CN110845418B - 基于醌式吸电子基团型的化合物及其制备方法和应用 - Google Patents
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Abstract
本发明涉及一种基于醌式吸电子基团型的化合物及其制备方法和应用。本发明合成的一系列基于醌式吸电子基团型的化合物,不仅具有良好的聚集诱导发光特性,搭配两性化合物和生物正交反应官能基团,包覆成聚集诱导发光型纳米颗粒的探针,能在体外或体内对癌细胞或肿瘤进行特异性标记与成像,对于推进生物荧光检测技术和生物医学领域具有相当重要的意义与价值。
Description
技术领域
本发明涉及检测分析技术领域,具体涉及一种基于醌式吸电子基团型的化合物及其制备方法和应用。
背景技术
近年来,透过给电子基团和吸电子基团的搭配,调控不同发光色团的吸收和发射光谱,一直是广泛被采用的设计材料的策略,开发新型的给电子基团或吸电子基团一直都是最重要且最关键的研究。
AIE发光材料(AIE分子、AIE荧光团、AIEgen)在溶液中几乎不发光,在固态或聚集态下发光增强,其结构的设计策略,主要理论依据为分子内运动受限(RIM)机理模型,即分子内运动导致激发态分子的能量以非辐射形式衰减,产生弱的荧光发射。当这些分子聚集时,彼此的牵制作用限制了分子内部的运动,降低能量的耗散,增加光输出的能量比例,从而表现出荧光增强的现象。经过近二十年的发展,具有AIE特性的材料几乎在众多发光材料领域得到应用,包含刺激响应及可逆型传感的智能材料、可调谐折射率的液晶或偏振光材料、高效率的有机发光二极管器件和照明材料、光波导材料、生物传感探针以及在生物体系中的细胞器、病毒、细菌或血管成像等荧光探针。
生物正交反应(Bioorthogonal reaction)是指一类可以在活体细胞中进行的化学反应。这类反应可以在生物体内的生理条件下发生,不会与体内同时发生的其他生化反应互相干扰,也不会对生物体和目标生物分子产生损伤。其中又以无需催化剂环境的环张力诱导型环加成反应(Strain promoted cycloaddition reaction)最受关注。为了避免使用一价铜离子带来的细胞毒性,研究人员通过改变炔基底物的结构,开发出了不需要铜离子催化的叠氮-炔基环加成反应(Strain promoted azide-alkyne cycloaddition,SPAAC),也被称为无铜点击化学(copper free click chemistry)。首先,将含有叠氮基团的非天然糖通过代谢的方法引入癌细胞或肿瘤细胞表面的糖蛋白上,然后与八元环炔基OCT(cyclooctyne)、八元环底物(difluorocyclooctyne,DIFO)或双苯并八元环炔(dibenzocyclooctyne,DBCO)修饰的生物荧光探针进行反应,实现体外癌细胞标记显像以及体内肿瘤细胞的标记显像,此标记方式不仅没有发现明显的细胞毒性,而且还能改善体内肿瘤表面讯号表达不佳的问题,提升肿瘤组织的显像工作。近年来,透过具有荧光增强(turn on)效应的生物正交反应策略,利用具有较长激发波长的近红外染料的互相结合,可以减少生物成像的背景,进一步用于组织以及活体动物的标记和成像已受到关注。
发明内容
本发明的目的是提供一种基于醌式吸电子基团型的化合物及其制备方法和应用,解决现有技术中红光及近红外探针不足以及商业化标记探针高制备成本、高自身吸收、低稳定性、低灵敏性等问题。
本发明解决技术问题所采用的技术方案是:一种基于醌式吸电子基团型的化合物,所述化合物的结构式为式I-III所示的任一结构式:
其中,醌式吸电子基团QA选自下述任一结构式的基团:
