CN105440065B - 一种萘酰亚胺‑氟硼二吡咯荧光分子np‑bodipy及其制备方法和应用 - Google Patents
一种萘酰亚胺‑氟硼二吡咯荧光分子np‑bodipy及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种萘酰亚胺‑氟硼二吡咯荧光分子NP‑BODIPY。本发明还公开了该萘酰亚胺‑氟硼二吡咯荧光分子的制备方法及其应用。本发明的萘酰亚胺‑氟硼二吡咯荧光分子通过1,3‑偶极环加成反应制备，该分子存在从萘酰亚胺能量给体到氟硼二吡咯能量受体之间的分子内荧光共振能量转移，具有聚集诱导荧光性质。萘酰亚胺‑氟硼二吡咯荧光分子稳定性好，细胞毒性低，荧光性能优异，可作为有机荧光染料用于制备染料负载的二氧化硅荧光纳米粒子以及肿瘤细胞荧光成像，在活细胞成像、荧光传感器、生物荧光分析、荧光标记、药物高通量筛选等领域具有极为重要的应用。
Description
技术领域
本发明涉及荧光化合物及其制备和应用领域，具体涉及一种萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY及其制备方法和应用。
背景技术
氟硼二吡咯荧光分子的摩尔消光系数大，荧光量子产率高，荧光谱峰窄，灵敏度高，稳定好，具有优良的光学性能，可广泛用于生物荧光分析领域，是近年来的研究热点。萘酰亚胺-氟硼二吡咯复合荧光分子在文献中鲜有报道，其荧光性能优异，荧光量子效率高，存在从萘酰亚胺能量给体到氟硼二吡咯能量受体之间的分子内荧光共振能量转移，具有聚集诱导荧光性质，可作为有机荧光染料用于制备染料负载的二氧化硅荧光纳米粒子以及肿瘤细胞荧光成像，在活细胞成像、荧光传感器、生物荧光分析、荧光标记、药物高通量筛选等领域具有极为重要的应用。
发明内容
发明目的：本发明所要解决的第一个技术问题是提供了一种萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY。
本发明所要解决的第二个技术问题是提供了一种萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY的制备方法。
本发明所要解决的第三个技术问题是提供了一种萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY的应用。
本发明通过铜催化的1,3-偶极环加成反应，制备得到一种新型萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY。该荧光分子在现有技术中未见报道，具有聚集诱导荧光性质，并且存在分子内荧光共振能量转移。该萘酰亚胺-氟硼二吡咯荧光分子可作为荧光性能优异的有机染料用于制备染料负载二氧化硅荧光纳米粒子以及用于肿瘤细胞荧光成像，在活细胞成像、荧光传感器、生物荧光标记等领域具有极为重要的应用价值。
技术方案：为了解决上述技术问题，本发明提供了一种萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY，由如下结构式构成：
上述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY的制备方法，所述萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY由8-[4-(2-叠氮乙氧基)苯基]-1,3,5,7-四甲基-氟硼二吡咯(BODIPY)和N-正丁基-4-乙炔基-1,8-萘二甲酰亚胺(Ey-NP)通过1,3-偶极环加成反应得到，反应在二氯甲烷、乙醇和纯水的混合溶液中进行，以五水合硫酸铜和抗坏血酸钠、三乙胺为催化体系，具体反应式如下：
上述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在作为染料负载荧光纳米粒子制备方面的应用。
上述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在肿瘤细胞成像方面的应用。
上述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY作为分子内荧光共振能量转移荧光化合物的应用。
有益效果：本发明具有以下优点：本发明的新型荧光化合物包含N-正丁基-1,8-萘二甲酰亚胺和8-烷氧苯基-1,3,5,7-四甲基氟硼二吡咯两种复合荧光团，其荧光性能优异，荧光量子效率高，存在从萘酰亚胺能量给体到氟硼二吡咯能量受体之间的分子内荧光共振能量转移，具有聚集诱导荧光性质，可作为有机荧光染料用于制备染料负载的二氧化硅荧光纳米粒子以及肿瘤细胞荧光成像，在活细胞成像、荧光传感器、生物荧光分析、荧光标记、药物高通量筛选等领域具有极为重要的应用。萘酰亚胺-氟硼二吡咯荧光化合物NP-BODIPY的结构、合成、荧光性质及应用在现有文献中未见报道。
附图说明
图1是萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在四氢呋喃溶液中的荧光光谱(NP-BODIPY浓度为10-5mol/L)；
图2为负载NP-BODIPY染料的二氧化硅荧光纳米粒子的透射电镜图；
