CN105969339A - 具有聚集诱导荧光增强特性的氟离子传感器的合成及应用 - Google Patents
具有聚集诱导荧光增强特性的氟离子传感器的合成及应用 Download PDFInfo
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Abstract
本发明公开了一种具有聚集诱导荧光增强特性的氟离子传感器的合成及应用。本发明以二苯甲酮衍生物为起始原料合成目标化合物1。本发明开展了目标化合物1对各种阴离子的检测研究，发现其对氟离子具有很好的检测效果，与现有技术相比，本发明具有合成原料易得、目标化合物荧光量子产率高、抗光漂白能力强，避免了传统荧光染料不宜在高浓度下检测的缺点，并且该目标化合物1成功用于细胞内氟离子的检测。因此，其在对环境或体内氟离子的检测方面具有很大的应用前景。
Description
技术领域
本发明属于生物化学材料领域，涉及一种氟离子荧光传感器的合成方法及应用。
背景技术
氟离子是生物体中最重要的阴离子之一，是维持牙齿和骨骼正常生长的必需物质，低浓度的氟离子对牙齿健康和骨质疏松的治疗具有重要作用，当体内氟离子浓度偏高时会导致氟斑牙、氟骨症、骨癌、抑制胚胎神经传递素的生物合成等疾病，所以严格掌握氟离子的摄入量是十分必要的。目前，对于氟离子的检测主要采用分光光度法和电化学法，前者由于受光源的非单色性，溶液对光的散射等因素的影响，常常会出现测量结果偏离Lambert-Beer定律的现象，导致测量误差。后者则存在电极已被污染、零点和满刻度经常需要标定、维护成本高等缺点，在实际应用中受到了一定的限制。而荧光传感器由于具有操作简单、选择性强、灵敏度高等优点，近年来成为了氟离子检测重要研究热点。
聚集诱导荧光增强(AIE)，即在溶液状态下呈现无荧光或弱荧光，但是在聚集态呈现强荧光。具有AIE效应的荧光分子由于具有高荧光量子产率、强抗漂白性、无需低浓度下检测等优点，为Turn-on型的荧光传感器分子的设计提出了新的思路。其中四苯乙烯类分子(tetraphenylethylene,TPE)更是设计AIE类荧光传感器的热门分子。本发明利用TPE分子的AIE特性，通过调节TPE分子的聚集/解聚过程，设计一种基于TPE分子的氟离子荧光传感器，具有选择性强、灵敏度高、抗漂白能力强、能够在活细胞中检测氟离子的特点。
发明内容
本发明的内容是一种具有聚集诱导荧光增强特性的氟离子传感器的合成及应用。实现本发明目的的技术解决方案是：一种氟离子荧光传感器，具有如下结构：
该目标化合物具有聚集诱导荧光增强特性，即在溶解状态下具有弱荧光，聚集状态下具有强荧光。
一种氟离子荧光传感器的合成方法，合成路线如下：
第一步：4-溴二苯甲酮与4-甲氧基二苯甲酮在四氯化钛作用下发生McMurry反应，生成具有AIE特性的化合物2；
第二步：化合物2与4-吡啶硼酸在[1,1'-双(二苯基磷)二茂铁]二氯化钯(Pd(dppf)Cl2)的催化下发生Suzuki偶联反应，生成化合物3；
第三步：对羟基苯甲醛与三异丙基氯硅烷在DBU的作用下室温下反应生成化合物5；
第四步：化合物5和还原剂硼氢化钠反应后，被还原为化合物6；
第五步：化合物6与三溴化磷反应后生成化合物7；
第六步：化合物7与化合物3在甲苯中回流得到目标化合物1，利用柱层析法进行分离后，结构经1HNMR，13CNMR，HR-MS鉴定。
一种氟离子荧光传感器的应用研究：
在目标化合物1中含有一个吡啶盐结构，赋予了该化合物一定的水溶性，因此，该传感器可以用于水样检测，简单实用，对环境、人体污染低。在本发明中，用于检测氟离子的溶剂为PBS溶液(含1％的DMSO，样品浓度为5μM)，向溶液中加入10μM氟离子后，监测荧光强度随时间的变化情况，结果表明，在37℃下15min后荧光强度基本达到饱和。
在5μM目标化合物1的PBS溶液中，加入不同浓度的氟离子，在37℃下孵化15min后，测定目标化合物1的荧光强度随氟离子浓度的变化情况。在2.5μM至5μM氟离子浓度范围内目标化合物1的荧光强度呈现良好的线性关系。
目标化合物1与氟离子作用后发生硅醚键的断裂，进一步发生消除反应生成化合物4-methylenecyclohexa-2,5-dienone和化合物3。而化合物3较化合物1在水中的溶解性差，所以形成聚集态，荧光强度大大增强。为了了解目标化合物1对氟离子的选择性，本发明对其他阴离子如：Cl-，Br-，I-，Ac-，H2PO4 -，HPO4 2-，BrO3 -，NO2 -，NO3 -，OH-，SO4 2-与目标化合物1的反应前后的荧光强度也进行了测定，结果表明，除氟离子外其他阴离子与目标化合物1的反应前后的荧光强度均没有明显增强。
