CN110407865B - 基于苯磺酰胺结构的式（i）化合物及其制备方法与应用 - Google Patents
基于苯磺酰胺结构的式（i）化合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种基于苯磺酰胺结构的式(I)化合物及其制备方法与应用，式(I)化合物，其结构式为：
该化合物作用荧光探针，表现出优益的高尔基体靶向定位效果，且能对过氧化氢进行成像，且具有灵敏度高、选择性高以及合成简便的优点。
Description
技术领域
本发明涉及一种新型的基于苯磺酰胺结构靶向定位高尔基体检测H2O2的荧光探针的设计策略及合成方法，尤其是能够靶向定位高尔基体检测H2O2的荧光探针Np-Golgi的合成方法。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
高尔基体是一种广泛存在于所有真核生物中的光面膜性细胞器，其主要功能是将内质网生成的蛋白质经加工、分选、运输到质膜、内涵体、溶酶体或细胞外等。高尔基体保证蛋白质和脂类运输到轴突和树突；在突触囊泡的组装和轴浆运输中是必需的。除了在蛋白质转运和加工中发挥作用，哺乳动物细胞中的高尔基体在细胞极性、伤口愈合、细胞周期的调控、凋亡中也发挥了重要作用。
在神经元中，高尔基体不仅对离子通道、受体、信号分子的正确顺向运输起到重要作用，而且通过逆向和跨突触运输途径调节外源分子的运输。神经元是有极性的细胞，高尔基体将特定货物运输到相应的轴突和树突，在维持神经元极性中起重要作用，高尔基体结构的改变会损害其精确的加工和分选相应蛋白到神经元特定区域的功能。蛋白堆积与神经变性疾病，如，阿尔兹海默病、肌萎缩侧索硬化、帕金森病等；凋亡与神经变性疾病。此外，高尔基体还与其他的一些疾病有关系，如肝脏疾病等。
随着荧光技术的不断革新与进步，探究高尔基体与各种疾病之间的相互联系被越来越多的研究者所重视。传统的靶向定位高尔基体的基团主要包括半胱氨酸和具有高尔基体靶向效果的多肽类。半胱氨酸由于缺乏脂溶性而常常在合成路线的设计上存在困难，而多肽类设计复杂且合成花费较大而限制了其应用。
此外，过氧化氢作为细胞氧化应激过程中的ROS的重要一员，与老年痴呆、老年帕金森氏病、脑中风、动脉硬化、糖尿病性肾病、糖尿病性神经性病变、眼部疾病等的发展密切相关，所以，过氧化氢的浓度对指示相关疾病的氧化损伤程度尤为重要。但是目前还没有较好的对高尔基体进行定位，并对高尔基体中的过氧化氢进行辅助检测的荧光染料。
发明内容
针对上述现有技术中存在的技术问题，本发明的目的是提供一种基于苯磺酰胺结构的式(I)化合物及其制备方法与应用。该化合物作用荧光探针，表现出优益的高尔基体靶向定位效果，且能对过氧化氢进行成像，且具有灵敏度高、选择性高以及合成简便的优点。
为了解决以上技术问题，本发明的技术方案为：
式(I)化合物，其结构式为：
式(I)所述化合物的制备方法，以4-溴-1,8-萘二甲酸酐、双联频哪醇硼酸酯和磺胺为原料，按照如下反应路线进行反应制备：
在一些实施例中，4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯反应的催化剂为PdCl2。
在一些实施例中，4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯反应体系的溶剂为1,4-二氧六环。1,4-二氧六环为严格除水的。
在一些实施例中，4-溴-1,8-萘二甲酸酐的浓度为0.5-1.5mmol；双联频哪醇硼酸酯 1-1.5mmol。
在一些实施例中，还包括向4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯的反应体系中加入K2CO3的步骤。K2CO3作为强碱弱酸盐为反应提供碱性反应条件的同时，能够起到稳定 Pd催化剂活性中心的作用。
在一些实施例中，4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯反应的温度为85-95℃，反应的时间为10-14h。
在一些实施例中，式(II)所述化合物与磺胺反应的温度为150-170℃，反应的时间为10-14h。
进一步的，式(II)所述化合物与磺胺反应的温度为160℃，反应的时间为12h。
在一些实施例中，式(II)所述化合物与磺胺反应的溶剂为乙酸。
进一步的，磺胺的浓度为5mmol-10mmol。
