CN108586506B - 一种氟硼荧乙烯基香豆素衍生物及其合成方法和应用 - Google Patents
一种氟硼荧乙烯基香豆素衍生物及其合成方法和应用 Download PDFInfo
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Abstract
本发明提供了一种氟硼荧乙烯基香豆素衍生物及其合成方法和应用,所述的衍生物是(E)7‑(二乙基氨基)‑3‑(2‑(5,5‑二氟‑10‑(4‑甲氧基)‑1,7,9,‑三甲基‑5氢‑二吡咯[1,3,2]二氮杂硼‑3‑)乙烯基‑4‑(苯哌啶‑1‑)‑2氢‑色烯‑2‑酮。衍生物合成方法:1)N2保护下,在二氯甲烷中4‑甲氧基苯甲醛与2,4‑二甲基吡咯缩合,加入DDQ氧化,再加入三乙胺、三氟化硼络合得到固体;2)将上述固体与7‑二乙胺基‑4‑氯‑3‑醛基‑香豆素催化回流反应,后处理即得所述衍生物。该衍生物不仅可用于溶液中ClO‑的检测,也可用于制备关节炎检测试剂,还可用作荧光染料。本发明还提供了一种检测ClO‑的方法,该方法对ClO‑实现了比率型检测,并显示了高的选择性,且检测过程简便、检测结果准确。
Description
技术领域
本发明涉及荧光染料和次氯酸检测,具体涉及一种氟硼荧乙烯基香豆素衍生物及其合成方法和应用。
背景技术
次氯酸是一种比较常见的强氧化剂,因其价格实惠也具有良好的杀菌效果,常作为消毒液、漂白剂、抗菌剂等广泛应用于我们的日常生活中。近现代的生物医学研究表明,生物体内的次氯酸在维持细胞内的氧化还原平衡状态起着非常重要的作用。另外,它对人体免疫系统具有不可或缺的意义。但生物体内过量的次氯酸常常会引起诸多与炎症相关的疾病,如动脉硬化症、神经元坏死、肺病、胆囊炎、风湿性关节炎和癌症等等。为了更加深入的了解次氯酸的相关生物学生理学方面的功能和作用机理,建立快速便捷、灵敏度高、选择性好、能满足环境样品检测和生物体系检测需要的次氯酸分析方法,具有重要的研究意义和应用价值。荧光成像分析法具有灵敏度高,选择性好,操作简单,能够对分析物进行实时定量检测,还能够在生物环境下高效的检测生物分子并且具有较高的时空分辨率等优点,因此设计合成高选择性、高灵敏度且能够用于生物体成像的次氯酸荧光探针具有重要意义。
发明内容
本发明的目的在于提供一种氟硼荧乙烯基香豆素衍生物及其合成方法和应用。
本发明提供的一种氟硼荧乙烯基香豆素衍生物,是(E)7-(二乙基氨基)-3-(2-(5,5-二氟-10-(4-甲氧基)-1,7,9,-三甲基-5氢-二吡咯[1,3,2]二氮杂硼-3-)乙烯基-4-(苯哌啶-1-)-2氢-色烯-2-酮;英文名:(E)-7-(diethylamino)-3-(2-(5,5-difluoro-10-(4-methoxyphenyl)-1,7,9-trimethyl-5H--dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-3-yl)vinyl)-4-(piperidin-1-yl)-2H-chromen-2-one;结构式为:
本发明提供的一种氟硼荧乙烯基香豆素衍生物的合成方法,包括如下步骤:
1)在N2保护下,在二氯甲烷中加入1摩尔当量的4-甲氧基苯甲醛,2-2.2摩尔当量的2,4-二甲基吡咯,搅拌条件下滴入微量的三氟乙酸,室温搅拌6-8h;然后加入1摩尔当量的溶解于二氯甲烷中的2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ),再搅拌4-5h;加入60-80摩尔当量的三乙胺,15-20min后,在0℃下,滴加20-30摩尔当量的三氟化硼,然后升温至室温再搅拌反应6-8h;把反应液倒入水中,用二氯甲烷萃取,合并有机相,加入无水Na2SO4除去水,然后将二氯甲烷旋转蒸发除去,最后柱色谱分离得到桔红色固体即(5,5-二氟-10-(4-甲氧基苯基)-3,7,9-三甲基-5H--4,5,-二吡咯并[1,2-c:2',1'-f]2]二氮杂硼环三烯-1-基)甲川;
