CN107033621A - 一种具有大Stokes位移近红外BODIPY染料及其制备和应用 - Google Patents

一种具有大Stokes位移近红外BODIPY染料及其制备和应用 Download PDF

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CN107033621A
CN107033621A CN201710332460.8A CN201710332460A CN107033621A CN 107033621 A CN107033621 A CN 107033621A CN 201710332460 A CN201710332460 A CN 201710332460A CN 107033621 A CN107033621 A CN 107033621A
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赵春常
费强
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East China University of Science and Technology
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Abstract

本发明公开了一种具有大Stokes位移近红外BODIPY染料NIR‑BOD及其合成与应用。本发明所述的染料NIR‑BOD是由醛基BODIPY通过合环反应制得的。本发明是利用分子内质子转移(ESIPT)机制，通过分子内羟基上的质子，与相邻杂环上的氮原子之间的氢键作用，使其产生具有大Stokes位移(>200nm)的近红外荧光发射。

Description

一种具有大Stokes位移近红外BODIPY染料及其制备和应用
技术领域
本发明属于精细化工领域，涉及可用于构建大Stokes位移近红外BODIPY染料，具体涉及一种具有大Stokes位移近红外BODIPY染料NIR-BOD及其合成与应用。
背景技术
氟化硼络合二吡咯甲川类(Boron-dipyrromethene，简称BODIPY)荧光染料是一类具有优异性能的新型荧光分子染料，在具有较高摩尔消光系数和荧光量子产率的同时，也具有较为稳定的光谱性质。此外，这类染料对溶剂极性和pH值均表现出较好的耐受性。染料分子一般具有一定的共轭平面，在特定条件下可以经得失电子调控其荧光发射，能够通过适当修饰，使该类染料可应用于荧光标记、生物检测等方面。具有近红外荧光发射的染料，能够大大减小对生物体的光损伤，也减少了背景荧光的干扰以及对深层组织的渗透，例如菁染料等。但这些染料都伴随有Stokes位移小的限制，容易导致严重的荧光自淬灭和检测灵敏度降低等负效应。增大染料Stokes位移常用的方法包括，共振能量转移(FRET)，构建扭曲内部电荷转移(TICT)，以及发展分子内质子转移(ESIPT)的发色团等。目前，对于此类染料的合成难度较大，很大程度上限制了其应用。
发明内容
为解决上述问题，本发明第一个目的是提供一种具有大Stokes位移近红外BODIPY染料NIR-BOD。
本发明第二个目的是提供一种具有大Stokes位移近红外BODIPY染料NIR-BOD的制备方法。
本发明第三个目的是提供一种具有大Stokes位移近红外BODIPY染料NIR-BOD的分子荧光探针，通过2，4-二硝基苯磺酰氯修饰羟基，获得检测硫醇化合物的分子荧光探针。
本发明第四个目的是提供一种检测硫醇化合物的分子荧光探针，在检测生物体中硫醇化合物的应用。
本发明的技术方案如下：
一种具有大Stokes位移近红外BODIPY染料NIR-BOD，所述染料NIR-BOD是由醛基BODIPY通过合环反应而制得；然后，再进一步对羟基进行修饰，获得检测硫醇化合物的荧光探针BOD-thiol。
所述化合物NIR-BOD的结构式为：
X为O，S，N；R1，R2，R3，R4为甲基或乙基。
所述化合物BOD-thiol的结构式为：
X为O，S，N；R1，R2，R3，R4为甲基或乙基。
所述BODIPY染料NIR-BOD具有大Stokes位移为>200nm。
所述BODIPY染料NIR-BOD具有在740nm近红外荧光发射。
本发明还提供一种具有大Stokes位移近红外BODIPY染料NIR-BOD的制备，包括如下步骤：醛基BODIPY通过合环反应，得到具有大Stokes位移近红外BODIPY染料NIR-BOD。
本发明还提供一种检测硫醇化合物的分子荧光探针BOD-thiol，其应用上述具有大Stokes位移近红外BODIPY染料NIR-BOD，通过2,4-二硝基苯磺酰氯修饰羟基，获得检测硫醇化合物的分子荧光探针BOD-thiol。
本发明独创性的利用分子内质子转移(ESIPT)，构建了具有大Stokes位移近红外BODIPY染料NIR-BOD；通过对羟基的修饰获得了检测硫醇化合物的分子荧光探针BOD-thiol，并应用于生物体内硫醇化合物的检测，实现了具有大Stokes位移近红外BODIPY染料的制备和应用。
本发明是醛基BODIPY通过合环反应，得到具有大Stokes位移近红外BODIPY染料NIR-BOD；该染料BOD-NIR与2,4-二硝基苯磺酰氯反应，制得检测硫醇化合物的分子荧光探针BOD-thiol。