给电子基团Ar1和Ar2分别独立选自下述任一结构式的基团:
间隔基团π1和π2分别独立选自下述任一结构式的基团:
其中,取代基团R1、R2、R3、R4、R5、R6、R7和R8分别各自独立地选自氢基、三氟甲基、氰基、硝基、卤素、羟基、胺基、任选被取代的烷基、烷胺盐基、烷氧基、烷硫基、烯基、炔基、环烷基、环烷基氧基、环烷氧基硫基、酰基、芳香基、杂环基、杂芳基、杂环烷基、单取代胺基或二取代胺基。
在本发明的化合物中,醌式吸电子基团QA选自下述任一结构式的基团:
给电子基团Ar1和Ar2分别各自独立地选自下述任一结构式的基团:
间隔基团π1和π2分别各自独立选自下述任一结构式的基团:
其中,取代基团R1、R2、R3、R4、R5、R6、R7和R8分别各自独立地选自氢基、三氟甲基、氰基、硝基、卤素、羟基、任选被取代的烷基、烷胺盐基、烷氧基、烷硫基、环烷基、环烷氧基、芳香基、杂环基、杂芳基、杂环烷基、单取代胺基或二取代胺基。
在本发明的化合物中,醌式吸电子基团QA选自下述任一结构式的基团:
给电子基团Ar1和Ar2分别各自独立地选自下述任一结构式的基团:
间隔基团π1和π2分别各自独立选自下述任一结构式的基团:
其中,取代基团R1、R2、R3、R4、R7和R8分别各自独立地选自氢基、三氟甲基、硝基、氟基、任选被取代的烷基、烷胺盐基、烷氧基、环烷基、环烷氧基、芳香基、杂环基或杂芳基。
在本发明的化合物中,所述化合物选自式I’至III’所示的结构式的化合物中的任一种:
其中,X选自氧原子或硫原子;取代基团R1、R2、R7和R8分别各自独立地选自氢基、三氟甲基、氟基、任选被取代的烷基、烷氧基、环烷基、环烷氧基或芳香基。
在本发明的化合物中,所述化合物选自下述结构式的化合物中的任一种:
本发明还提供了上述的化合物的制备方法,包括:将式I"所示的双溴醌式芳香化合物、式II"所示的烷锡取代型芳香化合物、式III"所示的含间隔基的烷锡取代型芳香化合物中的至少一化合物以及钯催化剂置于无水无氧的有机溶剂中,回流搅拌得到基于醌式吸电子基团型的反应产物;其中,式I"-III"的结构式如下:
具体工艺如下:
需要说明的是,式I"所示的化合物中的Ar和II"所示的化合物中的Ar可以各自为Ar1和Ar2,也就是说Ar基团可以相同,也可以不同;π即为π1;
其中,醌式吸电子基团QA选自下述任一结构式的基团:
给电子基团Ar任意选择Ar1和Ar2,且Ar1和Ar2分别独立选自下述任一结构式的基团:
间隔基团π任意选择π1和π2,且π1和π2分别独立选自下述任一结构式的基团:
其中,取代基团R1、R2、R3、R4、R5、R6、R7和R8分别各自独立地选自氢基、三氟甲基、氰基、硝基、卤素、羟基、胺基、任选被取代的烷基、烷胺盐基、烷氧基、烷硫基、烯基、炔基、环烷基、环烷基氧基、环烷氧基硫基、酰基、芳香基、杂环基、杂芳基、杂环烷基、单取代胺基或二取代胺基。
在本发明的制备方法中,所述有机溶剂是二氧六环(1,4-dioxane)、四氢呋喃(THF)或二甲基甲酰胺(DMF)等,其中有机溶剂优选为二甲基甲酰胺;所述钯催化剂是四三苯基膦合钯、双二苯基膦基二茂铁二氯化钯或二三苯基膦二氯化钯(Pd(PPh3)2Cl2),其中钯催化剂优选为二三苯基膦二氯化钯(Pd(PPh3)2Cl2)。
在本发明的制备方法中,该制备方法还包括将得到的基于醌式吸电子基团型的反应产物于减压下除去有机溶剂后,经由层析柱纯化得到固体成品。其中,层析柱所选择的固定相为硅胶,流动相为乙酸乙酯和石油醚的混合溶剂。
本发明还提供了上述的化合物在搭配生物正交反应的官能基团制备用于聚集诱导发光型纳米探针的应用以及在搭配生物正交反应的官能基团制备用于标记癌细胞或肿瘤组织的生物荧光探针中的应用;所述生物正交反应的官能基团包括八元环炔基(OCT)、含氟原子的八元环底物(DIFO)和双苯并八元环炔(DBCO)。