2)在N2保护下,将1摩尔当量的上述桔红色固体、1摩尔当量的7-二乙胺基-4-氯-3-醛基-香豆素,在哌啶和冰乙酸催化下于甲苯中回流4-6h,冷却至室温后旋转蒸发除去甲苯,将反应得到的混合物通过柱色谱分离得到蓝黑色固体氟硼荧乙烯基香豆素衍生物。
所述的氟硼荧乙烯基香豆素衍生物可用于溶液中ClO-的检测,也可用于制备关节炎检测试剂,还可用作荧光染料。
本发明提供的一种检测ClO-的方法,其特征在于,包括如下步骤:
(1)、配制pH=7.4、浓度为10mM的PBS缓冲溶液,配制2mM的氟硼荧乙烯基香豆素衍生物的乙腈溶液;
(2)、将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈、5μL 2mM的氟硼荧乙烯基香豆素衍生物的乙腈溶液加到荧光比色皿中,在荧光分光光度仪上检测,随着待测样的加入,510nm的荧光强度逐渐增强,660nm的荧光逐渐减弱;
(3)、将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈、5μL 2mM的氟硼荧乙烯基香豆素衍生物的乙腈溶液加到另外七个荧光比色皿中,分别再加入体积为20、40、60、80、100、120、140μL的ClO-溶液,在荧光分光光度仪上测定510/660对应的强度比值R为0.99、3.08、5.64、8.30、11.20、14.34、17.82,以ClO-浓度为横坐标,以比值R为纵坐标绘制图,得到ClO-浓度的工作曲线;线性回归方程为:R=0.15c-2.46,c的单位为μM;
(4)将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈、5μL氟硼荧乙烯基香豆素衍生物的乙腈溶液加到干净的荧光比色皿中,用微量进样器吸取VμL待测样品溶液,加入到此荧光比色皿中,在荧光分光光度仪上检测,将测得的比值代入步骤(3)的线性回归方程,得到浓度c,待测样品C待测样=2000μL×c×10-6/VμL,即可求得ClO-的浓度。
与现有技术相比,本发明具有如下优点和效果:
1)本发明提供了一种氟硼荧乙烯基香豆素衍生物,不仅可用于溶液中ClO-的检测,也可用于制备关节炎检测试剂,还可用作荧光染料。
2)本发明提供了一种检测ClO-的方法,是在乙腈/PBS=1/1,v/v,pH 7.4缓冲溶液中,通过荧光分光光度计定量检测ClO-的含量。该方法对ClO-实现了比率型检测,并显示了高的选择性,且是一种发射波长在近红外区的检测试剂。该方法检测过程简便、检测结果准确。
附图说明:
图1实施例1制备的氟硼荧乙烯基香豆素衍生物的核磁氢谱图
图2实施例1制备的氟硼荧乙烯基香豆素衍生物的核磁碳谱图
图3实施例1制备的氟硼荧乙烯基香豆素衍生物的质谱图
图4氟硼荧乙烯基香豆素衍生物与ClO-作用的荧光发射图
图5氟硼荧乙烯基香豆素衍生物与各种分析物的荧光柱状图
图6氟硼荧乙烯基香豆素衍生物测定ClO-的工作曲线
图7氟硼荧乙烯基香豆素衍生物测定样品的荧光发射图
图8氟硼荧乙烯基香豆素衍生物检测小鼠关节炎的活体成像图
具体实施方式:
实施例1氟硼荧乙烯基香豆素衍生物即(E)7-(二乙基氨基)-3-(2-(5,5-二氟-10-(4-甲氧基)-1,7,9,-三甲基-5氢-二吡咯[1,3,2]二氮杂硼-3-)乙烯基-4-(苯哌啶-1-)-2氢-色烯-2-酮的合成及表征。