图3为萘酰亚胺-氟硼二吡咯荧光染料NP-BODIPY负载的二氧化硅纳米粒子在纯水溶液中的荧光光谱(NP-BODIPY浓度为10-6mol/L)；
图4为萘酰亚胺-氟硼二吡咯荧光染料NP-BODIPY与乳腺癌细胞MCF-7共同孵化后的激光共聚焦荧光显微照片。
具体实施方式
实施例1萘酰亚胺-氟硼二吡咯荧光分子的制备
化合物BODIPY按文献方法制备(Huanren Cheng,Ying Qian.Intramolecularfluorescence resonance energy transfer in a novel PDI-BODIPY dendriticstructure:synthesis,Hg2+sensor and living cell imaging,Sensors and ActuatorsB,2015,219,57-64)。具体合成方法如下：
将3.09g(13.55mmol)的4-(2-溴乙氧基)苯甲醛和1.03g(15.85mmol)的叠氮化钠溶于45mL DMF中，室温下磁力搅拌反应24h，然后将反应液倒入45mL冰水中，萃取，洗涤，干燥，减压蒸馏，得到2.50g(4-(2-叠氮基乙氧基)苯甲醛)，将其溶于150mL二氯甲烷溶液中，继续加入2.48g(0.026mol)2,4-二甲基吡咯，滴加两滴三氟乙酸，室温搅拌下反应12h。然后向反应液中加入3.17g(0.013mol)四氯苯醌，继续搅拌12h，再向混合液中加入15mL三乙胺和15mL三氟化硼乙醚络合物，在0℃下反应12h。结束反应，萃取，洗涤，干燥，柱色谱提纯，得到BODIPY红色固体。产率25％。分析所得化合物BODIPY：
FT-IR(KBr):2960,2923,2860,2119,2106,1605,1544,1507,1370,1192,1054,838,761cm-1
1H NMR(CDCl3,300MHz)δ:7.18(d,J＝8.34Hz,2H),7.01(d,J＝8.37Hz,2H),5.97(s,2H),4.12(t,J1＝5.85Hz J2＝5.85Hz,2H),3.58(t,J1＝6.51Hz J2＝6.45Hz,2H),2.55(s,6H),1.43(s,6H)。
化合物Ey-NP的制备按文献方法制备(Huimin Guo,Maria L.Muro-Small,ShaominJi,Jianzhang Zhao,Felix N.Castellano.Naphthalimide phosphorescence finallyexposed in a platinum(II)diimine complex.Inorg.Chem.,2010,49,6802-6804)。
萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY的制备
氮气保护及磁力搅拌下，在15mL二氯甲烷/乙醇/纯水混合溶液(二氯甲烷/乙醇/纯水的体积比为12:1:1)中分别加入0.14g(0.34mmol)BODIPY和0.10g(0.36mmol)Ey-NP，充分搅拌下继续加入抗坏血酸钠0.041g(0.20mmol)和五水合硫酸铜0.026g(0.10mmol)，滴加三乙胺1mL，室温反应48h。结束反应，向反应体系加入15mL水，萃取，干燥，柱色谱提纯，得到红色固体即化合物NP-BODIPY，产率为65％。
化合物NP-BODIPY的合成路线如下：
分析所得化合物NP-BODIPY：
核磁共振氢谱1H NMR(CDCl3,ppm):δ9.11(d,J＝7.89Hz,1H),8.71(t,J1＝4.86Hz,J2＝5.04Hz,2H),8.27(s,1H),8.05(d,J1＝7.08Hz,1H),7.86(t,J1＝7.53Hz J2＝7.47Hz,1H),7.29(d,J＝7.71Hz,2H),7.11(d,J＝7.5Hz,2H),6.02(s,2H),5.04(s,2H),4.62(s,2H),4.27(t,J1＝6.27Hz J2＝6.63Hz,2H),2.60(s,6H),1.81(t,J1＝6.30Hz J2＝6.90Hz,2H),1.65(s,2H),1.44(s,6H),1.05(t,J1＝7.08Hz J2＝6.75Hz,3H)。
核磁共振碳谱13C NMR(CDCl3,ppm):δ160.92,135.07,134.00,133.24,132.24,129.97,129.89,127.23,123.81,117.68,68.98,55.97,52.67,42.91,32.80,22.97,17.15,16.39。
高分辨质谱HRMS Calcd for C39H37BF2N6O3Na[M+Na]+709.2880Found 709.2818。
所获得化合物NP-BODIPY的结构式为：
实施例2萘酰亚胺-氟硼二吡咯荧光分子的光物理性质
测定了萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY及其荧光组成单元氟硼二吡咯、萘酰亚胺的紫外吸收及荧光光谱。NP-BODIPY的紫外吸收峰位于366和500nm。NP-BODIPY的荧光光谱呈双峰结构，荧光峰位于430和510nm，最大荧光发射波长510nm处的荧光峰强度是其氟硼二吡咯荧光单元的两倍。萘酰亚胺-氟硼二吡咯荧光化合物NP-BODIPY存在很强的分子内荧光共振能量转移，其中萘酰亚胺荧光单元作为能量给体，氟硼二吡咯荧光单元是能量受体。图1是萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY(浓度为10-5mol/L)在四氢呋喃溶液中的荧光光谱。