为了获得产率更高的探针Np-Golgi，选择溶剂乙酸以增加可调控的反应温度，该步亚胺化的反应，传统上多采用乙醇作为反应溶剂，限制了其温度的调控，选用乙酸作为溶剂，将温度设定为160℃有利于亚胺化反应的脱水以提高探针的产率。该步的溶剂及反应温度为优选条件。
式(I)所述化合物作为荧光探针在靶向定位高尔基体检测过氧化氢中的应用。
当(I)所述化合物作为荧光探针，遇到H2O2时，探针结构中萘二酰亚胺的4-位上的频哪醇硼酸酯结构就会被氧化成羟基使得探针的结构由原来的A-π-A结构变为A-π-D结构，产生ICT效应，荧光发射波长红移至560nm处，即可对高尔基体中的过氧化氢进行检测。
本发明的有益效果为：
1.本发明提供了一种基于苯磺酰胺结构的能够高精度靶标定位高尔基体的合成设计策略，是具有普适性的，即该策略可以应用于多种高尔基体定位类探针的设计当中以解决高尔基体靶向性的问题。
2.靶向定位高尔基体检测H2O2的比率型荧光探针Np-Golgi在检测H2O2的应用中展现出了响应倍数高、选择性好、靶向效果佳等诸多优势，并且成功应用到了动物疾病模型的成像当中，是一种新型的成像工具，为今后发展一系列高尔基体成像探针提供了新思路和新策略。
3.本发明的探针Np-Golgi的生物相容性好，对细胞和活体损伤小。
4.本发明的探针Np-Golgi应用了双光子成像技术，能够增加成像的穿透深度。
5.本发明的设计策略和合成路线简便，且原料均为廉价易得的，有望应用于市场化的生产。
附图说明
构成本发明的一部分的说明书附图用来提供对本申请的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1是本发明实施例1制备的荧光探针反应前后的吸收、荧光发射光谱图，其中，横坐标为波长(nm)，左侧纵坐标为紫外吸收强度，右侧纵坐标为荧光发射强度，黑色表示探针，红色表示探针与过氧化氢反应后，虚线表示紫外吸收光谱，实线表示荧光发射光谱；
图2是本发明实施例1制备的荧光探针与细胞内相关氨基酸、金属离子、活性氧等成分的选择性测定柱状图；
图3是本发明实施例1制备的荧光探针在人肝细胞HL-7702中与四种市售的不同亚细胞器的商业化染料共染后的细胞荧光成像图；
图4是本发明实施例1制备的荧光探针在人肝癌细胞SMCC-7721中的不同刺激或清除效果下，细胞内H2O2浓度的共聚焦荧光成像图；
图5是本发明实施例1制备的荧光探针在高血压小鼠模型中肾脏部位的双光子共聚焦荧光成像图。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本申请的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
正如背景技术所介绍的，现有技术中存在对于靶向定位高尔基体检测H2O2的探针极其缺乏的不足，为了解决如上的技术问题，本申请提出了一种新型的基于苯磺酰胺结构靶向定位高尔基体检测H2O2的比率型双光子荧光探针的设计策略及合成方法。
实施例1
荧光探针的合成
取原料4-溴-1,8-萘二甲酸酐(0.3g)及双联频哪醇硼酸酯(0.38g)溶于15mL的1,4- 二氧六环中，再加入PdCl2(dppf)(0.0732g)和K2CO3(0.3g)，90℃下回流12h。反应完毕后，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇＝20:1作为洗脱剂，柱层析法提纯化合物即得白色固体中间产物Np-Cyto(62％)。
取中间产物Np-Cyto(0.3g)与磺胺(1.7g)，溶于15mL乙酸中，160℃回流加热12h。反应完毕后，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇10:1，柱层析法提纯化合物即得浅黄色粉末Np-Golgi(产率为10％)。
核磁及质谱表征：
1H NMR(400MHz,CDCl3)δ9.20(d,J＝8.5Hz,1H),8.64–8.57(m,2H),8.34(d,J＝6.6Hz,1H),8.09(d,J＝7.9Hz,2H),7.82(t,J＝7.8Hz,1H),7.50(d,J＝7.9Hz,2H),4.99(s,2H), 1.47(s,12H).13C NMR(101MHz,CDCl3)δ129.92,127.70,84.78,29.71,25.02.HRMS(ESI) m/z:[M+]calculated for C24H23BN2O6S,479.1430found 479.1398；[M+Na]calculated for C24H23BN2O6S,501.1268found 501.1205.