本发明还提供了上述的化合物在制备聚集诱导发光型纳米探针中的应用以及在制备用于标示肿瘤细胞、正常细胞、淡水藻、咸水类海藻、辨识细菌的荧光探针、发光二极管、光电放大器、光信息存储器、液晶显示器、光波导材料、生物传感器或逻辑门、无损读出的生物探针中的应用。
本发明还提供了上述的化合物在制备用于肿瘤组织标记的聚集诱导发光型纳米探针中的应用以及在制备用于预防和治疗肿瘤疾病的生物医学领域的诊疗一体化的药物和/或药物组合物中的应用。
具体地,本发明还提供了上述的化合物在制备用于体外癌细胞和体内肿瘤组织的标记和成像的生物荧光探针中的应用。在该应用中,所述癌细胞和肿瘤组织为人乳腺癌细胞MCF-7。
本发明还提供了上述的化合物在制备用于标示肿瘤细胞、正常细胞的生物荧光探针、辨识细菌的荧光探针、发光二极管、光电放大器、光信息存储器、液晶显示器、光波导材料、生物传感器或逻辑门、无损读出的生物探针中的应用。
本发明还提供一种体外检测癌细胞特异性标记方法,以及体内肿瘤组织的标记和成像,本发明仅以MCF-7细胞唯一示范样品,该发明亦可广泛被应用于其他类型的肿瘤细胞,如HeLa、A549等,包括如下步骤:
A、使用上述化合物制备成具有生物正交能力的荧光探针,与事先做好生物标记的癌细胞或肿瘤细胞,进行体内或体外生物正交反应的孵育;
B、通过荧光显微镜或共聚焦激光扫描显微镜,检测体外癌细胞或体内肿瘤的标记和成像。
术语和定义
术语“卤素”代表氟、氯、溴和碘,特别是氟或氯,优选为氟。
术语“烷基”代表一类仅含有碳、氢两种原子的直链或支链烷基团,例如C1-10烷基是指具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链烷基团,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、壬基、癸基、2-乙基丁基、2-乙基己基、2-丁基辛基。优选烷基含有1、2、3或4个碳原子(C1-4烷基),例如甲基、乙基、正丙基或正丁基。
术语“烯基”一般意指直链或支链、含有2-20个碳原子且含有1个或多个双键,例如乙烯基、丙烯基、(E)-2-甲基乙烯基或(Z)-2-甲基乙烯基。
术语“炔基”一般意指直链或支链、含有2-12个碳原子且含有2个或多个双键,例如乙炔基、丙炔基、2-丁炔基或2-戊炔基。
术语“烷氧基”一般意指通过氧原子键合的直链或支链烷基,其中术语“烷基”具有上述定义,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、戊氧基或其异构体。优选烷氧基含有1或2个碳原子(C1-2烷氧基),例如甲氧基或乙氧基。
术语“烷硫基”一般意指通过硫原子键合的直链或支链烷基,其中术语“烷基”具有如上所述定义。
术语“环烷基”一般意指直链或支链、含有3-8个碳原子的饱和单环烃环,例如环丙基、环丁基、环戊基、环己基、环庚基或环辛基。优选环烷基含有5、6或7个碳原子(C5-7环烷基),例如环戊基、环己基或环庚基。
术语“环烷基氧基”一般意指通过氧原子键合的直链或支链环烷基,其中术语“环烷基”具有如上所述的定义。
术语“环烷基硫基”一般意指通过硫原子键合的直链或支链环烷基,其中术语“环烷基”具有如上所述的定义。
术语“芳基”一般意指芳香性或部分芳香性的单环、双环或三环烃环,其包含6-14个碳原子,特别是具有6个碳原子的环(例如苯环基或联苯环基)、具有9个碳原子的环(例如茚基)、具有10个碳原子的环(例如二氢化奈基或萘基)、具有13个碳原子的环(例如芴基)或具有14个碳原子的环(例如葱基)。优选芳基为含有1-4个碳原子“烷氧基”取代的苯环基。
