure of Sophora flavescens to improve their viral activity. The preliminary structure-activity relationship of these compounds against CVB3 virus is summarized. The first phase structure-activity relationship indicated that 12-N- benzene sulfonyl group was the necessary active group. When the benzenesulfonyl group is attached to the benzenesulfonyl group, the activity of the compound is better. The side chain of C11 is an inactive essential group. However, the solubility and pharmacological parameters of the target compounds can be adjusted by changing their liposolubility and other parameters to improve the drug formation, in order to further improve the drug activity and drug formation. And reduce the cost and time of research and development. This subject is based on its structure-activity relationship, referring to the five principles of drugs. The pharmacological parameters such as C1ogP and tPSA of presynthetic compounds were calculated by computer to make them meet the standard of Gao Cheng. In this paper, matrine was used as raw material through a series of chemical synthesis methods, such as ring opening, esterification, hydrolysis, reductive amination, Sven oxidation, lithium tetrahydroaluminate reduction, ether formation, acid amine condensation and so on. A total of 34 target compounds were synthesized and confirmed by 1H-NMRs, 13C-NMRs, MS and HRMS. Good activity data were obtained for both Sophora flavescens butane and Sophora flavescens. In addition, the former structure-activity relationships were further verified and modified. It was further verified that only the benzenesulfonyl group on 12-N was found. Even if there is a strong electron group, it has the best activity and therapeutic window. In addition. Based on a large amount of experimental data, it is considered that the 11 side chain group is also a necessary active group, and the PKa value of the side chain will directly affect the anti CVB activity of the compound. 21j and ks-dw-1ks-dw-3 have shown very good anti- CVB3 activity and therapeutic window index, which have been used for further research.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R914.5;R96

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