CN113620980A - 一种-N=N-双氮键侨联Aβ抑制剂的荧光探针及其制备方法 - Google Patents
一种-N=N-双氮键侨联Aβ抑制剂的荧光探针及其制备方法 Download PDFInfo
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- CN113620980A CN113620980A CN202110800231.0A CN202110800231A CN113620980A CN 113620980 A CN113620980 A CN 113620980A CN 202110800231 A CN202110800231 A CN 202110800231A CN 113620980 A CN113620980 A CN 113620980A
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Abstract
本发明提供一种‑N＝N‑双氮键侨联Aβ抑制剂的荧光探针及其制备方法，Aβ抑制剂(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当量含有双氮键的(M:M)Linker，50～100℃搅拌1～6h，真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物M‑LN＝N；NB与M‑LN＝N按照摩尔比1:1～3溶解到氯仿中，加入0.1～1当量(M:M)催化剂B，60℃～70℃搅拌1h～12h，25℃～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‑N＝N‑M。‑N＝N‑双氮键作为反应活性位点，引入后可在原有体系单一功能的基础上使得多功能有机结合。本项目中通过‑N＝N‑双氮键连接BODIPY与Aβ抑制剂得到一种‑N＝N‑双氮键侨联Aβ抑制剂的荧光探针，使得BODIPY与Aβ抑制剂协同发挥实时监测与抑制β‑淀粉样蛋白的功能，从而达到阿尔兹默症早期诊断与治疗的目的。
Description
技术领域
本发明属于有机合成技术领域，特别涉及一种-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)及其制备方法。
背景技术
阿尔茨海默病(AD)是一种认知功能逐渐退化的致死性神经退行性疾病。2020年9月21日是世界第七个阿尔兹海默症日，根据美国的报告，因患有阿尔兹海默症而死亡的人口大大增加，从2010年开始，阿尔兹海默症已经成为美国的第六大死亡原因，有三分之一的老年人死于阿尔兹海默症或其他痴呆症。依据目前医疗水平，阿尔兹海默病没有良好的治疗方案，其药物研发的进展可谓困难重重，且阿尔兹海默症的早期确诊也是一项不小的挑战。世界上阿尔兹海默症的病例逐年累增，AD的早期准确诊断和疾病监测的缺乏进一步阻碍了治疗性药物的发展。因此，及时准确的诊断前驱期AD是预防和治疗AD的关键。
伴随AD发病机制的研究，β–淀粉样蛋白(Aβ)及其聚集状态的作用成为研究热点。到目前为止，已经开发了多种检测Aβ的荧光探针，如ZT-1，NIAD-11，5a1，CRANAD-2，CQ等。近红外荧光探针其荧光发射波长位于近红外区，在生物组织中穿透力强，灵敏度高、干扰小、安全可靠。但现有技术中的AD检测荧光探针存在荧光发射性能差，灵敏度低、选择性弱、生物相容性差的问题，极大地限制了其应用范围，且只能起到监测作用却不能进行有效干预。因此，研究开发制备荧光发射性能好，灵敏度高、选择性强、生物相容性好、能实现早期阿尔兹海默症诊断治疗的荧光探针是近期的研究热点。
发明内容
本发明的主要目的在于提供一种对β-淀粉样蛋白起到靶向抑制作用、高精度、高选择性的阿尔兹海默症早期诊断治疗荧光探针，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-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)，其分子结构式为：
式中二吡咯甲川氟硼络合物的8位有一个与Aβ抑制剂(M)侨联的苯基取代基、1,7-位有两个烷基，3,5-位有两个三苯胺，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：
一种如权利要求1所述的-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)的制备方法，包括如下步骤：
(1)将甲基吡咯、对-乙羟基苯甲醛按照摩尔比2～3:1～1.5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，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A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)Aβ抑制剂(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当量含有双氮键的(M:M)Linker，50～100℃搅拌1～6h，25℃～60℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物M-LN＝N；
(3)NB与M-LN＝N按照摩尔比1:1～3溶解到氯仿中，加入0.1～1当量(M:M)催化剂B，60℃～70℃搅拌1h～12h，25℃～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-N＝N-M。
优选地，所述催化剂A为对甲苯磺酰胺。
优选地，所述M-LN＝N的合成步骤：DCC/DMAP为催化剂。