本发明还提供一种上述检测硫醇化合物的分子荧光探针BOD-thiol在检测生物体中硫醇化合物的应用。
本发明还提供一种上述具有大Stokes位移近红外BODIPY染料NIR-BOD在检测生物体中硫醇化合物的应用。
本发明同现有技术相比，具有以下优点和有益效果：
本发明是利用分子内质子转移(ESIPT)构建了BODIPY染料，有效减少了检测过程中的光损伤，以及荧光自淬灭和检测灵敏度降低等负效应，并且首次实现了具有大Stokes位移近红外BODIPY染料的制备，及其在生物体中的应用。
附图说明
图1为NIR-BOD在缓冲溶液体系中的光谱图。
图2为NIR-BOD在不同pH值的缓冲溶液体系中740nm处的荧光强度。
图3为探针BOD-thiol与Cys反应随时间变化的紫外吸收图(a)和荧光发射图(b)。
图4为探针BOD-thiol的选择性柱状图。探针只与硫醇化合物产生响应，不与其它测试物种发生反应。
图5探针BOD-thiol在HeLa细胞中检测硫醇化合物的激光共聚焦荧光成像图。
图6为NIR-BOD的氢谱，氘代试剂为氘代氯仿。1H NMR(CDCl3,400MHz,ppm):δ＝7.94(d,1H,J＝8.0Hz),7.85(d,1H,J＝8.0Hz),7.81(s,1H),7.57-7.55(m,3H),7.50-7.46(m,1H),7.39-7.34(m,4H),2.70(s,3H),2.37(q,2H,J＝7.6Hz),3.20(s,3H),1.39(s,3H),1.03(t,3H,J＝7.6Hz).
图7为NIR-BOD的碳谱，氘代试剂为氘代氯仿。13C NMR(CDCl3,100MHz,ppm):δ＝170.0,163.7,159.2,151.9,147.4,142.0,141.0,137.7,136.5,135.0,134.3,132.3,132.2,129.3,128.3,126.6,126.4,125.3,122.2,122.0,121.3,114.0,100.1,17.2,14.2,13.6,12.2,11.3.
图8为NIR-BOD的质谱。HRMS(ESI):calcd for C31H27BF2N3OS+:538.1936；found:538.1941[M+H]+.
图9为BOD-thiol的氢谱，氘代试剂为氘代氯仿。1H NMR(CDCl3,400MHz,ppm):δ＝8.86(s,1H),8.61(d,1H,J＝2.4Hz),8.36(dd,1H,J1＝8.4Hz,J2＝2.0Hz),8.29(d,1H,J＝8.0Hz),8.06(d,1H,J＝8.8Hz),7.92(d,1H,J＝7.6Hz),7.59-7.56(m,4H),7.49(t,1H,J＝7.4Hz),7.34-7.32(m,2H),7.07(s,1H),2.62(s,3H),2.39(t,2H,J＝7.6Hz),1.74(s,3H),1.43(s,3H),1.06(t,3H,J＝7.6Hz).
图10为BOD-thiol的碳谱，氘代试剂为氘代氯仿。13C NMR(CDCl3,100MHz,ppm):δ＝168.5,164.0,150.5,148.4,147.5,145.8,144.2,143.8,143.2,141.6,139.5,138.2,135.2,134.1,134.0,133.4,130.5,130.1,129.8,129.6,127.9,126.7,126.3,125.7,124.7,122.5,121.5,120.0,109.1,17.2,13.9,13.8,12.5,11.1.
图11为BOD-thiol的质谱。HRMS(ESI):calcd for C37H29BF2N5O7S2 +:768.1570；found:768.1572[M+H]+.
具体实施方式
下面结合实施例对本发明作进一步阐述，本领域技术人员应当理解，所述实施例仅用于示例，而不对本发明构成任何限制。实例中X＝S，O，N；R1，R2，R4＝CH3，R3＝CH2CH3。
术语：
实施例1化合物NIR-BOD(X＝S，O)的合成
N2气体保护下，在DMF中加入HO-B-CHO(130mg，0.3mmol；R1，R2，R4＝CH3，R3＝CH3CH2)，邻氨基苯硫酚(75.1mg，0.6mmol)和偏重亚硫酸钠(57.7mg，0.304mmol)回流2小时，冷却，旋干溶剂，柱层析提纯得到红棕色固体，产率52.8％。X＝O时，与实例1中的方法一致。(HO-B-CHO为本实验室自制，自制方法参考专利号：ZL 201310636785.7，邻氨基苯硫酚和偏重亚硫酸钠为购买)
实施例2化合物NIR-BOD(X＝N)的合成
N2气体保护下，在醋酸中加入HO-B-CHO(200mg，0.46mmol；R1，R2，R4＝CH3，R3＝CH3CH2)，邻苯二胺(99.5mg，0.92mmol)回流2小时，冷却，旋干溶剂，柱层析纯化得到深棕色固体，产率43.2％。
实施例3化合物BOD-thiol(X＝S)的合成
用干燥二氯甲烷溶解化合物NIR-BOD(50mg，0.093mmol，R1，R2，R4＝CH3，R3＝CH3CH2)，向其中加入三乙胺(25.8μL，0.19mmol)，然后于冰浴下加入2，4-二硝基苯磺酰氯(50.7mg，0.19mmol)，随后撤去冰浴，于室温下反应1h。反应完成后，蒸除溶剂，柱层析进行分离纯化，得到红色固体，产率39.0％。(X＝O，N的制备方法实例3中的方法一致)