1)在N2保护下,往二氯甲烷中加入4-甲氧基苯甲醛(3mmol,0.408g),2,4-二甲基吡咯(6mmol,0.855g),搅拌条件下滴入几滴三氟乙酸,室温搅拌6h;然后加入溶解于二氯甲烷中的2,3-二氯-5,6-二氰基-1,4-苯醌(3mmol,0.68g)溶液,再搅拌4h;加入9mL三乙胺,15min后,在0℃下,滴加9mL三氟化硼乙醚溶液,然后升温至室温再搅拌6-8h反应完成。把反应液倒入水中,用二氯甲烷萃取,合并有机相,加入Na2SO4除水,然后将二氯甲烷转旋蒸发除去,然后柱色谱分离(石油醚:二氯甲烷=4:1)得到桔红色固体(5,5-二氟-10-(4-甲氧基苯基)-3,7,9-三甲基-5H--4,5,-二吡咯并[1,2-c:2',1'-f]2]二氮杂硼环三烯-1-基)甲川0.356g,产率:33%。
2)在N2保护下,将上一步产物(0.5mmol,0.177g)、7-二乙胺基-4-氯-3-醛基-香豆素(0.5mmol,0.14g)在0.3mL哌啶和0.3mL冰乙酸催化下在甲苯中回流4h,冷却至室温后旋转蒸发除去甲苯,将反应混合物用柱色谱分离(洗脱剂为甲醇:二氯甲烷=1:10)得到蓝黑色固体(E)7-(二乙基氨基)-3-(2-(5,5-二氟-10-(4-甲氧基)-1,7,9,-三甲基-5氢-二吡咯[1,3,2]二氮杂硼-3-)乙烯基-4-(苯哌啶-1-)-2氢-色烯-2-酮0.05g,产率:10.2%。
实施例2
配制pH=7.4、浓度为10mM的PBS缓冲溶液,并用乙腈配制2mM氟硼荧乙烯基香豆素衍生物的溶液;把将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈溶液及5μL氟硼荧乙烯基香豆素衍生物的乙腈溶液加到荧光比色皿中,取ClO-的溶液,逐渐用微量进样器加到此比色皿中,加样的同时在荧光分光光度仪上检测,随着ClO-的加入,510nm的荧光强度逐渐增强,660nm的荧光逐渐减弱。荧光发射图见图4。
实施例3
配制pH=7.4、浓度为10mM的PBS缓冲溶液,并用乙腈配制2mM的氟硼荧乙烯基香豆素衍生物溶液;在22个荧光比色皿中,各加入将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈溶液和5μL氟硼荧乙烯基香豆素衍生物的乙腈溶液,再分别加入100μL ClO-,以及100μL(2×10-2M)的各种分析物:F-,Cl-,Br-,I-,CN-,NO3 -,NO2 -,SO3 2-,SCN-,AcO-,CO3 2-,SO4 2-,ClO2 -,ClO3 -,HS-,CO3 2-,PO4 3-,HCO3 -,Cys,Hcy和GSH在荧光分光光度仪上检测,绘制不同分析物对应的510/660相对荧光强度比值R的柱状图,(见图5)。ClO-使得试剂的510/660荧光强度比值由0.99增加到17.82,其它的分析物基本没有引起氟硼荧乙烯基香豆素衍生物荧光强度比值的变化。
经实验证明,其它分析物不干扰上述体系对ClO-的测定。
实施例4
配制pH=7.4、浓度为10mM的PBS缓冲溶液,并用乙腈配制2mM的氟硼荧乙烯基香豆素衍生物溶液,用蒸馏水配制20mM的ClO-溶液;把将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈溶液和5μL的氟硼荧乙烯基香豆素衍生物的乙腈溶液加到荧光比色皿中,分别再加入体积为20、40、60、80、100、120、140μL的ClO-溶液,在荧光分光光度仪上测定510/660对应的荧光强度比值R为0.99、3.08、5.64、8.30、11.20、14.34、17.82,以ClO-浓度为横坐标,以比值R为纵坐标绘制图,得到ClO-浓度的工作曲线(见图6);线性回归方程为:R=0.15c-2.46,c的单位为μM;
实施例5
配制pH=7.4的PBS(10mM)缓冲溶液,配制20mM的ClO-水溶液,并用乙腈配制2mM的氟硼荧乙烯基香豆素衍生物溶液;把将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈溶液和5μL的氟硼荧乙烯基香豆素衍生物的乙腈溶液加到干净的荧光比色皿中,取ClO-的溶液120μL,用微量进样器加到此比色皿中,同时在荧光光谱仪上测定510/660的对应的荧光强度比值为14.34,通过实施例4的线性回归方程,求得c=112×10-5mol/L,偏差为0.67%。见图7。
