CN106496216A - 一种快速检测生物硫醇类的荧光探针和制备方法以及应用 - Google Patents

一种快速检测生物硫醇类的荧光探针和制备方法以及应用 Download PDF

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CN106496216A
CN106496216A CN201610911744.8A CN201610911744A CN106496216A CN 106496216 A CN106496216 A CN 106496216A CN 201610911744 A CN201610911744 A CN 201610911744A CN 106496216 A CN106496216 A CN 106496216A
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赵云
薛园园
李好样
朱瑞涛
史清华
王松
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Shanxi Lingde Technology Co.,Ltd.
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Abstract

本发明提供了一种快速检测生物硫醇的荧光探针。具体涉及一种新型荧光探针的制备方法及其应用,属于精细化工和化学分析领域。此荧光探针由2‑(2‑羟基‑5‑氨基苯基)苯并噻唑和顺丁烯二酸酐在冰乙酸回流4‑5小时，最后采用硅胶色谱法进行纯化，得荧光探针。这种荧光探针水溶性好、原料便宜、合成过程简单、易于生产。具有良好的荧光发射光谱特性(450～500nm)和大的斯托克斯位移(90nm)，并且检测过程简便、快速，检测结果准确。结合激光共聚焦扫描显微技术，还可获取该新型荧光探针在活细胞内的荧光成像。