Claims (8)

1.一种具有大Stokes位移近红外BODIPY染料NIR-BOD，其特征在于，所述化合物NIR-BOD的结构式为：
X为O，S，N；R1，R2，R3，R4为甲基或乙基。
2.根据权利要求1所述具有大Stokes位移近红外BODIPY染料NIR-BOD，其特征在于，所述BODIPY染料NIR-BOD具有大Stokes位移为>200nm。
3.根据权利要求1所述具有大Stokes位移近红外BODIPY染料NIR-BOD，其特征在于，所述BODIPY染料NIR-BOD具有在740nm近红外荧光发射。
4.一种权利要求1-3任一项所述具有大Stokes位移近红外BODIPY染料NIR-BOD的制备方法，包括如下步骤：醛基BODIPY通过合环反应制得NIR-BOD染料。
5.一种用于检测硫醇化合物的分子荧光探针BOD-thiol，其特征在于，所述分子荧光探针BOD-thiol为权利要求1-3任一项所述具有大Stokes位移近红外BODIPY染料NIR-BOD通过2,4-二硝基苯磺酰氯修饰羟基而得到，所述分子荧光探针BOD-thiol的结构式为：
X为O，S，N；R1，R2，R3，R4为甲基或乙基。
6.一种权利要求5所述用于检测硫醇化合物的分子荧光探针BOD-thiol的制备方法，权利要求1-3任一项所述具有大Stokes位移近红外BODIPY染料NIR-BOD与2,4-二硝基苯磺酰氯反应得到。
7.一种权利要求5所述检测硫醇化合物的分子荧光探针BOD-thiol或权利要求6制备的分子荧光探针BOD-thiol在检测生物体中硫醇化合物的应用。
8.一种权利要求1-3任一项所述具有大Stokes位移近红外BODIPY染料NIR-BOD在检测生物体中硫醇化合物的应用。
CN201710332460.8A 2017-05-12 2017-05-12 一种具有大Stokes位移近红外BODIPY染料及其制备和应用 Pending CN107033621A (zh)

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