【摘要】：目的:作為半徑最小的陰離子,氟離子在很多方面發(fā)揮著重大作用,如在醫(yī)學方面,氟離子攝入不足會引發(fā)齲齒和骨質疏松,而攝入過量又會引發(fā)氟斑牙,氟骨病。另外慢性長期接觸低劑量的氟離子會導致胃和腎臟疾病,尿石病甚至死亡。因此識別、監(jiān)測氟離子具有重要的意義。熒光探針不僅具有選擇性好、靈敏度高等優(yōu)點,同時又能應用于生命體系。目前大多數(shù)已報道的氟離子熒光探針僅能在有機溶劑體系中或是大比例的有機溶劑中檢測四丁基氟化銨(TBAF),而能夠用于水中氟化鈉檢測的探針多數(shù)需要加入一定比例的有機溶劑,或是加入表面活性劑如十六烷基三甲基溴化銨(CTAB)以提高響應速率。能夠應用于純水體系中的探針少有報道。本課題的研究目的是探討純水體系中氟離子熒光探針對氟化鈉的響應速率與探針結構的關系,并進一步發(fā)現(xiàn)能夠應用于純水溶液體系,響應迅速的氟離子熒光探針。方法:1.設計合成了兩個系列的氟離子熒光探針,系列一以6-羥基苯并噻唑為母核,以叔丁基二甲基硅醚(TBDMS)保護6位羥基作為氟離子識別位點,母核的2位通過酰胺鍵連接糖基(化合物101),甲基(化合物102),芐基(化合物103);系列二以4-三氮唑基-7-羥基香豆素為母核,以叔丁基二苯基硅醚(TBDPS)保護7位羥基作為氟離子識別位點,三氮唑基上通過酰胺鍵引入糖基(化合物201),甲基(化合物202),對甲氧基芐基(化合物203)。2.分別測定濃度為10μM的各個探針在不同氟化鈉濃度(200μM,500μM,1000μM)下的準一級速率常數(shù),進而求得每個探針與氟離子(氟化鈉)的二級反應速率常數(shù)。3.通過比較二級反應速率常數(shù),修飾探針結構。在系列二的三氮唑基上引入聚乙二醇單甲醚(分子量:1000),得到新的探針,化合物204,測定其二級反應速率常數(shù),并且研究了新探針對氟離子的靈敏度,選擇性,以及細胞毒性和細胞成像。結果:1.首先得到了兩個系列共六個化合物,其結構新穎,均是未見報道的化合物,經(jīng)核磁共振氫譜,碳譜和高分辨質譜(ESI)確證了結構。2.測定了以上六個探針與氟離子反應的二級反應速率常數(shù),系列一3個探針的二級反應速率常數(shù)關系為:化合物101化合物102化合物103;系列二3個探針的二級反應速率常數(shù)的關系為:化合物201化合物202化合物203。3.合成了新探針化合物204,經(jīng)核磁共振氫譜,碳譜和質譜(MALDI)確證結構。該探針的二級反應速率常數(shù)明顯大于化合物101和化合物201,對氟離子的檢測限為0.34 mg L-1,并且對氟離子的選擇性明顯優(yōu)于其他陰離子。以香豆素120為參比,化合物204的熒光量子產(chǎn)率為0.318。細胞毒性結果表明,該探針在實驗濃度下對細胞無明顯毒性。MB-231細胞經(jīng)20μM氟化鈉培養(yǎng)后,再用10μM化合物204處理后,可顯示出明亮熒光。結論:本文先是設計合成了兩個系列六個氟離子熒光探針,經(jīng)二級反應速率常數(shù)對比得知,該類探針對氟離子的響應速度取決于探針的親水性,親水性越高,響應速度越快。然后以此結論為指導,設計合成了一個反應速率更高的氟離子熒光探針——化合物204,該探針對氟離子的檢測限明顯低于世界衛(wèi)生組織對飲用水中氟離子含量上限的規(guī)定(1.5 mg L-1),并且對氟離子的選擇性明顯優(yōu)于其他陰離子。細胞實驗證明,化合物204對細胞無毒,且可用于檢測細胞內氟離子。
[Abstract]:Objective: As the least-radius anion, fluoride ion plays a significant role in many aspects, such as the lack of fluoride ion in medicine, dental caries and osteoporosis. In addition, chronic long-term exposure to low-dose fluoride ions can lead to stomach and kidney diseases, urolithiasis and even death. Therefore, it is of great significance to identify and monitor the fluoride ion. The fluorescent probe not only has the advantages of good selectivity, high sensitivity and the like, but also can be applied to the life system. At present, most of the reported fluoroionic fluorescent probes can only be used for the detection of tetrabutyl fluoride (TBAF) in an organic solvent system or in a large proportion of organic solvents, and most of the probes that can be used in the detection of sodium fluoride in water need to be added with a certain proportion of organic solvent, Or a surfactant such as cetyl trimethylammonium bromide (CTAB) is added to increase the response rate. The probe which can be applied to the pure water system is rare to report. The purpose of this study is to study the relationship between the response rate and the probe structure of the fluoride ion fluorescent probe in the pure water system. Method:1. two series of fluorine ion fluorescent probes are designed and synthesized, a series of 6-hydroxybenzene is used as a mother core, a 6-position hydroxyl group is protected by a t-butyl dimethyl silicon ether (TBDMS) as a fluorine ion recognition site, and the 2-position of the mother nucleus is connected to the glycosyl (compound 101) through a melamine linkage, a methyl (compound 102), a phenyl group (compound 103), a series of 2-4-triaza-base-7-hydroxycoumarin