F16618类似物的设计、合成与活性研究

发布时间：2018-06-09 04:16

本文选题：抗血栓 + 凝血酶受体拮抗剂　；参考：《青岛理工大学》2015年硕士论文

【摘要】：血栓性疾病是一种临床常见的心血管疾病,其发病率高居各种疾病之首,已成为当今人类所面临的重要健康问题。目前用于治疗该类疾病的主要代表药物是阿司匹林和波立维,但有限的药效和出血问题严重限制了其使用范围。上世纪90年代美国Coughlin教授团队发现和克隆的血小板凝血酶受体,为研发性能更优的抗血栓新药提供了一个新的方向。凝血酶受体拮抗剂在不影响人体正常止血的情况下可以选择性地抑制凝血酶介导的血小板活化作用,阻止血栓形成,是十分理想的抗血栓药物。F16618是法国Pierre Fabre研究中心研发的新型小分子PAR-1拮抗剂,它结构简单,有很好的体外、体内抗血栓活性,并且无出血副作用,因此F16618可能比之前的抗血栓药物有更好的药效,具有良好的开发前景。本文以课题前期对F16618类似物的研究为指导,将F16618结构中的一些不理想基团优化改造,设计并合成了一系列新的联苯骨架化合物,且进行了体外活性测试。这些化合物结构与F16618相似,合成路线简单,有望在保留F16618生物活性的前提下降低其副作用。本文根据设计出的新型F16618类似物的结构式,利用简单、高效、环保、经济的方法来合成这些化合物,共合成44个新型化合物。不仅验证了合成方法的可行性,也为更深入的研究打下了坚实的基础。合成的化合物通过薄层色谱法(TLC)、快速柱层析法(FC)和重结晶法分离提纯,再通过液相色谱-质谱联用技术(LC-MS)、核磁共振(NMR)等分析技术对其纯度和结构进行鉴定。以F16618和QTU-003的活性数据为参考,与上海辉源生物科技有限公司和法国Eurofins Cerep SA公司合作,对这44个新型化合物的体外生物活性进行测试,得到了各个化合物结构与活性之间的关系,同时也揭示了活性优良化合物的结构特征。测试结果表明,QTU-114和QTU-118具有与F16618相同或更好的生物活性。它们结构简单且稳定,合成路线实际,产率高,为类似结构PAR-1拮抗剂的深入研究提供了丰富的数据基础。
[Abstract]:Thrombotic disease is a common clinical cardiovascular disease, the incidence of which ranks first among all kinds of diseases, and has become an important health problem faced by human beings. At present, the main drugs used in the treatment of these diseases are aspirin and Polivir, but their limited efficacy and bleeding problems severely limit their use. The discovery and cloning of platelet thrombin receptors by Professor Coughlin's team in the 1990s provides a new direction for the development of better antithrombotic drugs. Thrombin receptor antagonists can selectively inhibit thrombin mediated platelet activation and prevent thrombus formation without affecting human normal hemostasis. F16618 is an ideal antithrombotic drug. F16618 is a new type of small molecule PAR-1 antagonist developed by Pierre Fabre Research Center in France. It has simple structure, good antithrombotic activity in vivo and no bleeding side effects. Therefore, F 16618 may be more effective than the previous antithrombotic drugs, and has a good prospect of development. Based on the previous study of F16618 analogues, a series of novel biphenyl skeleton compounds were designed and synthesized by optimizing and modifying some unideal groups in F16618 structure, and the bioactivity of these compounds was tested in vitro. The structure of these compounds is similar to that of F16618, and the synthesis route is simple, which is expected to reduce the side effects of F16618 while preserving its biological activity. According to the structural formula of the novel F16618 analogue, these compounds were synthesized by simple, efficient, environmentally friendly and economical methods. A total of 44 new compounds were synthesized. It not only verifies the feasibility of the synthesis method, but also lays a solid foundation for further research. The synthesized compounds were separated and purified by TLC, FCC and recrystallization. The purity and structure of the compounds were identified by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) and other analytical techniques. Based on the activity data of F16618 and QTU-003, and in cooperation with Shanghai Huiyuan Biotechnology Co., Ltd and Eurofins Cerep SA of France, the in vitro bioactivity of the 44 new compounds was tested, and the relationship between the structure and activity of each compound was obtained. At the same time, the structural characteristics of the active compounds were also revealed. The results showed that QTU-114 and QTU-118 had the same or better biological activity as F 16618. Their structure is simple and stable, the synthetic route is practical and the yield is high, which provides a rich data base for the further study of PAR-1 antagonist with similar structure.
【学位授予单位】：青岛理工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R914

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