CN113620979A - 一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针及其制备方法 - Google Patents
一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种‑Se‑Se‑双硒键侨联β淀粉样蛋白抑制药物的荧光探针及其制备方法，将β淀粉样蛋白抑制药物(M)、DCC/DMAP按照摩尔比1:0.1～1/0.1～1溶解到氯仿中，加入1～1.3当量(M:M)含双硒键的linker，50～100℃搅拌1～6h，25℃‑70℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物M‑LSeSe。本发明利用含有双硒键的配体把BODIPY与β淀粉样蛋白抑制药物侨联在一起，得到一种‑Se‑Se‑双硒键侨联β淀粉样蛋白抑制药物的荧光探针。众所周知，β‑淀粉样蛋白缠结是阿尔兹海默病主要原因之一，本发明开发的荧光探针其双硒键在脑脊液氧化还原微环境中断裂，使得BODIPY和β淀粉样蛋白抑制药物协同发挥对β淀粉样蛋白聚集体诊断抑制作用，达到AD诊疗目的。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)及其制备方法。
背景技术
阿尔茨海默病(Alzheimer disease，AD)，又叫老年性痴呆，是一种中枢神经系统变性病，起病隐袭，病程呈慢性进行性，是老年期痴呆最常见的一种类型。主要表现为渐进性记忆障碍、认知功能障碍、人格改变及语言障碍等神经精神症状，严重影响社交、职业与生活功能。
AD的病因及发病机制尚未阐明，特征性病理改变为β-淀粉样蛋白沉积形成的细胞外老年斑和tau蛋白过度磷酸化形成的神经细胞内神经原纤维缠结，以及神经元丢失伴胶质细胞增生等。及时准确的诊断前驱期AD是诊断和抑制AD的关键。
β-淀粉样蛋白沉积形成的细胞外老年斑是AD的病因及发病机制之一。前人在β-淀粉样蛋白级联假说的基础上研究创造了很多诊断β-淀粉样蛋白的近红外荧光探针，但是这些探针仍具有这样或那样的问题，可载药的荧光探针更是少之又少。因此，研究具有亲和性、高选择性和集诊断和抑制一体的可携带药物的新型荧光探针对AD的诊断与抑制具有重要意义。
发明内容
本发明的主要目的在于提供一种近红外长波长、高亲和性、高选择性的集阿尔兹海默症诊断和抑制于一体的荧光探针，可以有效解决背景技术中的问题。
为实现上述目的，本发明提供如下技术方案：一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)，其分子结构式为：
式中二吡咯甲川氟硼络合物通过linker与β淀粉样蛋白抑制药物(M)结合在一起，linker中间通过双硒键连接，M具体为山柰酚、姜黄素和白藜芦醇中的任一种；
其反应路线如下式所示：
一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)制备方法，其特征在于，包括如下步骤：
(4)将甲基吡咯、对-乙羟基苯甲醛按照摩尔比2～2.3:1～1.3混合溶解到二氯甲烷中，加入1～1.3当量三乙胺(M:M)，室温搅拌1h～6h，冰浴中缓慢滴加1～3当量的三氟化硼乙醚(M:M)，搅拌0.5～3h，加入1～3当量的2,3-二甲基-5,6-二氰基苯醌，二氯甲烷萃取，无水Na2SO4干燥，25℃-70℃真空除去溶剂，采用层析柱分离提纯，得到橙黄色固体产物BODIPY；
将BODIPY、4-N,N-二苯基胺苯甲醛、催化剂按照摩尔比1～1.3:2～2.3:0.1～1溶于甲苯和哌啶的混合溶液中(v/v:1/1)，置于装有Dean-Stark装置的圆底烧瓶中，120℃-150℃加热回流，直到所有溶剂都被Dean-Stark装置收集，再向反应介质中加入甲苯和哌啶，重复3-5次，TLC跟踪至原料反应完全后，柱层析，减压蒸馏除去溶剂后，得到黑色固体产物NB；
(5)将β淀粉样蛋白抑制药物(M)、DCC/DMAP按照摩尔比1:0.1～1/0.1～1溶解到氯仿中，加入1～1.3当量(M:M)含双硒键的linker，50～100℃搅拌1～6h，25℃-70℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物M-LSeSe；
(6)NB与M-LSeSe按照摩尔比1:1～1.3溶解到氯仿中，加入0.1～1当量(M:M)催化剂，60～100℃搅拌1h～24h，25℃-70℃真空旋蒸除去溶剂，采用层析柱分离提纯，反应结束后得到最终产物NB-Se-Se-M。