as a mother core, a 7-position hydroxyl group is protected by a t-butyl diphenyl silicon ether (TBDPS) as a fluorine ion recognition site, a sugar group (compound 201) is introduced through a melamine bond on the triazine base, Methyl (compound 202), p-methoxyphenyl (compound 203). The quasi-primary rate constants of each probe with a concentration of 10. m u.M at different concentrations of sodium fluoride (200. mu.M,500. mu.M,1000. mu.M) were measured, respectively, and the second-order reaction rate constant of each probe and fluoride ion (sodium fluoride) was determined. The structure of the probe is modified by comparing the secondary reaction rate constant. Polyethylene glycol monomethyl ether (molecular weight:1000) was introduced on the triazine base of the series 2, a new probe was obtained, the compound 204 was obtained, the second-order reaction rate constant was determined, and the sensitivity, the selectivity, and the cytotoxicity and the cell imaging of the new probe to the fluorine ion were studied. Results:1. The two series of six compounds were obtained, and their structure was novel, all of which were not reported, and the structure was confirmed by nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high resolution mass spectrometry (ESI). The two-stage reaction rate constant of the above six probes and the fluorine ion is determined, and the second-order reaction rate constant of the series of three probes is as follows: compound 101 compound 102 compound 103; the relationship between the two-stage reaction rate constant of the series of two three probes is as follows: Compound 201 compound 202 compound 203.3. A new probe compound 204 was synthesized and the structure was confirmed by nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrometry (MALDI). The second-order reaction rate constant of the probe is obviously higher than that of the compound 101 and the compound 201, the detection limit of the fluorine ions is 0.34 mg L-1, and the selectivity of the fluorine ions is obviously superior to other anions. The fluorescence quantum yield of compound 204 was 0.318, based on coumarin 120. The cytotoxicity of the probe showed no significant toxicity to the cells at the experimental concentration. The MB-231 cells were incubated with 20.mu. M sodium fluoride and then treated with 10.mu. M of compound 204 to show bright fluorescence. The response speed of the probe to the fluoride ion is dependent on the hydrophilicity of the probe, the higher the hydrophilicity and the faster the response speed. Based on this conclusion, the fluorine ion fluorescent probe _ compound 204 with higher reaction rate is designed and synthesized, and the detection limit of the probe to the fluoride ion is obviously lower than that of the World Health Organization (1.5 mg L-1) for the upper limit of the fluorine ion content in the drinking water. And the selectivity of the fluorine ions is obviously superior to other anions. Cell experiments demonstrate that compound 204 is non-toxic to cells and can be used to detect intracellular fluoride ions.
【學位授予單位】：天津醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R123.1

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