效果实验：
通常，可以将染料分子溶解在生理盐水、缓冲液或由乙腈、二甲亚砜等水溶性有机溶剂，然后加入适当缓冲液及其他有机试剂进行测试。分别研究了探针Np-Golgi在pH＝7.4缓冲水溶液及各种常见的有机试剂中的光物理性质并将其用于活细胞和高血压小鼠活体成像实验。活细胞的染色方法是将培养好的细胞放于含有探针分子的缓冲溶液中孵育，孵育一定的时间后除去孵育液，进行共聚焦成像实验。小鼠的染色方法是将探针原位滴加到小鼠肾脏部位，一段时间后，对小鼠的肾脏进行双光子激光共聚焦成像。
探针Np-Golgi与H2O2反应的紫外吸收、荧光发射及选择性实验：
对照组：Np-Golgi(2μM)、PBS缓冲溶液(10mM)、pH＝7.4；实验组：Np-Golgi(2μM)、PBS缓冲溶液(10mM)、pH＝7.4、H2O2(100μM)。将对照组和实验组都在37℃下孵育 30min，然后分别以其最大吸收为单光子激发波长，测量其紫外吸收与荧光发射光谱图，其光谱图显示于图1。横坐标为波长(nm)，左侧纵坐标为紫外吸收强度。图2 为Np-Golgi 对多种的生物学相关成分的响应情况，已检测的生物学相关成分包括生物硫醇(半胱氨酸、谷胱甘肽)、盐(KCl、NaCl、ZnCl、Na3C6H5O7、NaS2O3)、活性氧、活性氮及自由基 (t-BuOOH、·OH、NO、O2 ·-、ClO-、ROO·、1O2、H2O2)和维生素C。如图2所示，只有当H2O2存在时，荧光强度有显著的增强且响应倍数高达74倍。这个说明与生物体内其他组分相比，Np-Golgi对H2O2有极好的选择性，可以用在复杂的细胞及活体生物环境中，特异性检测H2O2。
Np-Golgi的高尔基体靶向性实验：
人肝细胞HL-7702是由高糖的DMEM培养液培养的，分别加入10μM的探针以及 0.5μM不同亚细胞器的商业化染料(包括高尔基体、线粒体、溶酶体、内质网四种)共孵育细胞30min后，使用激光共聚焦显微镜进行共定位成像实验。共定位细胞成像实验如图3 所示，探针展现了优异的高尔基体定位效果。
探针对活细胞共聚焦荧光成像实验：
人肝细胞HL-7702是由高糖的DMEM培养液培养的，提前用各种条件处理(包括20mMNAC清除组、1μg/mLPMA刺激组、1μg/mLPMA刺激后20mM NAC清除组)，然后分别加入10μM的探针在37℃中孵育30分钟，然后将细胞带有探针孵育液洗掉，进行激光共聚焦荧光成像，如图4所示。PMA刺激后，细胞中的H2O2浓度上升，荧光强度更亮。PMA 刺激后用NAC再清除，与对照组相比荧光减弱。图4中B图为成像图的荧光数据输出图。单光子激发光为405nm，蓝色通道收集430-580nm，绿色通道收集530-580nm。
探针对在高血压小鼠模型的肾脏组织中的双光子共聚焦荧光成像实验：
小鼠通过20天的长期腹腔注射药物哇巴因诱导产生高血压。原位在模型小鼠的肾脏部分滴加100μL浓度为10μM的探针Np-Golgi，30min后使用双光子共聚焦成像显微镜进行成像。如图5所示，高血压小鼠肾脏部位的荧光强度明显高于对照空白组小鼠，说明探针成功地应用于了模型小鼠的活体成像中。
实施例2
荧光探针的合成
取原料4-溴-1,8-萘二甲酸酐(0.277g)及双联频哪醇硼酸酯(0.35g)溶于15mL的1,4- 二氧六环中，再加入PdCl2(dppf)(0.082g)和K2CO3(0.32g)，90℃下回流10h。反应完毕后，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇＝20:1作为洗脱剂，柱层析法提纯化合物即得白色固体中间产物Np-Cyto(42％)。