进一步地，所述M-LN＝N的合成步骤：所述Aβ抑制剂(M)和linker的摩尔比为1:1～1.3。
优选地，所述M-LN＝N的合成步骤：所述Linker为偶氮苯-4,4-二羧酸。
进一步地，所述NB-N＝N-M的合成步骤：所述催化剂B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、本发明设计的近红外荧光探针BODIPY与Aβ上的二苯丙氨酸二肽(FF)具有很好的特异性结合，再与含有-N＝N-双氮键的连桥侨联Aβ抑制剂得到能够对AD早期诊疗一体化；
二、FF作为Aβ识别最小单位和核心，在阿尔兹海默症早期的Aβ聚集过程中起到关键作用，当Aβ聚集形成寡聚体时，FF肩并肩形成一个通道，为探针与FF的有效结合创造了良好的机会，当Aβ发生聚集的作用点FF被探针占据时β-淀粉样蛋白聚集就会被抑制；
三、-N＝N-双氮键作为反应活性位点，引入后可在原有体系单一功能的基础上使得多功能有机结合；-N＝N-双氮键作为反应活性位点，使得BODIPY与Aβ抑制剂协同发挥实时监测与抑制β-淀粉样蛋白的功能，从而达到阿尔兹默症早期诊断与治疗的目的。
附图说明
图1是本发明得到的BODIPY类荧光探针NB-N＝N-K(kaempferol)的核磁氢谱图。
图2是本发明得到的BODIPY类荧光探针NB-N＝N-C(curcumin)的核磁氢谱图。
图3是本发明得到的BODIPY类荧光探针NB-N＝N-R(resveratrol)的核磁氢谱图。
图4是本发明得到的BODIPY类荧光探针NB-N＝N-K(resveratrol)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1，例2与例3所用的NB制备方法，如下：
将甲基吡咯(2.2mmol)、对-乙羟基苯甲醛(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，60℃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；
将BODIPY(1mmol)、4-N,N-二苯基胺苯甲醛(2.2mmol)、甲苯磺酰胺(0.5mmol)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，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4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。
实施例1
将Aβ抑制剂山柰酚(0.3mmol)、DCC(0.02mmol)、DMAP(0.02mmol)溶解到氯仿中，加入偶氮苯-4,4-二羧酸(0.3mmol)，70℃搅拌3h，25℃真空旋蒸除去溶剂，粗产品采用层析柱提纯，得到产物K-LN＝N，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝12.71(s,1H),9.55(s,1H),8.38-8.39(m,4H),8.06-8.12(m,4H),7.77(d,J＝8.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.30-7.37(m,2H),6.91-7.18(m,5H),6.24(d,J＝8.8Hz,1H),4.59(s,2H),3.83-3.87(m,6H)。
将K-LN＝N(0.5mmol)、DCC(0.01mmol)、DMAP(0.01mmol)溶解到氯仿中，加入NB(0.5mmol)，70℃搅拌3h，30℃真空旋蒸除去溶剂，层析柱提纯，得到黑色固体产物NB-N＝N-K，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝9.55(s,1H),8.39(d,J＝4.4Hz,2H),8.22(d,J＝4.4Hz,2H),8.02-8.06(m,4H),7.77(m,5H),7.60(d,J＝4.4Hz,1H),6.99-7.37(m,36H),6.95(d,J＝4.4Hz,1H),6.24(d,J＝4.4Hz,2H),6.00-6.02(m,2H),5.67(d,J＝4.4Hz,1H),5.22(s,2H),4.59(s,2H),3.83-3.87(m,6H),2.12(s,6H)。
实施例2
将Aβ抑制剂姜黄素(0.1mmol)、DCC(0.01mmol)、DMAP(0.01mmol)溶解到氯仿中，加入偶氮苯-4,4-二羧酸(0.1mmol)，80℃搅拌2h，50℃真空旋蒸除去溶剂，层析柱提纯，得到产物C-LN＝N，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝12.71(s,1H),9.55(s,1H),8.38-8.39(m,4H),8.06-8.12(m,4H),7.77(d,J＝8.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.30-7.37(m,2H),6.91-7.18(m,5H),6.24(d,J＝8.8Hz,1H),4.59(s,2H),3.83-3.87(m,6H)。
将C-LN＝N(0.2mmol)、DCC(0.01mmol)、DMAP(0.01mmol)溶解到氯仿中，加入NB(0.2mmol)，60℃搅拌5h，30℃真空旋蒸除去溶剂，层析柱提纯，得到黑色固体产物NB-N＝N-C，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝9.55(s,1H),8.39(d,J＝4.4Hz,2H),8.22(d,J＝4.4Hz,2H),8.02-8.06(m,4H),7.77(m,5H),7.60(d,J＝4.4Hz,1H),6.99-7.37(m,36H),6.95(d,J＝4.4Hz,1H),6.24(d,J＝4.4Hz,2H),6.00-6.02(m,2H),5.67(d,J＝4.4Hz,1H),5.22(s,2H),4.59(s,2H),3.83-3.87(m,6H),2.12(s,6H)。
