基于BODIPY的反應(yīng)型熒光探針對生物硫醇和苯硫酚的選擇性檢測
發(fā)布時間：2019-03-09 09:44
【摘要】：含巰基化合物包括硫醇和苯硫酚,其在生命活動、工業(yè)生產(chǎn)以及自然環(huán)境中都扮演著十分重要的角色。生物硫醇主要有半胱氨酸Cys,同型半胱氨酸Hcy和谷胱甘肽GSH,在多個生理過程中起著重要作用,其濃度以及分布的異常與許多疾病有著緊密聯(lián)系;而苯硫酚及其衍生物為有毒化合物,但是是重要的化工原料,工業(yè)生產(chǎn)中含苯硫酚的廢水排入自然水體,勢必會對水體和土壤造成污染,從而危害人體健康。因此,發(fā)展選擇性檢測生物硫醇和苯硫酚的熒光探針有著重要意義。本論文以光物理性能優(yōu)異的BODIPY作為熒光團,結(jié)合巰基化合物的結(jié)構(gòu)以及反應(yīng)活性的差別,設(shè)計、合成了選擇性檢測GSH,Cys/Hcy以及苯硫酚的熒光探針,研究了其對含巰基化合物的識別檢測性能,取得了如下研究成果:1.在BODIPY的3位引入了香豆素基團,合成了探針BC,用于半胱氨酸Cys和谷胱甘肽GSH的同時檢測。生物硫醇的巰基通過親核取代反應(yīng)釋放出藍色熒光的香豆素作為內(nèi)標(biāo)分子,此外,GSH/Hcy生成巰基取代的黃色和紅色BODIPY,而Cys的氨基可進一步經(jīng)過五元環(huán)或六元環(huán)過渡態(tài)通過分子內(nèi)重排生成氨基取代的藍色BODIPY,從而體系呈現(xiàn)不同的發(fā)光顏色,實現(xiàn)了對GSH/Hcy和Cys的同時檢測。特別是,在谷胱甘肽GSH濃度為0.4 mM時,溶液顯示出白色的熒光。該探針成功用于活細胞內(nèi)谷胱甘肽和半胱氨酸的同時成像檢測。2.通過點擊化學(xué)反應(yīng),在BODIPY的3位引入了具有線粒體定位功能的三苯基膦基團,合成了熒光探針BODIPY-PPh3,其能夠準(zhǔn)確定位于細胞線粒體,并且其與Cys/Hcy反應(yīng)生成氨基取代產(chǎn)物,而與GSH反應(yīng)生成巰基取代產(chǎn)物,不同產(chǎn)物的發(fā)光波長不同,從而實現(xiàn)了線粒體內(nèi)GSH的選擇性成像檢測。3.通過調(diào)節(jié)BODIPY的3位取代基的推拉電子能力,合成并篩選了選擇性檢測苯硫酚的熒光探針Amide-BODIPY。利用苯硫酚和脂肪硫醇的反應(yīng)活性不同,在生理條件下Amide-BODIPY能夠與苯硫酚發(fā)生親核取代反應(yīng),發(fā)射光譜紅移,而脂肪硫醇則不發(fā)生反應(yīng),實現(xiàn)了對苯硫酚的選擇性檢測。該探針成功用于實際水樣以及活細胞中苯硫酚的選擇性檢測。4.合成了一種新型的"O代F"成環(huán)BODIPY結(jié)構(gòu),通過用核磁、質(zhì)譜和單晶衍射技術(shù)對目標(biāo)產(chǎn)物進行了結(jié)構(gòu)表征,測試數(shù)據(jù)表明該結(jié)構(gòu)有著較長的吸收、發(fā)射波長,較高的量子產(chǎn)率和理想的熒光壽命,是一種潛在的有著良好光學(xué)性能熒光染料。
[Abstract]:Mercapto compounds, including mercaptan and phenol, play an important role in life activities, industrial production and natural environment. Biomercaptan mainly includes cysteine Cys, homocysteine Hcy and glutathione GSH, which play an important role in many physiological processes. The abnormal concentration and distribution of biomercaptan are closely related to many diseases. However, phenol and its derivatives are toxic compounds. However, the waste water containing phenol in industrial production is discharged into natural water, which is bound to cause pollution to water body and soil, thus endangering human health. Therefore, it is of great significance to develop fluorescent probes for selective detection of biomercaptan and phenylene mercaptan. In this paper, BODIPY, which has excellent photophysical properties, is used as fluorescent group. Combining with the difference of structure and reaction activity of sulfhydryl compounds, a fluorescent probe for selective detection of GSH,Cys/Hcy and phenol has been synthesized. The recognition and detection of sulfhydryl compounds were studied, and the following results were obtained: 1. The coumarin group was introduced into BODIPY and the probe BC, was synthesized for simultaneous detection of cysteine Cys and glutathione GSH. The sulfhydryl group of biomercaptan releases blue fluorescent coumarin as internal standard by nucleophilic substitution reaction. In addition, GSH/Hcy produces yellow and red sulfhydryl substituted BODIPY,. On the other hand, the amino groups of Cys can pass through five-or six-membered ring transition states to produce amino-substituted blue BODIPY, through intramolecular rearrangement, which results in different luminescence colors, and realizes simultaneous detection of GSH/Hcy and Cys. In particular, when the concentration of glutathione GSH was 0.4 mM, the solution showed white fluorescence. The probe was successfully used for simultaneous imaging detection of glutathione and cysteine in living cells. 2. By clicking chemical reaction, triphenylphosphine group with mitochondrial localization function was introduced in the third position of BODIPY, and fluorescence probe BODIPY-PPh3, was synthesized, which can accurately locate the cell mitochondria and react with Cys/Hcy to produce amino substituted products. The sulfhydryl substituted products were produced by the reaction with GSH, and the luminescence wavelengths of different products were different, thus the selective imaging detection of GSH in mitochondria was realized. 3. By adjusting the push-pull electron capacity of the three substituents of BODIPY, a fluorescent probe Amide-BODIPY. for selective detection of phenol was synthesized and screened. According to the different reactivity of thiophenol and fatty mercaptan, the nucleophilic substitution reaction between Amide-BODIPY and phenylene mercaptan can take place under physiological conditions, and the emission spectrum is red-shifted, but the fatty mercaptan does not react, so the selective detection of p-phenylene mercaptan is realized. The probe was successfully applied to the selective detection of phenol in real water samples and living cells. 4. A novel "O-substituted F" ring-forming BODIPY structure was synthesized and characterized by NMR, MS and single crystal diffraction. The results show that the structure has a long absorption and emission wavelength. High quantum yield and ideal fluorescence lifetime are potential fluorescent dyes with good optical properties.