HeLa细胞氟离子传感荧光成像：目标化合物1用二甲基亚砜(DMSO)溶解准确配制成1mM的母液，然后再用培养基稀释成5μM的稀释液。移取200μL的稀释液加入到细胞培养皿中，于室温下孵育15min，用PBS缓冲溶液冲洗细胞培养皿洗去多余染料分子。其中一半细胞加入10μM四丁基氟化铵水溶液，继续在37℃、5％CO2、100％饱和湿度的培养箱中培养15min后，倒出培养基，用新鲜培养基清洗细胞3遍。在405nm激发下用共聚焦荧光显微镜观察细胞的荧光成像情况，采集450-550nm的荧光信号进行荧光成像。
发明人通过设计与合成，将目标化合物1成功用于氟离子检测。与现有技术相比，本发明合成简单，较易大规模生产和应用，克服了传统染料分子易漂白、仅能在稀溶液中检测的缺点。
附图说明
图1(a)在5μM化合物1的PBS缓冲溶液中加入不同浓度的氟离子，37℃孵化15min后的荧光发射光谱；(b)在504nm处荧光强度与氟离子浓度的关系图。
图2在5μM化合物1的PBS缓冲溶液中加入5μM不同阴离子，37℃孵化15min后，在504nm处荧光强度柱状图。
图3化合物1与HeLa细胞在存在和不存在氟离子的情况下，37℃下孵化30min后的激光共聚焦显微成像照片。(a)化合物1与HeLa细胞在37℃下孵化30min后的明场照片；(b)化合物1与HeLa细胞在37℃下孵化30min后的荧光照片；(c)为(a)与(b)的叠加图；(d)化合物1与HeLa细胞在37℃下孵化15min,再与氟离子孵化15min后的明场照片；(e)化合物1与HeLa细胞在37℃下孵化15min,再与氟离子孵化15min后的荧光照片；(f)为(d)与(e)的叠加图。
具体实施方式
本实施例中所用的原料均为已知化合物，可以由商业途径获得，或可按相关文献设计方法合成。
实施例1
目标化合物1的合成
(1)化合物2的合成：将锌粉(1.56g,24mmol)、4-溴二苯甲酮(313mg,1.2mmol)和4-甲氧基二苯甲酮(212mg,1.0mmol)加入无水四氢呋喃中，将悬浮液在搅拌下冷却到0℃。然后用注射器缓慢滴入四氯化钛(2.276g,12mmol)，0℃下继续搅拌30min后，混合液回流4h。冷却，搅拌下滴入碳酸钠溶液直至无气泡产生为止。加入二氯甲烷和饱和食盐水分液、萃取，有机相用饱和食盐水洗涤三次，有机相用无水硫酸钠干燥、浓缩、柱层析分离后得到化合物2，产率为25％。
(2)化合物3的合成：将化合物2(220mg,0.5mmol)、4-吡啶苯硼酸(90mg,0.73mmol)、Pd(dppf)Cl2(80mg,0.100mmol)、CH2Cl2(1mL)、Bu4NI(25mg,0.068mmol)和碳酸钾水溶液(2M,10mL)加入甲苯中，将混合液在氮气保护条件下回流16h。冷却，加入二氯甲烷和饱和食盐水分液、萃取，有机相用饱和食盐水洗涤三次，有机相用无水硫酸钠干燥、浓缩、柱层析分离后得到化合物3，产率80％。1H NMR(400MHz,CDCl3)δ8.65(br,2H),7.67(br,2H),7.48–7.43(m,2H),7.21–7.04(m,12H),6.96(dd,J＝12.2,8.7Hz,2H),6.69–6.94(m,2H),3.76(s,3H).HR-MS:440.20082,[M+H]+。
(3)化合物5、6、7按照文献报道方法(Anal Chim Acta.2014,849:36-42.)合成。
(4)化合物1的合成：将化合物3和化合物7溶于甲苯中，80℃下反应4h。生成浅红色固体结晶物，过滤，滤饼用甲醇溶解后进行柱层析分离得到化合物1，产率85％。