术语“杂环基”一般意指含有饱和或部分饱和的单环或双环烃环,其含有5-8个碳原子且含有1-3个选自氧、硫或氮的含杂原子基团。例如呋喃基、噻吩基、吡咯基、噻唑基、噻二唑基、恶唑基、咪唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基或吡喃基。优选杂环基为噻吩基、吡啶基或其含有1-4个碳原子(C1-4烷基)取代杂环基。
术语“杂芳基”一般意指苯环与杂环稠合在一起的化合物基团,例如喹啉基、苯并噻唑基、苯并噻二唑基、苯并恶唑基、吲哚基或嘌呤基。
术语“杂环烷基”一般意指含有3-7个碳原子和1-3个氧、硫或氮杂原子所构成的杂环基团,例如哌啶基、羟基哌啶基、菲诺哌啶基、哌嗪基、N-甲基哌嗪基、四氢化吡咯基、四氢化呋喃基、四氢化噻吩基、吗啡林基或噻嗪基。优选杂环烷基为哌啶基、N-甲基哌嗪基或吗啡林基。
术语“单烷基胺基”一般意指胺基(NH2)的1个氢被“烷基”所取代,其中术语“烷基”具有如上所述的定义。例如甲基胺基、乙基胺基、丙基胺基、丁基胺基或其异构体。
术语“二烷基胺基”一般意指胺基(NH2)的2个氢被“烷基”所取代,其中术语“烷基”具有如上所述的定义。例如二甲基胺基、二乙基胺基、二丙基胺基、二丁基胺基或其异构体。优选二烷基胺基为二甲基胺基或二乙基胺基。
术语“杂原子”一般意指含有1个或多个氧、硫或氮原子。
术语“任选取代的”一般意指结构中的氢被所述取代基取代。除非另有说明,任选取代的基团可以在该基团每一个可取代的位置上具有取代基,或者在结构中的多于一个位置可以被取代。
本文使用的数值范围“C1-10”以及其所包含的亚范围一般意指具有限定数量的1-10个原子,亦即1、2、3、4、5、6、7、8、9或10个原子;其中包含碳原子数量范围的“C1-10”以及其所包含的亚范围一般意指具有限定数量的1-10个碳原子基团,亦即包含1、2、3、4、5、6、7、8、9或10个碳原子基团。
合适的取代基一般选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、硝基、氰基、羟基、C1-6二烷基胺基、N-甲基哌嗪基或吗啡林基。
实施本发明的基于醌式吸电子基团型的化合物及其制备方法和应用,具有以下有益效果:本发明提供的简易生产的一系列具有长波长吸收和发射特性的荧光化合物易于合成,并且显示出良好的AIE特性,搭配具有生物正交反应的官能基团制备成红光或近红外光型的生物荧光探针,与商业化的标记探针相比,具有高光稳定性、高深度的组织穿透性、低背景干扰、低自吸收以及对癌细胞或肿瘤组织的特异性标记和成像等功能与潜值,对于拓展生物荧光检测技术和体内肿瘤组织的标记领域具有相当重要的意义与价值。
附图说明
图1是基于醌式吸电子基团型的化合物的演进和作为AIE靶向探针应用于体内肿瘤标记的示意图;
图2是2TPE-BI在THF溶液中的归一化紫外-可见光吸收光谱和光致发光(PL)光谱(浓度:10μM,激发波长:470nm);
图3是2TPE-T-BI在THF溶液中的归一化紫外-可见光吸收光谱和光致发光(PL)光谱(浓度:10μM,激发波长:515nm);
图4是2TPE-2T-BI在THF溶液中的归一化紫外-可见光吸收光谱和光致发光(PL)光谱(浓度:10μM,激发波长:560nm);
图5是2TPE-BI在不同溶剂中的归一化光致发光(PL)光谱(浓度:10μM,激发波长:470nm);使用的溶剂包含正己烷(Hex)、甲苯(Tol)、四氢呋喃(THF)、二氯甲烷(DCM)和二甲基亚砜(DMSO);
图6是2TPE-BI、2TPE-T-BI和2TPE-2T-BI的热重量分析图;