优选地，所述催化剂A为对甲苯磺酰胺。
优选地，所述M-LSeSe的合成步骤：DCC/DMAP为催化剂。
进一步地，所述M-LSeSe合成步骤：所述β淀粉样蛋白抑制药物(M)和linker的摩尔比为1:1～1.3。
优选地，所述M-LSeSe的合成步骤：所述linker为偶硒二己酸。
进一步地，所述NB-Se-Se-M合成步骤：催化剂为DCC/DMAP，其摩尔比1:0.1～1/0.1～1。
与现有技术相比，本发明的有益效果是：
一、双硒键是一种动态共价键，在一定条件下可以可逆地断裂或形成的共价键，基于其独特的动态过程，它们被广泛地应用于动态组合化学、响应性体系、动态共价材料等领域。本发明利用含有双硒键的配体把BODIPY与β淀粉样蛋白抑制药物侨联在一起，得到一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针；本发明首先采用甲基吡咯和醛类化合物合成NB，然后通过具有双硒键的linker侨联药物山柰酚得到NB-Se-Se-M化合物，双硒键在AD患者的脑脊液氧化还原微环境中智能断裂；BODIPY和β淀粉样蛋白抑制药物协同作用，BODIPY可以通过与β-淀粉样蛋白中二苯丙氨酸二肽纤维结合，达到AD早期诊断的作用，探针上侨联的三种小分子药物具有对AD的靶向抑制作用，达到AD诊疗目的；
二、化合物制备过程条件温和，步骤简单，有很好的潜在应用价值。
附图说明
图1是本发明得到的-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针NB-Se-Se-K的核磁氢谱图。
图2是本发明得到的-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针NB-Se-Se-R的核磁氢谱图。
图3是本发明得到的-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针NB-Se-Se-C的核磁氢谱图。
图4是本发明得到的-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针NB-Se-Se-K对阿尔兹海默症小鼠脑组织切片的荧光染色成像。
具体实施方式
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施方式，进一步阐述本发明。
以下实施例中所用的NB制备方法如下：
(1)将甲基吡咯(206mg，2.2mmol)、苯甲醛(106mg，1.0mmol)、和三乙胺(0.5ml)混合溶解到二氯甲烷中，室温搅拌过夜，0℃缓慢滴加三氟化硼乙醚(0.5ml)，搅拌10分钟，加入2,3-二甲基-5,6-二氰基苯醌(227mg，1mmol)，二氯甲烷萃取，无水Na2SO4干燥，50℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到橙黄色固体产物BODIPY。
(2)将BODIPY(1.3mmol)、4-N,N-二苯基胺苯甲醛(2.3mmol)、对甲苯磺酰胺(0.1mmol)溶于10ml甲苯和哌啶的混合溶液中(v/v:1/1)，置于装有Dean-Stark装置的圆底烧瓶中，140℃加热回流，直到所有溶剂都被Dean-Stark装置收集，再向反应介质中加入甲苯和哌啶，重复3次，TLC跟踪至原料反应完全后，柱层析，减压蒸馏除去溶剂后，得到黑色固体产物NB所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝7.76(d,J＝8.8Hz,4H),7.35(S,2H),7.24-7.26(m,10H),6.93-7.11(m,18H),6.74(s,1H),6.01(s,2H)，5.64(s,1H)，5.26(s,1H)，4.63(s,2H)，2.27(s,3H)，1.97(s,3H)。
实施例1
将山柰酚(1.0mmol)、DCC/DMAP(0.3mmol)溶解到10ml氯仿中，加入含双硒键的linker(1.3mmol)，70℃搅拌5h，30℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物K-LSeSe，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝16.47(s,1H)，11.87(s,1H)，10.18(s,1H)，9.68(s,1H)，7.48(s,2H)，6.65(s,2H)，5.94-6.02(m,2H)，2.21-2.30(m,4H)，1.54(m,4H)，2.4-2.6(m,12H)。