实验发现萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY具有聚集诱导荧光性质。NP-BODIPY固体粉末在暗室中紫外灯下呈紫红色荧光；NP-BODIPY的THF溶液呈绿色荧光；NP-BODIPY在含水量为70％的H2O/THF混合溶液中荧光较强，量子产率为0.60。
具有荧光共振能量转移的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在文献中未有报道，并且首次发现该分子具有聚集诱导荧光性质，萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在有机发光器件，荧光传感器，生物标记及荧光探针等领域具有广阔的应用前景。
实施例3萘酰亚胺-氟硼二吡咯染料负载二氧化硅纳米粒子在水中的荧光性质
采用正相微乳液法制备并用纤维素透析膜透析得到了负载萘酰亚胺-氟硼二吡咯荧光染料NP-BODIPY的二氧化硅荧光纳米粒子(NP-BODIPY/SiO2)。具体方法如下：
将二(2-乙基己基)琥珀酸磺酸钠(AOT,0.22g)溶解在10mL去离子水中搅拌至澄清。0℃，超声下向其中加入0.4mL助表面活性剂正丁醇形成水包油的正相微乳液体系。将30μL含物质的量浓度为12mM NP-BODOIPY的DMF溶液缓慢加入微乳液体系中，超声3min后将0.1mL乙烯基三乙氧基硅烷(VTES)加入体系。室温下搅拌8h后加入10μL 3-氨基丙基三乙氧基硅烷(APTES)，继续在室温下搅拌24h，反应结束后，未反应的成分用截留分子量为8-14kDa的纤维素透析膜透析72h，将所得溶液在5℃下保存即得。
染料NP-BODIPY被包裹在二氧化硅纳米粒子内，形成稳定的核-壳结构，呈单分散球形，分布均匀，平均粒径为50nm。图2为负载NP-BODIPY染料的二氧化硅荧光纳米粒子的透射电镜图。
测定了二氧化硅荧光纳米粒子在纯水中的荧光性质。图3为染料负载二氧化硅荧光纳米粒子在纯水中的荧光光谱。在水中二氧化硅荧光纳米粒子荧光光谱与在纯THF中的荧光光谱类似，峰形保持不变，在425nm和510nm呈现双峰结构，荧光强度较大。负载NP-BODIPY染料的二氧化硅荧光纳米粒子易溶于水中，表面富含大量活性氨基，易于修饰，生物相容性好，荧光性质优良，可作为生物分子荧光探针用于生物荧光分析、药物高通量筛选等生命科学领域。
实施例4萘酰亚胺-氟硼二吡咯荧光分子用于肿瘤细胞荧光成像
将萘酰亚胺-氟硼二吡咯荧光染料NP-BODIPY与乳腺癌细胞MCF-7共同孵化后在双通道共聚焦荧光显微镜下观察MCF-7细胞成像照片。图4为MCF-7细胞与荧光染料NP-BODIPY共同孵化后的激光共聚焦荧光成像照片。在MCF-7细胞中加入荧光染料NP-BODIPY共同孵化后，荧光染料进入MCF-7细胞内部清晰成像。萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY可用于肿瘤细胞成像。
本发明的实例化合物萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY经铜催化叠氮-炔环加成反应制备得到，荧光性能优良，存在分子内荧光共振能量转移，具有聚集诱导荧光性质，可用于制备染料负载的二氧化硅荧光纳米粒子，可作为有机染料用于肿瘤细胞荧光成像，在活细胞成像、荧光传感器、生物荧光分析、荧光标记、药物高通量筛选等领域具有极为重要的应用。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY，其特征在于，由如下结构式构成：
2.权利要求1所述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY的制备方法，其特征在于，所述萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY由8-[4-(2-叠氮乙氧基)苯基]-1,3,5,7-四甲基-氟硼二吡咯和N-正丁基-4-乙炔基-1,8-萘二甲酰亚胺通过1,3-偶极环加成反应得到，反应在二氯甲烷、乙醇和纯水的混合溶液中进行，以五水合硫酸铜和抗坏血酸钠、三乙胺为催化体系，具体反应式如下：
3.权利要求1所述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在作为染料负载荧光纳米粒子制备方面的应用。
4.权利要求1所述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY在肿瘤细胞成像方面的应用。
5.权利要求1所述的萘酰亚胺-氟硼二吡咯荧光分子NP-BODIPY作为分子内荧光共振能量转移荧光化合物的应用。
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