图7是2TPE-BI在不同含水率(fW,vol%,体积%)的THF/水混合物中的PL谱图(浓度:10μM,激发波长:470nm);
图8是2TPE-BI的相对发射强度(I/I0)、最大发射的波长与THF/水混合物的含水率(fW,体积%)之间关系图(浓度:10μM,激发波长:470nm);
图9是2TPE-T-BI在不同含水率(fW,体积%)的THF/水混合物中的PL谱图(浓度:10μM,激发波长:515nm);
图10是2TPE-T-BI的相对发射强度(I/I0)、最大发射的波长与THF/水混合物的含水率(fW,体积%)之间关系图(浓度:10μM,激发波长:515nm);
图11是2TPE-2T-BI在不同含二氧六环率(fD,体积%)的THF/二氧六环混合物中的PL谱图(浓度:10μM,激发波长:560nm);
图12是2TPE-2T-BI的相对发射强度(I/I0)、最大发射的波长与THF/二氧六环混合物的含二氧六环率(fD,体积%)之间关系图(浓度:10μM,激发波长:560nm);
图13是2TPE-BI和2TPE-T-BI在THF溶液下的荧光衰减曲线图(IRF为仪器响应函数);
图14是2TPE-BI和2TPE-T-BI在固态粉末状态下的荧光衰减曲线图(IRF为仪器响应函数);
图15是2TPE-BI晶体分析中的单分子的晶体结构;
图16是2TPE-BI晶体分析中的晶包结构图;
图19是2TPE-BI理论模拟分析的正视图;
图20是2TPE-BI理论模拟分析的俯视图;
图21是2TPE-BI理论模拟分析的最高被占用分子轨道(HOMO)图;
图22是2TPE-BI理论模拟分析的分子最低空余轨道(LUMO)图;
图23是2TPE-T-BI理论模拟分析的最高被占用分子轨道(HOMO)图;
图24是2TPE-T-BI理论模拟分析的分子最低空余轨道(LUMO)图;
图25是2TPE-2T-BI理论模拟分析的最高被占用分子轨道(HOMO)图;
图26是2TPE-2T-BI理论模拟分析的分子最低空余轨道(LUMO)图;
图27是DBCO-AIEdots制备的示意图;
图28是DBCO-AIEdots在PBS水溶液中的归一化紫外-可见光吸收光谱和光致发光(PL)光谱(激发波长:570nm);
图29是DBCO-AIEdots在PBS水溶液中的动态光散射图;
图30是DBCO-AIEdots的透射电子显微镜图;
图31是共聚焦激光扫描显微镜检测,经由Ac4ManNAz处理过的MCF-7细胞,于DBCO-AIEdots纳米探针和商业化的细胞核(DAPI)探针共染的明场和暗场图;激发波长:575nm(DBCO-AIEdots)和488nm(DAPI);发射滤光片:600-750nm(DBCO-AIEdots)和490-600nm(DAPI);图像使用的比例尺为50μm;
图32是共聚焦激光扫描显微镜检测,未经由Ac4ManNAz处理过的MCF-7细胞,于DBCO-AIEdots纳米探针和商业化的细胞核(DAPI)探针共染的明场和暗场图;激发波长:575nm(DBCO-AIEdots)和488nm(DAPI);发射滤光片:600-750nm(DBCO-AIEdots)和490-600nm(DAPI);图像使用的比例尺为50μm;
图33是小动物荧光成像仪检测,经由Ac4ManNAz处理过的肿瘤组织的雌性BALB/c裸鼠,于DBCO-AIEdots纳米探针注射后的明场图,以及不同时间的暗场图;激发波长:605nm;发射滤光片:640-900nm;
图34是小动物荧光成像仪检测,未经由Ac4ManNAz处理过的肿瘤组织的雌性BALB/c裸鼠,于DBCO-AIEdots纳米探针注射后的明场图,以及不同时间的暗场图;激发波长:605nm;发射滤光片:640-900nm;