【學(xué)位授予單位】：北京科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：O657.3
本文編號：2437336
[Abstract]:Mercapto compounds, including mercaptan and phenol, play an important role in life activities, industrial production and natural environment. Biomercaptan mainly includes cysteine Cys, homocysteine Hcy and glutathione GSH, which play an important role in many physiological processes. The abnormal concentration and distribution of biomercaptan are closely related to many diseases. However, phenol and its derivatives are toxic compounds. However, the waste water containing phenol in industrial production is discharged into natural water, which is bound to cause pollution to water body and soil, thus endangering human health. Therefore, it is of great significance to develop fluorescent probes for selective detection of biomercaptan and phenylene mercaptan. In this paper, BODIPY, which has excellent photophysical properties, is used as fluorescent group. Combining with the difference of structure and reaction activity of sulfhydryl compounds, a fluorescent probe for selective detection of GSH,Cys/Hcy and phenol has been synthesized. The recognition and detection of sulfhydryl compounds were studied, and the following results were obtained: 1. The coumarin group was introduced into BODIPY and the probe BC, was synthesized for simultaneous detection of cysteine Cys and glutathione GSH. The sulfhydryl group of biomercaptan releases blue fluorescent coumarin as internal standard by nucleophilic substitution reaction. In addition, GSH/Hcy produces yellow and red sulfhydryl substituted BODIPY,. On the other hand, the amino groups of Cys can pass through five-or six-membered ring transition states to produce amino-substituted blue BODIPY, through intramolecular rearrangement, which results in different luminescence colors, and realizes simultaneous detection of GSH/Hcy and Cys. In particular, when the concentration of glutathione GSH was 0.4 mM, the solution showed white fluorescence. The probe was successfully used for simultaneous imaging detection of glutathione and cysteine in living cells. 2. By clicking chemical reaction, triphenylphosphine group with mitochondrial localization function was introduced in the third position of BODIPY, and fluorescence probe BODIPY-PPh3, was synthesized, which can accurately locate the cell mitochondria and react with Cys/Hcy to produce amino substituted products. The sulfhydryl substituted products were produced by the reaction with GSH, and the luminescence wavelengths of different products were different, thus the selective imaging detection of GSH in mitochondria was realized. 3. By adjusting the push-pull electron capacity of the three substituents of BODIPY, a fluorescent probe Amide-BODIPY. for selective detection of phenol was synthesized and screened. According to the different reactivity of thiophenol and fatty mercaptan, the nucleophilic substitution reaction between Amide-BODIPY and phenylene mercaptan can take place under physiological conditions, and the emission spectrum is red-shifted, but the fatty mercaptan does not react, so the selective detection of p-phenylene mercaptan is realized. The probe was successfully applied to the selective detection of phenol in real water samples and living cells. 4. A novel "O-substituted F" ring-forming BODIPY structure was synthesized and characterized by NMR, MS and single crystal diffraction. The results show that the structure has a long absorption and emission wavelength. High quantum yield and ideal fluorescence lifetime are potential fluorescent dyes with good optical properties.
【學(xué)位授予單位】：北京科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：O657.3
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