兰州大学机构库 >化学化工学院
甲基亚砜小分子化合物的合成与生物应用
Alternative TitleSynthesis and Biological Application of Methylsulfoxide Compounds
康洁
Thesis Advisor张良伟
Degree Name硕士
2018-06-12
Keyword荧光探针 蛋氨酸亚砜还原酶 生物巯基 蛋白标记 抑制剂
Abstract

活细胞内的氧化还原平衡对于维持有机体的正常生理过程有着非常重要的作用。其平衡主要依赖于细胞内的各种氧化性物质与还原性物质之间量的平衡。正常情况下,代谢过程产生的氧化性物质对于机体是有利的,会起到信号传导以及自我保护的作用。一旦氧化性物质超出机体的正常承受能力,就会导致机体蛋白结构及功能的破坏和疾病的发生。还原性物质在氧化损伤修复方面起到了非常重要的作用。在生物体内,还原性物质主要包括小分子巯基化合物和蛋白质类物质。发展活细胞内还原活性物质的检测方法用来探究其在生理和病理过程所起的作用是非常有意义的。荧光探针因其高选择性、非破坏性和实时监测等独特优势备受关注,被应用于众多的领域,如生物学,生理学,药理学和环境科学等。本论文以甲基亚砜为受体设计合成了小分子化合物库,通过筛选发现部分化合物可以应用于活细胞内生物大分子(蛋氨酸亚砜还原酶)的检测和小分子硫醇的检测及含巯基蛋白的标记。同时,构建了蛋氨酸亚砜还原酶抑制剂的快速筛选方法。本论文主要由四部分组成,其结构如下:

第一章,主要介绍了荧光探针的发光机理和发展状况。结合我们课题组的研究方向,简单介绍了荧光探针在生物硫醇(半胱氨酸,高半胱氨酸和谷胱甘肽)和生物大分子检测方面所取得的进展。第二章,针对本课题报道的探针Msr-blue和探针Msr-TFMCM存在的缺点,以苯并噻唑基香豆素为荧光基团,设计合成了发射波长较长的Msrs探针benzo-1,该探针波长在490 nm,且对Msrs有较好的荧光响应。本章详细研究了其与Msrs的作用。第三章,我们合成了一系列含有甲基亚砜的小分子化合物,利用课题组报道的探针Msr-blue,以小白鼠肾裂解液为蛋氨酸亚砜还原酶的来源,对分子库中的化合物进行了筛选,得到了Msrs的抑制剂。首次利用荧光探针Msr-blue构建了快速筛选Msrs抑制剂的方法。第四章,以香豆素为荧光基团,甲基亚砜为识别基团设计合成了探针COU-1,对生物巯基(GSH、Cys、Hcy)有较好的荧光响应。并借助质谱,核磁和高效液相进一步证明该探针与巯基作用机制,即发生了亲核取代反应。最终,将该探针用于巯基蛋白的标记和细胞内的巯基分子成像技术的研究。

Other Abstract

The oxidize and redox balances in living cells play an important role in maintaining the normal physiological processes of the organism, which mainly depends on the balance between various oxidizing substances and reducing substances in the cells. Under normal circumstances, the oxidative substances produced in the metabolic process are beneficial to the body and can act as signal transduction. Once the exceeding the normal capacity of the body, it will lead to the destruction of the protein structure and function, and then resulting in the series of disease. Reducing substances play a very important role in the repair of this type of oxidative damage, which mainly including protein thiols and small molecule thiols. It is of great importance to develop assays for detection of these species in living cells and to explore their role in physiological and pathological processes. Fluorescent probe has attracted much attention due to its merits, including high selectivity and sensitivity, real-time monitoring and non-destructiveness to samples. And large numbers of probes are used in many fields, such as biology, physiology, pharmacology and environmental science. We created a series of compounds uniformly decorated with a methyl sulfoxide group. After screening, some compounds can be applied to detect biothiols in living cells and biological macromolecules (methionine sulfoxide reductase), respectively. And a rapid screening method for methionine sulfoxide reductase inhibitors was constructed by using the fluorescent probe Msr-blue.

Chapter 1.This chapter mainly introduces the mechanism and recent development of fluorescent probes. We briefly introduced the recent progress on fluorescent probes for detection of bio-thiols (cysteine, homocysteine and glutathione) and biomolecules. Chapter 2. In order to improve the performance of current probe for Msrs, the probe benzo-1 was synthesized based benzothiazolyl coumarin group. The probe has a longer emission wavelength around 490 nm after incubation with Msrs. The detailed spectral studies were carried out in this chapter. Chapter 3. We created a focused small library containing 20 compounds uniformly decorated with a methyl sulfoxide group. A rapid screening method for Msrs inhibitors was constructed by using the fluorescent probe Msr-blue which was reported by our group. Chapter 4. The coumarin-based probe COU-1, bearing with a methyl sulfoxide group, was synthesized. The probe showed good fluorescence response to the biological thiols (GSH, Cys, Hcy). The mechanism was confirmed by mass spectrometry, nuclear magnetic resonance and high-performance liquid phase. Finally, the probe was used for labeling of thiol proteins and imaging intracellular biothiols.

URL查看原文
Degree Grantor兰州大学
Place of Conferral兰州
Language中文
Document Type学位论文
Identifierhttp://ir.lzu.edu.cn/handle/262010/237281
Collection化学化工学院
Recommended Citation
GB/T 7714
康洁. 甲基亚砜小分子化合物的合成与生物应用[D]. 兰州. 兰州大学,2018.
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