CN112047977A - 一种线粒体靶向荧光探针及其合成方法和应用 - Google Patents
一种线粒体靶向荧光探针及其合成方法和应用 Download PDFInfo
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Abstract
本发明涉及了一种线粒体靶向荧光探针及其合成方法和应用。该线粒体靶向荧光探针(TPP‑TPEDCH)以荧光分子TPEDCH为母体，以三苯基膦衍生物TPP为线粒体靶向基团，通过化学反应合成。该线粒体靶向荧光探针可在水性介质中通过聚集诱导效应自发稳定的荧光。本发明还涉及合成该线粒体靶向荧光探针的方法，以及其细胞线粒体动态监测作用。
Description
技术领域
本发明涉及药物化学技术领域，尤其涉及一种线粒体靶向荧光探针及其合成方法和应用。
技术背景
随着生物科学与技术的不断发展，人们逐渐从细胞层面过渡到亚细胞层面认识和研究生命活动的本质。线粒体作为细胞内关键的细胞器，负责细胞大部分能量的产生；另外，它们在程序性细胞死亡(如凋亡)中也起着关键作用。大量研究表明，线粒体的数量、分布、结构与功能变化等与神经退行性病变、代谢型疾病、心血管疾病及癌症等病症关系密切。线粒体被冠以“细胞信号传导细胞器”和“细胞死亡之马达”等称号，与之相关的“线粒体学”已经成为生命科学和医学等领域的研究热点。
线粒体内活性小分子作为信号载体参与线粒体内的生物化学反应，它们的浓度和时空分布能够影响细胞乃至生物体的多种生理过程。因此，开展线粒体内活性小分子的相关研究对深入揭示生物体生命活动规律起着至关重要的作用，愈来愈受到研究者们的青睐。
最近数十年来，荧光成像技术在科学研究、生物检测、环境分析和临床检测等领域中的应用越来越广泛。在生物体内，各种小分子对生物功能的正常发挥起着极其重要的作用，因此准确检测这些小分子在生物细胞内的含量在科学研究和临床应用上都具有重要意义。然而，荧光分子大多含有四吡咯环、萘或二苯甲酮等共轭结构，由于其强烈的π-π叠加效应，光敏分子很容易聚集导致淬灭荧光(Aggregation Caused Quenching,ACQ)，影响光敏化效率。因此，设计一种能够克服ACQ的新型光敏分子将成为光敏剂发展的新方向。
近年来，聚集诱导发光(Aggregation-Induced Emission,AIE)类化合物以其特有的优势，如良好的生物相容性、独特的荧光性能(在溶液中几乎不发光，而在聚集状态发光大大增强)、抗光漂白等，在疾病诊断和治疗领域扮演着越来越重要的角色。与传统小分子相反，AIE分子在聚集状态下由于分子内运动受阻，受到光激发后，能量损失较低，从而表现出荧光增强的现象。鉴于AIE分子的特殊性质，可以将其应用于光敏剂，克服上述传统光敏分子带来的ACQ效应，同时AIE分子自身也可以作为细胞内的显影剂，示踪细胞及胞内细胞器。
发明内容
基于上述背景，本发明要解决的技术问题是提供一种线粒体靶向荧光探针的合成方法。
本发明具体采用的技术方案如下：
第一方面，本发明提供了一种线粒体靶向荧光探针，其结构式为：
作为优选，以荧光分子TPEDCH为母体，通过化学合成反应连接作为线粒体靶向基团的三苯基膦衍生物TPP，得到所述线粒体靶向荧光探针TPP-TPEDCH。
第二方面，本发明提供了一种上述线粒体靶向荧光探针的合成方法，其包括如下步骤：
S1：以锌粉和四氯化钛作为偶联试剂，四氢呋喃为反应溶剂,由4,4'-二甲氧基二苯甲酮和4-溴苯甲酰苯经过麦克默里偶联(McMurry Coupling)反应，制得中间物1；
S2：以正丁基锂为溴-锂交换试剂，将中间物1活化后与硼酸三甲酯反应，最后用盐酸水解制得中间物2；
S3：采用Suzuki偶联方法，以四(三苯基膦)钯为催化剂，碳酸钾为碱，中间物2和中间物3为反应物，四氢呋喃和水为溶剂，制得中间物4；
S4：通过克脑文盖尔缩合(Knoevenagel Condensation)反应，将中间物4与丙二腈在四氯化钛作用下生成化合物5；
S5：将中间物5和三溴化硼置于冰浴中，将甲氧基水解得到含有两个羟基的中间物6；
S6：将4-羧丁基三苯基溴化膦先酰氯化，然后与中间物6混合，在含有碱的溶剂中，通过亲核取代反应制得线粒体靶向荧光探针TPP-TPEDCH；
其中中间物1、中间物2、中间物3、中间物4、中间物5和中间物6的结构式分别为：