实施例3
将Aβ抑制剂白藜芦醇(0.3mmol)、DCC(0.03mmol)、DMAP(0.03mmol)溶解到氯仿中，加入偶氮苯-4,4-二羧酸(0.3mmol)，70℃搅拌6h，50℃真空旋蒸除去溶剂，层析柱分离提纯，得到产物R-LN＝N，所述化合物通过核磁1H NMR谱图进行表征，1H NMR(300MHz,DMSO-D6):δ＝12.71(s,1H),9.07(s,2H),8.38-8.39(m,4H),8.06-8.12(m,4H),7.81(d,J＝4.4Hz,2H),7.41(d,J＝4.4Hz,2H),6.56(s,2H),6.38(s,2H),6.12(s,1H)。
将R-LN＝N(1mmol)、DCC(0.03mmol)、DMAP(0.03mmol)溶解到氯仿中，加入NB(1mmol)，80℃搅拌10h，40℃真空旋蒸除去溶剂，层析柱提纯，得到黑色固体产物NB-N＝N-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),8.39(d,J＝4.4Hz,2H),8.22(d,J＝4.4Hz,2H),8.02-8.06(m,4H),7.77-7.81(m,6H),6.99-7.41(m,32H),6.95(d,J＝4.4Hz,1H),6.56(s,2H),6.38(s,2H),6.12(s,1H),6.00-6.02(d,J＝4.4Hz,2H),5.67(d,J＝4.4Hz,1H),5.22(s,2H),2.29(s,3H),1.95(s,3H)。
实施例中所制备NB-N＝N-K的应用：
对阿尔兹海默症小鼠脑组织切片的荧光染色成像：
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。切片用50％乙醇NB-N＝N-K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-N＝N-K荧光成像形成环形近红外荧光成像。说明NB-N＝N-K对β-淀粉样蛋白早期聚集体有特殊的响应，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-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-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的8位有一个与Aβ抑制剂(M)侨联的苯基取代基、1,7-位有两个烷基，3,5-位有两个三苯胺，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.权利要求1所述的一种-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)的制备方法，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2～3:1～1.5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℃～60℃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A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)Aβ抑制剂(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当量含有双氮键的(M:M)Linker，50～100℃搅拌1～6h，25℃～60℃真空旋蒸除去溶剂，采用层析柱分离提纯，得到固体产物M-LN＝N；
(3)NB与M-LN＝N按照摩尔比1:1～3溶解到氯仿中，加入0.1～1当量(M:M)催化剂B，60℃～70℃搅拌1h～12h，25℃～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-N＝N-M。
3.权利要求2所述的一种-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-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-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)的制备方法，其特征在于：所述M-LN＝N的合成步骤：DCC/DMAP为催化剂。
5.权利要求2所述的一种-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)的制备方法，其特征在于：所述M-LN＝N的合成步骤：所述Aβ抑制剂(M)和linker的摩尔比为1:1～1.3。
6.权利要求2所述的一种-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)的制备方法，其特征在于：所述M-LN＝N的合成步骤：所述Linker为偶氮苯-4,4-二羧酸。
7.权利要求2所述的一种-N＝N-双氮键侨联Aβ抑制剂的荧光探针(NB-N＝N-M)的制备方法，其特征在于：所述NB-N＝N-M的合成步骤：所述催化剂B为DCC/DMAP，其摩尔比1:0.1～1/0.1～1。
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