NB(0.5mmol)与K-LSeSe(0.5mmol)溶解到5ml氯仿中，加入DCC/DMAP(0.3mmol)，60℃搅拌5h，30℃真空旋蒸除去溶剂，采用层析柱分离提纯，反应结束后得到最终产物NB-Se-Se-K，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝16.47(s,1H)，10.18(s,1H)，9.68(s,1H)，7.76(d,J＝8.8Hz,4H)，7.48(s,2H)，7.37(s,2H)，6.79-7.24(m,28H)，6.95(s,1H)，6.65(s,2H)，6.02(s,2H)，5.94(s,2H)，5.67(s,1H)，5.20(s,2H),2.29-2.32(m,7H)，1.95(s,3H)，1.54-1.66(m,4H)，2.4-2.6(m,12H)。
实施例2
将白藜芦醇(0.5mmol)、DCC/DMAP(0.1mmol)溶解到4ml氯仿中，含双硒键的linker(0.5mmol)，80℃搅拌6h，50℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物R-LSeSe，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝11.87(s,1H)，9.07(s,2H)，7.74(s,2H)，7.33(s,2H)，6.92(m,1H)，6.82(m,1H)，6.38(s,2H)，6.12(s,1H)，2.52(m,2H)，2.21(m,2H)，1.54-1.66(m,4H)，2.4-2.6(m,12H)。
NB(0.3mmol)与R-LSeSe(0.3mmol)溶解到5ml氯仿中，加入DCC/DMAP(0.05mmol)，70℃搅拌10h，60℃真空旋蒸除去溶剂，采用层析柱分离提纯，反应结束后得到最终产物NB-Se-Se-R，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝9.07(s,2H)，7.74-7.77(m，6H)，7.23-7.37(m,14H)，6.79-7.24(m,19H)，6.82-6.95(m,2H)，6.38(m,2H)，6.12(s,1H)，6.00(s,2H)，5.67(s,1H),5.20(s,2H)，2.52(s,2H)，2.32-2.29(m,5H)，1.95(s,3H)，1.66(m,4H)，2.4-2.6(m,12H)。
实施例3
将姜黄素(0.5mmol)、DCC/DMAP(0.5mmol)溶解到5ml氯仿中，加入含双硒键的linker(0.6mmol)，60℃搅拌6h，60℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物C-LSeSe，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝11.87(s,1H)，9.55(s,1H)，7.60(s,2H)，7.23-7.30(m,2H)，7.10-7.11(m,2H)，6.91-6.99(m,3H)，6.79(s,1H)，4.59(s,2H)，3.83-3.87(m,6H)，2.52(m,2H)，2.21(m,2H)，1.54-1.66(m,4H)，2.4-2.6(m,12H)。
NB(1mmol)与C-LSeSe(1.3mmol)溶解到8ml氯仿中，加入DCC/DMAP(0.5mmol)，80℃搅拌10h，40℃真空旋蒸除去溶剂，采用层析柱分离提纯，反应结束后得到最终产物NB-Se-Se-C，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝9.56(s,1H)，7.77(d,J＝8.8Hz,4H)，7.60(s,2H)，7.00-7.37(m,14H)，6.79-7.13(m,23H)，6.79-6.95(m,2H)，6.02(s,2H)，5.67(s,1H)，5.20(s,2H),4.59(s,2H)，3.83-3.87(m,6H)，2.52(s,2H)，2.32(s,2H)，2.12(s,6H)，1.66(m,4H)，2.4-2.6(m,12H)。
实施例中所制备NB-Se-Se-K的应用：