作为优选，在步骤S2中，正丁基锂的浓度为2.5M，活化后的中间物1与硼酸三甲酯按摩尔比1：2反应，水解所用的盐酸浓度为3M。
作为优选，在步骤S3中，中间物2和中间物3的摩尔比为1：：2，四氢呋喃和水的体积比为3：1。
作为优选，在步骤S4中，中间物4与丙二腈的摩尔比为1：3。
作为优选，在步骤S5中，中间物5和三溴化硼的摩尔比为1：：3。
作为优选，在步骤S6中，酰氯化的4-羧丁基三苯基溴化膦与中间物6的摩尔比为5：1，酰氯化试剂为二氯亚砜，通过亲核取代反应制备线粒体靶向荧光探针TPP-TPEDCH时，所用的碱为三乙胺或N,N-二异丙基乙胺，溶剂为二氯甲烷。
第三方面，本发明提供了一种上述任一方案所述方法制备得到的线粒体靶向荧光探针。
第四方面，本发明提供了一种上述任一方案所述线粒体靶向荧光探针在监测和跟踪活细胞中线粒体动态运动中的用途。
本发明提供的线粒体靶向荧光探针，可在水性介质中通过聚集诱导效应自发稳定的荧光。本发明还涉及合成该线粒体靶向荧光探针的方法，以及其细胞线粒体动态监测作用。其他具体的技术效果将通过后续实施例进行展示。
附图说明
图1为实施例中TPP-TPEDCH的核磁氢谱图(500MHz,Chloroform-d)；
图2为实施例中TPP-TPEDCH的核磁碳谱(126MHz,Chloroform-d)；
图3为实施例中TPP-TPEDCH的核磁磷谱(162MHz,Chloroform-d)；
图4为实施例中TPP-TPEDCH的高分辨质谱(ESI-HRMS)；
图5为TPP-TPEDCH在不同浓度的二甲基亚砜/水溶液中的荧光发射光谱图(A)和不同浓度TPP-TPEDCH的荧光发射光谱图(B)；
图6为TPP-TPEDCH与溶酶体、线粒体和内质网共定位图片；
图7为TPP-TPEDCH标记的线粒体空间动态分布。
具体实施方式
下面结合附图和具体实施方式对本发明做进一步阐述和说明。
本发明设计了一种线粒体靶向荧光探针TPP-TPEDCH，结构如式(I)所示
上述线粒体靶向荧光探针包含荧光分子TPEDCH和线粒体靶向基团溴化三苯基膦衍生物TPP，二者通过化学反应合成。该化合物在纯有机溶剂中几乎没有荧光，而在水溶液由于产生强烈荧光,可利用荧光成像监测癌细胞中线粒体的活动。
下面通过实施例说明该线粒体靶向荧光探针TPP-TPEDCH的制备过程和技术效果。
实施例
本实施例中，上述线粒体靶向荧光探针的合成路径如下：
其中：上述结构式下部的粗体数字代表中间物的序号，后续为了便于叙述直接以该序号代替结构式。
本实施例的TPP-TPEDCH的合成方法具体包括如下步骤：
1.向100mL干燥的圆底烧瓶中加入4,4'-二甲氧基二苯甲酮(1.96g,8.1mmol)、4-溴苯甲酰苯(2.74g,10.5mmol)和锌粉(3.05g,47mmol)，在氩气保护下加入40mL干燥的四氢呋喃。混合液冷却至-78℃，在搅拌下滴加2.5mL四氯化钛，滴加完毕后将体系逐渐升至室温，并加热回流16小时。反应结束后，冷却至室温，在冰浴下缓慢滴加50mL饱和碳酸氢钠水溶液，反应液用乙酸乙酯萃取，合并有机相，水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩得黄色粗产品，柱层析分离得到淡黄色固体，即中间物1，收率37％，采用核磁氢谱、碳谱和高分辨质谱进行结构表征。1H NMR(500MHz,Chloroform-d)δ7.24–7.18(m,2H),7.13–7.07(m,3H),7.04–6.97(m,2H),6.91(dddd,J＝18.2,10.0,5.7,1.8Hz,6H),6.64(ddd,J＝18.0,8.7,1..7Hz,4H),3.76(s,3H),3.73(s,3H).13C NMR(126MHz,Chloroform-d)δ158.27,158.18,143.78,143.30,140.77,137.90,136.01,135.92,133.04,132.55,132.51,131.33,130.84,127.80,126.29,120.01,113.20,113.02,77.22,55.11,55.08.HR-MS(ESI):m/z C28H23O2Br,calcd for[M+H]+471.0954,found 471.0953.