图35是小动物荧光成像仪检测,经由Ac4ManNAz处理过的肿瘤组织和重要器官(心脏、肝脏、脾脏、肺脏、肾脏),于DBCO-AIEdots纳米探针注射24小时后的明场和暗场图;激发波长:605nm;发射滤光片:640-900nm;
图36是小动物荧光成像仪检测,未经由Ac4ManNAz处理过的肿瘤组织和重要器官(心脏、肝脏、脾脏、肺脏、肾脏),于DBCO-AIEdots纳米探针注射24小时后的明场和暗场图;激发波长:605nm;发射滤光片:640-900nm。
具体实施方式
下面结合附图和实施例,对本发明的基于醌式吸电子基团型化合物及其制备方法和应用作进一步说明:
针对现有技术中关于生物荧光标记探针,如商业化探针存在的高制备成本、低稳定性、低灵敏性等诸多问题。本发明提出了一种简易生产的高性能的生物荧光探针,透过醌式吸电子基团构建红光、甚至近红外光的AIE型材料,透过生物正交反应,能有效应用于体内肿瘤组织的标记和成像。本发明所提出的透过醌式型的结构所构建的吸电子基团,不仅拥有较佳的吸电子能力,有助于调控出长波长吸收和发射的材料分子,并且搭配四苯乙烯、三苯基胺等推电子基团,有利于设计出具有聚集诱导发光(Aggregation-inducedemission,AIE)的荧光材料。
本发明采用醌式吸电子基团结构作为推-拉电子(donor-acceptor)分子框架的电子受体,如图1所示,相较于一般传统的苯并噻唑(benzothiazole)吸电子基团,拥有较长的吸收和发射波长,进一步引入噻吩(thiophene)间隔基团后,能较简易的开发出具有聚集诱导发光特性的近红外光材料,包覆成带有生物正交反应的DBCO官能基的聚集诱导发光型纳米粒子后,作为生物荧光探针成功在体外和体内对癌细胞和肿瘤组织进行特异性的标记和成像,在生物荧光检测技术领域提供了一类光稳性佳、特异性标记佳、生物光损伤低、组织穿透深度高且生物兼容性佳的荧光探针,在生物荧光检测技术等领域具有重要的意义与价值。
下面通过具体实施例进行详细说明。
实施例1:产品的制备
(1)合成2TPE-BI
于100mL带有抽器开关的单口圆底瓶中,加入4,7-dibromo-spiro[benzo[d]imidazole-2,1'-cyclohexane](Br-BI-Br;1.00g,2.91mmol)、三正丁烷基四苯乙烯基锡(tributyl(4-(1,2,2-triphenylvinyl)phenyl)stannane,TPE-SnBu3;3.62g,5.82mmol)、二三苯基膦二氯化钯(Pd(PPh3)2Cl2;0.25g,0.35mmol)和无水无氧的二甲基甲酰胺(DMF;20mL)溶剂,回流搅拌24小时。反应混合物置于减压环境抽去溶剂后,经由层吸柱纯化得到橙红色的2TPE-BI产品(0.64g),收率为26%。1H NMR(400MHz,CDCl3),δ(ppm):7.80-7.78(m,4H),7.23(s,2H),7.13-7.03(m,34H),1.95(m,4H),1.75-1.66(m,6H).13C NMR(100MHz,CDCl3,δ):159.22,144.05,143.90,143.83,143.82,141.49,140.75,134.78,134.38,131.60,131.58,131.51,131.48,130.86,127.94,127.83,127.76,127.61,126.69,126.63,126.58,107.53,33.30,25.95,25.07.HRMS(MALDI-TOF)m/z:[M]+calculated for C64H50N2,846.3974;found,846.3957.