NB-Se-Se-K对阿尔兹海默症小鼠脑组织切片检测分析：
采用成年阿尔茨海默病模型小鼠APPswe/PS1dE9脑组织进行组织学分析。石蜡包埋海马体的部分组织，切片10μm厚。硫黄素-T(ThT)是市售对β-淀粉样蛋白聚集体(Aβ纤维)特异性识别结合，以呈现绿色荧光。以硫黄素-T(ThT)作为参比，切片用50％乙醇NB-SS-K溶液(10uM)和50％乙醇ThT溶液(10uM)染色2小时，用50％乙醇洗涤20分钟，用激光共聚焦进行组织学评价，发现NB-SeSe-K荧光成像包围在ThT绿色荧光周围，形成环形近红外荧光成像。Aβ在聚集衍变过程中形成寡聚体，然后进一步缠结形成Aβ纤维，其中心是固态核，周围是正在向Aβ纤维衍变的Aβ寡聚体，这说明NB-SeSe-K、对Aβ寡聚体有特殊的响应，这对阿尔兹海默症早期诊断和抑制有潜在的应用价值。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (7)
1.一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)，其特征在于，其分子结构式为：
式中二吡咯甲川氟硼络合物通过linker与β淀粉样蛋白抑制药物(M)结合在一起，linker中间通过双硒键连接，M具体为山柰酚、姜黄素和白藜芦醇中的任一种；
其反应路线如下式所示：
2.一种如权利要求1所述的-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)制备方法，其特征在于，包括如下步骤：
(1)将甲基吡咯、对-乙羟基苯甲醛按照摩尔比2～2.3:1～1.3混合溶解到二氯甲烷中，加入1～1.3当量三乙胺(M:M)，室温搅拌1h～6h，冰浴中缓慢滴加1～3当量的三氟化硼乙醚(M:M)，搅拌0.5～3h，加入1～3当量的2,3-二甲基-5,6-二氰基苯醌，二氯甲烷萃取，无水Na2SO4干燥，25℃-70℃真空除去溶剂，采用层析柱分离提纯，得到橙黄色固体产物BODIPY；
将BODIPY、4-N,N-二苯基胺苯甲醛、催化剂按照摩尔比1～1.3:2～2.3:0.1～1溶于甲苯和哌啶的混合溶液中(v/v:1/1)，置于装有Dean-Stark装置的圆底烧瓶中，120℃-150℃加热回流，直到所有溶剂都被Dean-Stark装置收集，再向反应介质中加入甲苯和哌啶，重复3-5次，TLC跟踪至原料反应完全后，柱层析，减压蒸馏除去溶剂后，得到黑色固体产物NB；
(2)将β淀粉样蛋白抑制药物(M)、DCC/DMAP按照摩尔比1:0.1～1/0.1～1溶解到氯仿中，加入1～1.3当量(M:M)含双硒键的linker，50～100℃搅拌1～6h，25℃-70℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物M-LSeSe；
(3)NB与M-LSeSe按照摩尔比1:1～1.3溶解到氯仿中，加入0.1～1当量(M:M)催化剂，60～100℃搅拌1h～24h，25℃-70℃真空旋蒸除去溶剂，采用层析柱分离提纯，反应结束后得到最终产物NB-Se-Se-M。
3.权利要求2所述的一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)的制备方法，其特征在于：所述催化剂A为对甲苯磺酰胺。
4.权利要求2所述的一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)的制备方法，其特征在于：所述M-LSeSe的合成步骤：DCC/DMAP为催化剂。
5.权利要求2所述的一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)的制备方法，其特征在于：所述M-LSeSe合成步骤：所述β淀粉样蛋白抑制药物(M)和linker的摩尔比为1:1～1.3。
6.权利要求2所述的一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)的制备方法，其特征在于：所述M-LSeSe的合成步骤：所述linker为偶硒二己酸。
7.权利要求2所述的一种-Se-Se-双硒键侨联β淀粉样蛋白抑制药物的荧光探针(NB-Se-Se-M)的制备方法，其特征在于：所述NB-Se-Se-M合成步骤：催化剂为DCC/DMAP，其摩尔比1:0.1～1/0.1～1。
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