2.将中间物1(0.94g,2.0mmol)溶解于20mL干燥的四氢呋喃中，置于-78℃的冷阱中并不断搅拌，然后在氩气保护下滴加正丁基锂(2.5M in hexane,1.30mL,3.2mmol)。反应3小时后向其中滴加硼酸三甲酯(0.45mL,4.0mmol)，滴加完毕后，体系缓慢升至室温。5小时后反应液用盐酸(3M,10mL)淬灭，室温下继续搅拌8小时，体系用乙酸乙酯(50mL)和食盐水(100mL)分液。分离有机相，水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩得淡黄色粗产品，柱层析分离得到白色固体，即中间物2，收率45％，采用核磁氢谱、碳谱和高分辨质谱进行结构表征。1H NMR(500MHz,Chloroform-d)δ7.89(d,J＝7.8Hz,1H),7.21–7.05(m,6H),7.04–6.99(m,2H),6.98–6.90(m,4H),6.64(t,J＝7.5Hz,4H),3.74(s,3H),3.73(s,3H).13C NMR(126MHz,Chloroform-d)δ158.18,144.01,136.15,136.09,134.98,132.87,132.62,132.58,131.39,131.37,131.06,130.97,127.75,126.19,113.09,113.01,77.22,55.10,55.08.
3.向干燥的三颈烧瓶中加入4-溴苯甲酰氯(1.32g,6mmol)和无水三氯化铝(1.04g,7.8mmol)，氩气保护下加入10mL干燥的二氯甲烷。冰浴下滴加噻吩(0.50g,6mmol)的干燥二氯甲烷溶液，升温至室温，继续搅拌3小时。反应结束后，向体系中加入碎冰块淬灭反应，反应液用37％浓盐酸酸化，二氯甲烷萃取，有机相水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩、柱层析分离得到黄色固体，即中间物3，收率93％，采用核磁氢谱、碳谱和高分辨质谱进行结构表征。1H NMR(500MHz,Chloroform-d)δ7.78–7.69(m,3H),7.68–7.58(m,3H),7.18(dd,J＝5.0,3.8Hz,1H).13C NMR(126MHz,Chloroform-d)δ187.06,143.18,136.86,134.79,134.58,131.75,130.71,128.07,127.27.
4.向干燥的单口烧瓶中加入上述中间物2(160mg,0.37mmol)和中间物3(197mg,0.74mmol)，溶解在四氢呋喃和水的混合溶液中(v/v＝3/1,8mL)，然后加入碳酸钾(511mg,3.7mmol)和四(三苯基膦)钯(21mg,0.0185mmol)。反应回流24小时后冷却至室温，加入乙酸乙酯和水分液。分离有机相，水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩、柱层析分离得到黄色固体，即中间物4，收率61％，采用核磁氢谱、碳谱和高分辨质谱进行结构表征。1H NMR(500MHz,Chloroform-d)δ7.95–7.89(m,2H),7.72(dd,J＝4.9,1.1Hz,1H),7.71–7.66(m,3H),7.45–7.38(m,2H),7.17(dd,J＝5.0,3.8Hz,1H),7.16–7.09(m,5H),7.07(dd,J＝8.0,1.7Hz,2H),7.01–6.93(m,4H),6.72–6.61(m,4H),3.75(s,3H),3.74(s,3H).13C NMR(126MHz,Chloroform-d)δ158.24,158.15,144.68,144.49,140.72,138.52,137.10,136.54,136.23,134.58,134.04,132.63,132.61,132.02,131.45,129.82,127.94,127.79,126.73,126.41,126.24,113.15,113.02,55.12,55.10.HR-MS(ESI):m/z C39H30O3S,[M+H]+calcd 579.1988,found 579.1981；[M+Na]+calcd 601.1808,found 601.1806.