Description

一种快速检测生物硫醇类的荧光探针和制备方法以及应用
技术领域
本发明属于生物硫醇的检测技术领域，具体涉及一种快速检测生物硫醇类的荧光探针和制备方法以及应用。
背景技术
细胞内的生物硫醇，例如谷胱甘肽(GSH)，同型半胱氨酸(Hcy)，和半胱氨酸(Cys)，通过自由硫醇(RSH)和氧化二硫化物(RSSR)的平衡在维持生物氧化还原动态平衡中起着关键作用。然而异常的半胱氨酸、同型半胱氨酸、谷胱甘肽水平，与一些疾病密切相关，如细胞内Hcy的高表达与心血管疾病及阿尔茨海默(进行性老年痴呆)有直接关联；Cys缺乏会引起很多综合疾病，如儿童生长缓慢、水肿、肝脏损伤、肌肉；GSH是细胞内含量最多的生物硫醇，是抵御细胞中毒素和自由基的重要的抗氧化剂。它存在氧化型谷胱甘肽(GSSG)和还原型GSH的氧化还原动态平衡。大量资料显示谷胱甘肽在维持细胞的氧化还原动态平衡、氧化应激和在细胞的生长、功能中起着重要作用，而且谷胱甘肽的水平还与许多疾病和癌症有着直接的联系。因此，定量检测生物体系中硫醇的浓度在生物化学和临床化学中具有重要意义。
传统用于检测生物硫醇的方法包括高效液相色谱法、毛细管电泳法、质谱法等。然而这些方法通常会引起待测样品的破会，以及很难应用于生物体内硫醇的检测。
发明内容
本发明的目的是解决传统用于检测生物硫醇的方法存在会引起待测样品的破会和很难应用于生物体内硫醇的检测的技术问题，提供一种快速检测生物硫醇类的荧光探针和制备方法以及应用。本发明合成简单、水溶性好、对生物硫醇具有高选择性和灵敏性。
为解决上述技术问题，本发明采用的技术方案为：
一种快速检测生物硫醇类的荧光探针，它是2-(2-羟基-5-氨基苯基)苯并噻唑衍生物，其结构式为：
一种制备所述快速检测生物硫醇类的荧光探针的方法，将2-(2-羟基-5-氨基苯基)苯并噻唑和顺丁烯二酸酐按1:1-1.5的摩尔比溶于冰乙酸中，加热回流反应4-5h，冷却，过滤，柱色谱纯化即得快速检测生物硫醇类的荧光探针。
所述冰乙酸的用量为2-(2-羟基-5-氨基苯基)苯并噻唑和顺丁烯二酸酐总量的10-20倍。
所述快速检测生物硫醇类的荧光探针具有很好的细胞膜穿透性，可应用于细胞内生物硫醇的检测。
所述荧光探针应用于生物硫醇含量的定量评价。该荧光探针与生物硫醇发生加成反应，通过定量检测加成产物的荧光强度来测定生物硫醇的含量。具体测定方法为：
(1)配制pH＝7.4、浓度为0.01mol/L的磷酸盐缓冲溶液；用二甲亚砜配制0.002mol/L的荧光探针储备液；
(2)将2mL磷酸盐缓冲溶液和2μL荧光探针储备液加入荧光比色皿中，在荧光分光光度仪上检测，随着待测样的加入，460nm处的荧光强度逐渐增强；
(3)用蒸馏水配制1×10-4M的Cys、Hcy、GSH溶液，将2mL磷酸盐缓冲溶液和2μL荧光探针储备液加入荧光比色皿中，每次加入4μLCys进行荧光滴定实验，共加60μLCys；以Cys浓度为横坐标，以460nm处荧光强度为纵坐标绘制图，得到Cys浓度的工作曲线，线性回归方程为:F-F0＝634.878c-59.93，c的单位为10-6M；通过线性拟合得到荧光探针最佳线性响应Cys的范围为:0.0M-2.6×10-6M，线性相关系数为R2＝0.9917。
本发明采用以上技术方案，与背景技术相比，具有以下优点：
(1)本发明合成工艺简单易行，按照比例将2-(2-羟基-5-氨基苯基)苯并噻唑与顺丁烯二酸酐混合，加入冰醋酸，加热回流，最后采用硅胶色谱法进行纯化，得荧光探针；
(2)本发明为2-(2-羟基-5-氨基苯基)苯并噻唑衍生物，具有较大的斯托克斯位移。大斯托克斯位移的染料能够提供好的荧光信号分辨，有效提高荧光检测的灵敏度。反应灵敏对，对生物硫醇显示了高的灵敏性和选择性；
(3)本发明检测过程在水相中进行；
(4)本发明还可用于细胞内生物硫醇的检测。
附图说明
图1本发明荧光探针的氢谱；
图2本发明荧光探针的碳谱；
图3本发明荧光探针的质谱；
图4本发明荧光探针对Cys的滴定图；
图5本发明荧光探针对Cys的工作曲线；
图6本发明荧光探针对生物硫醇的选择性；
图7本发明荧光探针的细胞成像。
具体实施方式
实施例1
本实施例中的一种快速检测生物硫醇类的荧光探针，它是2-(2-羟基-5马来酰亚胺苯基)苯并噻唑，其结构式为：
一种制备本实施例所述快速检测生物硫醇类的荧光探针的方法，将2mmol的2-(2-羟基-5-氨基苯基)苯并噻唑和2mmol的顺丁烯二酸酐按溶于20ml的冰乙酸中，加热回流反应4h，冷却，过滤，柱色谱纯化即得快速检测生物硫醇类的荧光探针。(黄色固体，0.52g,81％)。表征结果见图1、图2和图3。1H NMR(DMSO-d6,600MHz)δ(ppm):11.75(s,1H),8.22(d,1H,J＝2.4Hz),8.16(d,1H,J＝7.8Hz),8.06(d,1H,J＝8.4Hz),7.56(t,1H,J＝8.4Hz),7.47(t,1H,J＝7.2Hz),7.36(dd,1H,J1＝6.6Hz,J2＝2.4Hz).13C NMR(150MHz,CDCl3)δ173.50,166.98,158.90,154.77,138.16,138.03,134.32,130.38,129.83,128.51,126.83,125.62,125.39,122.41,120.69.ESI-MS:calcd for[M+H]+323.0485,Found323.0478.