核磁和质谱表征数据：1H NMR(400MHz,MeOD)δ8.92(br,2H),8.39–8.27(m,2H),7.78(dd,J＝14.9,8.6Hz,2H),7.43(dd,J＝8.9,2.3Hz,2H),7.31–7.20(m,3H),7.18–6.89(m,13H),6.68(t,J＝8.6Hz,2H),5.71(s,2H),3.72(d,J＝4.4Hz,3H),1.26(m,3H),1.12(d,J＝7.3Hz,18H).13CNMR(101MHz,MeOD)δ158.85,158.69,157.39,155.87,148.96,148.86,144.01,143.39,143.30,143.15,142.85,142.83,138.74,138.66,135.34,135.28,132.48,132.28,132.19,131.08,131.04,131.02,130.96,130.58,129.58,128.51,127.76,127.65,127.42,127.31,127.22,126.75,126.50,126.46,125.94,124.32,120.51,113.10,112.87,62.95,54.31,17.03,12.48.HR-MS:702.37643,[M]+。
实施例2
氟离子传感器性能测试
(1)氟离子传感器响应速度测定：取10μL化合物1的DMSO溶液(1mM)于2mL PBS缓冲溶液中，然后加入20μL四丁基氟化铵的水溶液(1mM)。混合溶液在37℃下孵化，然后测定在不同孵化时间时混合液的荧光发射光谱(Ex＝344nm)，15min后荧光强度基本达到饱和。
(2)氟离子传感器荧光滴定测试：取10μL化合物1的DMSO溶液(1mM)于2mL PBS缓冲溶液中，然后加入不同量的四丁基氟化铵水溶液(1mM)。混合溶液在37℃下孵化15min后，然后测定加入不同浓度四丁基氟化铵后溶液的荧光发射光谱(Ex＝344nm)，在2.5μM至5μM氟离子浓度范围内混合液的荧光强度呈现良好的线性关系(如图1所示)。
(3)氟离子传感器的离子选择性测试：取10μL化合物1的DMSO溶液(1mM)于2mL PBS缓冲溶液中，然后加入10μL不同的阴离子水溶液(钠盐)(1mM)，如：Cl-，Br-，I-，Ac-，H2PO4 -，HPO4 2-，BrO3 -，NO2 -，NO3 -，OH-，SO4 2-。混合溶液在37℃下孵化15min后，然后测定加入不同阴离子后溶液的荧光发射光谱(Ex＝344nm)。结果表明，除氟离子外其他阴离子与目标化合物1的反应前后的荧光强度均没有明显增强(如图2所示)，说明该荧光传感器可以选择性识别氟离子。
实施例3
HeLa细胞激光共聚焦荧光显微成像：HeLa细胞经过复苏接种于含10％胎牛血清的培养基中，然后在37℃、5％CO2、100％饱和湿度的培养箱中培养。然后在18mm盖玻片上培养24h，待用。
将HeLa细胞浸入含5μM化合物1的培养基中，在37℃、5％CO2、100％饱和湿度的培养箱中培养15min后，倒出培养基，用新鲜培养基清洗细胞3遍。然后再加入新鲜培养基，其中一半细胞加入10μM四丁基氟化铵水溶液(20μL，1mM)，另一半细胞不做任何处理，继续在37℃、5％CO2、100％饱和湿度的培养箱中培养15min后，倒出培养基，用新鲜培养基清洗细胞3遍。分别对无氟离子孵化和经氟离子孵化的HeLa细胞在激光共聚焦荧光显微镜下观察，并对其进行明场和暗场下拍照(如图3所示)。
Claims (6)
1.一种氟离子荧光传感器，其特征在于：所述氟离子荧光传感器具有如下结构：
2.根据权利要求1所述的目标化合物1，其特征在于：含有三异丙基硅基作为触发基团。
3.根据权利要求1所述的目标化合物1，其特征在于：含有四苯乙烯结构作为荧光信号基团。
4.根据权利要求1所述氟离子荧光传感器目标化合物1的合成方法：
第一步：4-溴二苯甲酮与4-甲氧基二苯甲酮在四氯化钛作用下发生McMurry反应，生成具有AIE特性的化合物2；
第二步：化合物2与4-吡啶硼酸在[1,1'-双(二苯基磷)二茂铁]二氯化钯(Pd(dppf)Cl2)的催化下发生Suzuki偶联反应，生成化合物3；
第三步：对羟基苯甲醛与三异丙基氯硅烷在DBU的作用下室温下反应生成化合物5；
第四步：化合物5和还原剂硼氢化钠反应后，被还原为化合物6；
第五步：化合物6与三溴化磷反应后生成化合物7；
第六步：化合物7与化合物3在甲苯中回流得到目标化合物1，利用柱层析法进行分离后，结构经1HNMR，13CNMR，HR-MS鉴定。
5.根据权利要求1所述氟离子荧光传感器在氟离子荧光检测中的应用，其特征在于：可选择性检测氟离子。
6.根据权利要求1所述氟离子荧光传感器在氟离子荧光检测中的应用，其特征在于：可同时用于细胞内氟离子的检测。
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