5.向干燥的两口烧瓶中加入上述中间物4(130mg,0.22mmol)和丙二腈(44mg,0.66mmol)的5mL干燥二氯甲烷溶液,氩气保护冰浴下滴加四氯化钛(85μL,0.77mmol)，搅拌30分钟后加入吡啶(62μL,0.77mmol)继续反应30分钟。然后加热至40℃，回流5小时，反应完体系冷却至室温，加入10mL水淬灭反应，反应液由黑色变成棕色。分液，二氯甲烷萃取，合并有机相，然后用水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩、柱层析分离得到橙色固体，即中间物5，收率87％，采用核磁氢谱、碳谱和高分辨质谱进行结构表征。1H NMR(500MHz,Chloroform-d)δ7.81(dd,J＝10.6,4.5Hz,2H),7.70(d,J＝8.1Hz,2H),7.51(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),7.23(d,J＝4.6Hz,1H),7.16–7.09(m,5H),7.08–7.04(m,2H),6.97(dd,J＝15.5,8.4Hz,4H),6.65(t,J＝9.3Hz,4H),3.75(s,3H),3.74(s,3H).13CNMR(126MHz,Chloroform-d)δ158.27,144.79,144.07,140.85,138.69,138.44,136.60,136.40,136.18,136.00,132.64,132.61,132.09,131.44,130.31,128.95,127.81,126.94,126.38,126.27,113.16,113.03,55.13,55.10.
6.向干燥的两口烧瓶中加入上述中间物5(115mg,0.18mmol)的6mL干燥二氯甲烷溶液,冰浴下滴加三溴化硼的的干燥二氯甲烷溶液(1.0M,0.54mmol)，体系升温至室温搅拌5小时。然后冰浴下加入10mL水淬灭反应，反应液用二氯甲烷萃取，合并有机相，水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩的橙红色固体，即中间物6，收率87％，产物未经进一步纯化直接用于下一步反应。1H NMR(500MHz,Chloroform-d)δ7.85–7.77(m,2H),7.69(d,J＝8.2Hz,2H),7.50(d,J＝8.0Hz,2H),7.41(d,J＝8.2Hz,2H),7.24(t,J＝4.5Hz,1H),7.12(dt,J＝7.5,3.5Hz,5H),7.07–7.03(m,2H),6.92(dd,J＝14.6,8.6Hz,4H),6.58(dd,J＝9.8,8.5Hz,4H).13C NMR(126MHz,Chloroform-d)δ154.31,154.21,144.68,144.48,143.97,140.71,138.67,138.57,136.45,136.28,136.07,132.82,132.79,132.07,131.41,130.32,128.97,127.81,126.95,126.40,126.32,114.74,114.60.HR-MS(ESI):m/zC40H26N2O2S,M calcd 598.1715,found 598.1711.
7.向干燥的单口烧瓶中加入4-羧丁基三苯基溴化膦(222mg,0.5mmol)的10mL干燥二氯甲烷溶液,氩气保护下滴加0.5mL二氯亚砜,反应回流3小时，冷却至室温，旋干溶剂。将上述化合物溶于5mL干燥二氯甲烷中，冰浴下滴加含中间物6(60mg,0.1mmol)和三乙胺(0.5mL)的干燥二氯甲烷溶液。滴加完毕后升至室温，反应8小时，旋干溶剂，然后加入二氯甲烷和水分液，有机相用水洗、饱和食盐水洗、无水硫酸钠干燥、过滤、减压浓缩、柱层析分离得到橙色固体TPP-TPEDCH(结构式如式1)，收率46％，采用核磁氢谱、碳谱、磷谱和高分辨质谱进行结构表征(结果分别如图1、图2、图3、图4所示)。1H NMR(500MHz,Chloroform-d)δ7.90–7.81(m,14H),7.74–7.68(m,21H),7.56–7.43(m,5H),7.29–7.27(d,J＝4.4Hz,1H),7.20–7.12(m,4H),7.11–6.95(m,6H),6.82–6.61(m,4H),2.70–2.64(m,4H),2.26(t,J＝7.6Hz,4H),1.82–1.76(m,4H),1.41–1.15(m,4H).13C NMR(126MHz,Chloroform-d)δ171.60,136.32,135.17,135.03,135.02,133.72,133.71,133.64,133.53,133.48,133.40,132.26,132.06,132.01,132.00,131.33,130.64,130.57,130.55,130.47,130.45,130.32,128.58,128.48,127.03,117.95,77.26,58.37,21.85,18.43.31P NMR(162MHz,Chloroform-d)δ24.33.HR-MS(ESI):[C86H70N2O4SP2]2+[Br2]2-,z＝2,m/z calcd 644.2260,found 644.2251.