实施例2
本实施例中的一种快速检测生物硫醇类的荧光探针，它是2-(2-羟基-5马来酰亚胺苯基)苯并噻唑，其结构式为：
一种制备本实施例所述快速检测生物硫醇类的荧光探针的方法，将2mmol的2-(2-羟基-5-氨基苯基)苯并噻唑和2.5mmol的顺丁烯二酸酐按溶于30ml的冰乙酸中，加热回流反应5h，冷却，过滤，柱色谱纯化即得快速检测生物硫醇类的荧光探针。
实施例3
本实施例中的一种快速检测生物硫醇类的荧光探针，它是2-(2-羟基-5马来酰亚胺苯基)苯并噻唑，其结构式为：
一种制备本实施例所述快速检测生物硫醇类的荧光探针的方法，将2mmol的2-(2-羟基-5-氨基苯基)苯并噻唑和3mmol的顺丁烯二酸酐按溶于40ml的冰乙酸中，加热回流反应4.5h，冷却，过滤，柱色谱纯化即得快速检测生物硫醇类的荧光探针。
荧光探针的Cys滴定荧光图
将2mL pH＝7.4的磷酸盐缓冲溶液和2μL荧光探针储备液加入荧光比色皿中，在荧光光谱仪上以370nm激发波长，检测460nm处的荧光强度。随着Cys的加入，荧光强度逐渐增强。仪器参数:激发波长狭缝宽度分别为5.0nm；发射波长的狭缝宽度为10.0nm。荧光发射图见图4。
荧光探针Probel对Cys响应的工作曲线
用蒸馏水配制1×10-4M的Cys溶液，将2mL pH＝7.4的磷酸盐缓冲溶液和2μL荧光探针储备液加入荧光比色皿中，每次加入4μLCys进行荧光滴定实验，共加60μLCys；以Cys浓度为横坐标，以460nm处荧光强度为纵坐标绘制图，得到Cys浓度的工作曲线，线性回归方程为:F-F0＝634.878c-59.93，c的单位为10-6M；通过线性拟合得到荧光探针最佳线性响应Cys的范围为:0M-2.6×10-6M，线性相关系数为R2＝0.9917。荧光发射图见图5。
荧光探针对生物硫醇的选择性图：
在荧光比色皿中，各加入2mL的pH＝7.4的磷酸盐缓冲溶液和2μL荧光探针储备液，再分别加入2摩尔当量的Cysteine(Cys)、Homocysteine(Hcy)、Glutathione(GSH)、L-alanine(Ala)、L-arginine(Arg)、Lasparagine(Asp)、L-glutamine(Gln)、L-glutamicacid(Glu)、L-glycine(gly)、L-histidine(His)、L-isoleucine(Ile)、L-leucine(Leu)、L-lysine(Lys)、L-methionine(Met)、L-phenylalanine(Phe)、L-proline(Pro)、Lserine(Ser)、L-threonine(Thr)、L-tryptophan(Trp)、L-tyrosine(Tyr)and Lvaline(Val))，分别测其在460nm处的荧光强度。荧光发射图见图6。
经实验证明，荧光探针对生物硫醇具有特异性响应。
荧光探针对生物硫醇的细胞成像：
实验之前用二甲亚砜溶液体系配制2.0×10-3M的荧光探针储备液。将培贴的HeLa壁细胞进行如下处理：a)参比细胞；b)取上述荧光探针储备液加入含有贴壁细胞的培养基，置于37℃的5％CO2培养箱中孵育15min；c)将含有贴壁细胞的培养基预先用N-乙基马来酰亚胺处理，然后再加入上述荧光探针储备液；d)取上述荧光探针储备液加入含有贴壁细胞的培养基，置于37℃的5％C02培养箱中孵育15min。然后再加入Cys后，再孵育15min。将处理好的细胞在FL Auto Cell Imaging System的DAPI窗口(345-447nm)下，分别进行荧光成像(40倍物镜，e，f，g，h为相应明场)。如图7。

Claims (4)

1.一种快速检测生物硫醇类的荧光探针，其特征在于：它是2-(2-羟基-5-氨基苯基)苯并噻唑衍生物，其结构式为：
2.一种制备权利要求1所述快速检测生物硫醇类的荧光探针的方法，特征在于：将2-(2-羟基-5-氨基苯基)苯并噻唑和顺丁烯二酸酐按1:1-1.5的摩尔比溶于冰乙酸中，加热回流反应4-5h，冷却，过滤，柱色谱纯化即得快速检测生物硫醇类的荧光探针。
3.根据权利要求2所述的一种制备快速检测生物硫醇类的荧光探针的方法，特征在于：所述冰乙酸的用量为2-(2-羟基-5-氨基苯基)苯并噻唑和顺丁烯二酸酐总量的10-20倍。
4.一种快速检测生物硫醇类的荧光探针的应用，其特征在于：可应用于细胞内生物硫醇的检测。
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