实施例6
配制pH=7.4、浓度为10mM的PBS缓冲溶液,并用乙腈配制2mM的氟硼荧乙烯基香豆素衍生物溶液。首先向裸鼠的腹腔注射0.1mL戊巴比妥钠(1%)溶液对其进行麻醉。然后,在裸鼠的右脚踝注射20μLλ-角叉菜胶(5mg/mL,溶于PBS)用于诱导产生关节炎,同一只裸鼠的左脚踝注射20μL PBS作为对照组。4小时后,在裸鼠的左、右脚踝注射20μL氟硼荧乙烯基香豆素衍生物,立即拍照,通过活体成像仪可以观察到绿色通道右脚踝的荧光强度增强,左脚踝没有明显变化,说明右脚踝有次氯酸产生,左脚踝没有。随后,分别在5分钟,10分钟,20分钟对小鼠进行拍照,可以观察到绿色通道右脚踝的荧光强度随时间明显增强,左脚踝没有明显变化见图8。这些结果表明,氟硼荧乙烯基香豆素衍生物可以通过检测活体小鼠的关节处产生的ClO-,诊断小鼠是否患有关节炎。
Claims (5)
2.如权利要求1所述的一种氟硼荧乙烯基香豆素衍生物的合成方法,其特征在于,包括如下步骤:
1)在N2保护下,在二氯甲烷中加入1摩尔当量的4-甲氧基苯甲醛,2-2.2摩尔当量的2,4-二甲基吡咯,搅拌条件下滴入微量的三氟乙酸,室温搅拌6-8h;然后加入1摩尔当量的溶解于二氯甲烷中的DDQ,再搅拌4-5h;加入60-80摩尔当量的三乙胺,15-20min后,在0℃下,滴加20-30摩尔当量的三氟化硼,然后升温至室温再搅拌反应6-8h;把反应液倒入水中,用二氯甲烷萃取,合并有机相,加入无水Na2SO4除去水,然后将二氯甲烷旋转蒸发除去,最后柱色谱分离得到桔红色固体;
2)在N2保护下,将1摩尔当量的上述桔红色固体、1摩尔当量的7-二乙胺基-4-氯-3-醛基-香豆素,在哌啶和冰乙酸催化下于甲苯中回流4-6h,冷却至室温后旋转蒸发除去甲苯,将反应得到的混合物通过柱色谱分离得到蓝黑色固体氟硼荧乙烯基香豆素衍生物。
3.如权利要求1所述氟硼荧乙烯基香豆素衍生物在制备ClO-检测试剂中的应用。
4.一种检测ClO-的方法,其特征在于,包括如下步骤:
(1)、配制pH=7.4、浓度为10mM的PBS缓冲溶液,配制2mM的如权利要求1所述氟硼荧乙烯基香豆素衍生物的乙腈溶液;
(2)、将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈、5μL 2mM的氟硼荧乙烯基香豆素衍生物的乙腈溶液加到荧光比色皿中,在荧光分光光度仪上检测,随着待测样的加入,510nm的荧光强度逐渐增强,660nm的荧光逐渐减弱;
(3)、将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈、5μL 2mM的氟硼荧乙烯基香豆素衍生物的乙腈溶液加到另外七个荧光比色皿中,分别再加入体积为20、40、60、80、100、120、140μL的ClO-溶液,在荧光分光光度仪上测定510/660对应的强度比值R为0.99、3.08、5.64、8.30、11.20、14.34、17.82,以ClO-浓度为横坐标,以比值R为纵坐标绘制图,得到ClO-浓度的工作曲线;线性回归方程为:R=0.15c-2.46,c的单位为μM;
(4)将1000μL pH 7.4的PBS缓冲溶液、1000μL乙腈、5μL如权利要求1所述衍生物的乙腈溶液加到干净的荧光比色皿中,用微量进样器吸取VμL待测样品溶液,加入到此荧光比色皿中,在荧光分光光度仪上检测,将测得的比值代入步骤(3)的线性回归方程,得到浓度c,待测样品C待测样=2000μL×c×10-6/VμL,即可求得ClO-的浓度。
5.如权利要求1所述氟硼荧乙烯基香豆素衍生物在制备关节炎检测试剂中的应用。
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