将上述制得的TPP-TPEDCH溶于不同比例的二甲基亚砜/水混合溶液，随着混合溶液中水的比例不断增加，TPP-TPEDCH产生AIE效应，荧光强度也随之增强(图5A)，且荧光呈浓度依赖性(图5B)。
以人乳腺癌(MCF-7)细胞为模型细胞，通过市售溶酶体、线粒体与内质网探针标记细胞器，考察TPP-TPEDCH的靶向分布特性。结果如图6所示，TPP-TPEDCH的荧光信号与市售线粒体的荧光探针信号高度重合，采用ImageJ软件进行共定位分析，得到两者的共定位相关系数值为0.91；而TPP-TPEDCH与溶酶体和内质网的共定位相关系数值为0.33和0.42，表明面TPP-TPEDCH具有较好的线粒体靶向性能。
以人乳腺癌(MCF-7)细胞为模型细胞，采用TPP-TPEDCH标记MCF-7细胞以考察胞内线粒体的空间动态分布。结果如图7所示，通过TPP-TPEDCH标记线粒体，可见该细胞器在活细胞内动态运动分布。
以上所述的实施例只是本发明的一种较佳的方案，然其并非用以限制本发明。有关技术领域的普通技术人员，在不脱离本发明的精神和范围的情况下，还可以做出各种变化和变型。因此凡采取等同替换或等效变换的方式所获得的技术方案，均落在本发明的保护范围内。
Claims (10)
1.一种线粒体靶向荧光探针，其特征在于，结构式为：
2.如权利要求1所述的线粒体靶向荧光探针，其特征在于，以荧光分子TPEDCH为母体，通过化学合成反应连接作为线粒体靶向基团的三苯基膦衍生物TPP，得到所述线粒体靶向荧光探针TPP-TPEDCH。
3.一种如权利要求1所述线粒体靶向荧光探针的合成方法，其特征在于，包括如下步骤：
S1：以锌粉和四氯化钛作为偶联试剂，四氢呋喃为反应溶剂,由4,4'-二甲氧基二苯甲酮和4-溴苯甲酰苯经过麦克默里偶联(McMurry Coupling)反应，制得中间物1；
S2：以正丁基锂为溴-锂交换试剂，将中间物1活化后与硼酸三甲酯反应，最后用盐酸水解制得中间物2；
S3：采用Suzuki偶联方法，以四(三苯基膦)钯为催化剂，碳酸钾为碱，中间物2和中间物3为反应物，四氢呋喃和水为溶剂，制得中间物4；
S4：通过克脑文盖尔缩合(Knoevenagel Condensation)反应，将中间物4与丙二腈在四氯化钛作用下生成化合物5；
S5：将中间物5和三溴化硼置于冰浴中，将甲氧基水解得到含有两个羟基的中间物6；
S6：将4-羧丁基三苯基溴化膦先酰氯化，然后与中间物6混合，在含有碱的溶剂中，通过亲核取代反应制得线粒体靶向荧光探针TPP-TPEDCH；
其中中间物1、中间物2、中间物3、中间物4、中间物5和中间物6的结构式分别为：
4.如权利要求3所述的方法，其特征在于，在步骤S2中，正丁基锂的浓度为2.5M，活化后的中间物1与硼酸三甲酯按摩尔比1：2反应，水解所用的盐酸浓度为3M。
5.如权利要求3所述的方法，其特征在于，在步骤S3中，中间物2和中间物3的摩尔比为1：2，四氢呋喃和水的体积比为3：1。
6.如权利要求3所述的方法，其特征在于，在步骤S4中，中间物4与丙二腈的摩尔比为1：3。
7.如权利要求3所述的方法，其特征在于，在步骤S5中，中间物5和三溴化硼的摩尔比为1：3。
8.如权利要求3所述的方法，其特征在于，在步骤S6中，酰氯化的4-羧丁基三苯基溴化膦与中间物6的摩尔比为5：1，酰氯化试剂为二氯亚砜，通过亲核取代反应制备线粒体靶向荧光探针TPP-TPEDCH时，所用的碱为三乙胺或N,N-二异丙基乙胺，溶剂为二氯甲烷。
9.一种如权利要求3～8任一所述方法制备得到的线粒体靶向荧光探针。
10.一种如权利要求1或9所述线粒体靶向荧光探针在监测和跟踪活细胞中线粒体动态运动中的用途。
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