取中间产物Np-Cyto(0.325g)与磺胺(0.85g)，溶于12mL乙酸中，140℃回流加热12h。反应完毕后，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇10:1，柱层析法提纯化合物即得浅黄色粉末Np-Golgi(产率为6％)。
实施例3
荧光探针的合成
取原料4-溴-1,8-萘二甲酸酐(0.28g)及双联频哪醇硼酸酯(0.40g)溶于15mL的1,4- 二氧六环中，再加入PdCl2(dppf)(0.075g)和K2CO3(0.31g)，90℃下回流12h。反应完毕后，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇＝20:1作为洗脱剂，柱层析法提纯化合物即得白色固体中间产物Np-Cyto(52％)。
取中间产物Np-Cyto(0.33g)与磺胺(1.2g)，溶于14mL乙酸中，150℃回流加热12h。反应完毕后，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇10:1，柱层析法提纯化合物即得浅黄色粉末Np-Golgi(产率为7％)。
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。
Claims (10)
1.式(I)化合物，其特征在于：其结构式为：
2.式(I)所述化合物的制备方法，其特征在于：以4-溴-1,8-萘二甲酸酐、双联频哪醇硼酸酯和磺胺为原料，按照如下反应路线进行反应制备：
3.根据权利要求2所述的式(I)所述化合物的制备方法，其特征在于：4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯反应的催化剂为PdCl2(dppf)。
4.根据权利要求2所述的式(I)所述化合物的制备方法，其特征在于：4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯反应体系的溶剂为1,4-二氧六环。
5.根据权利要求2所述的式(I)所述化合物的制备方法，其特征在于：还包括向4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯的反应体系中加入K2CO3的步骤。
6.根据权利要求2所述的式(I)所述化合物的制备方法，其特征在于：4-溴-1,8-萘二甲酸酐和双联频哪醇硼酸酯反应的温度为85-95℃，反应的时间为10-14h。
7.根据权利要求2所述的式(I)所述化合物的制备方法，其特征在于：式(II)所述化合物与磺胺反应的温度为150-170℃，反应的时间为10-14h。
8.根据权利要求7所述的式(I)所述化合物的制备方法，其特征在于：式(II)所述化合物与磺胺反应的温度为160℃，反应的时间为12h。
9.根据权利要求2所述的式(I)所述化合物的制备方法，其特征在于：式(II)所述化合物与磺胺反应的溶剂为乙酸。
10.权利要求1中式(I)所述化合物作为荧光探针在以非疾病的诊断与治疗为目的的靶向定位高尔基体检测过氧化氢中的应用。
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| CN112851556B (zh) * | 2021-01-29 | 2022-05-24 | 深圳大学 | 新型聚集诱导发光高尔基体荧光探针及其制备方法与应用 |
| CN114032094B (zh) * | 2021-11-20 | 2023-09-29 | 太原理工大学 | 基于环氧合酶-2靶点快速定位高尔基体的橙光碳点及其制备和应用 |
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