(2)合成2TPE-T-BI
于100mL带有抽器开关的单口圆底瓶中,加入4,7-dibromo-spiro[benzo[d]imidazole-2,1'-cyclohexane](Br-BI-Br;1.00g,2.91mmol)、三正丁烷基四苯乙烯噻吩基锡(tri-n-butyl(5-(4-(1,2,2-triphenylvinyl)phenyl)thiophen-2-yl)stannane,TPE-T-SnBu3;2.05g,2.91mmol)、二三苯基膦二氯化钯(Pd(PPh3)2Cl2;0.25g,0.35mmol)和无水无氧的二甲基甲酰胺(DMF;20mL)溶剂,回流搅拌2小时后,加入三正丁烷基四苯乙烯基锡(tributyl(4-(1,2,2-triphenylvinyl)phenyl)stannane,TPE-SnBu3;1.81g,2.91mmol)再继续回流24小时。反应混合物置于减压环境抽去溶剂后,经由层吸柱纯化得到紫红色的2TPE-T-BI产品(0.97g),收率为36%。1H NMR(400MHz,CDCl3),δ(ppm):8.05(d,J=3.6Hz,1H),7.80(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.29(d,J=7.6Hz,2H),7.25-7.03(m,35H),2.00-1.71(br,10H).HRMS(MALDI-TOF)m/z:[M-H]+calculated for C64H50N2,929.2189;found,928.3851.
(3)合成2TPE-2T-BI
于100mL带有抽器开关的单口圆底瓶中,加入4,7-dibromo-spiro[benzo[d]imidazole-2,1'-cyclohexane](Br-BI-Br;1.00g,2.91mmol)、三正丁烷基四苯乙烯噻吩基锡(tri-n-butyl(5-(4-(1,2,2-triphenylvinyl)phenyl)thiophen-2-yl)stannane,TPE-T-SnBu3;4.10g,5.82mmol)、二氯化二三苯基膦合钯(Pd(PPh3)2Cl2;0.25g,0.35mmol)和无水无氧的二甲基甲酰胺(DMF;20mL)溶剂,回流搅拌24小时。反应混合物置于减压环境抽去溶剂后,经由层吸柱纯化得到深紫色的2TPE-2T-BI产品(1.85g),收率为66%。1H NMR(400MHz,CDCl3),δ(ppm):8.03(d,2H,J=4.0Hz),7.40(d,4H,J=8.0Hz),7.26-7.25(m,5H),7.14-7.01(m,33H),2.03(m,4H),1.81(br,2H),1.74(br,4H).13C NMR(100MHz,THF-d8,δ):157.51,145.02,143.67,143.57,143.40,141.38,141.34,140.36,140.13,138.13,138.07,138.04,137.07,136.06,132.19,132.03,131.97,131.96,131.83,131.68,131.63,131.34,131.33,131.28,131.12,131.08,131.00,130.26,129.22,129.15,128.09,127.82,127.78,127.72,127.58,127.56,127.37,127.34,127.32,127.25,127.21,126.62,126.60,126.54,126.51,126.23,126.12,126.09,124.80,124.78,124.37,124.26,124.11,124.11,124.04,124.04,123.61,123.59,107.56,33.12,32.79,24.87,24.80,24.60.HRMS(MALDI-TOF)m/z:[M]+calculated for C72H54N2S2,1010.3728;found,1010.3748.
(4)其他实施例产品,例如2TPA-BI、2TPA-NI或2TPA-2T-NI,合成步骤和条件同上述(1)~(3)中的2TPE-BI、2TPE-T-BI、2TPE-2T-BI的合成。
实施例2:产品的光学和聚集诱导发光特性研究
以三个醌式吸电子基团型荧光产品2TPA-BI、2TPA-T-BI和2TPA-2T-BI作为实施例进行说明,研究其光学性质和聚集诱导发光特性。其它产品同理,不再进行详细赘述。
(1)光学特性和热稳定性的研究
2TPA-BI、2TPA-T-BI和2TPA-2T-BI在四氢呋喃(THF)溶液中的紫外-可见(UV-vis)吸收光谱和光致发光(PL)光谱分别如图2-4所示。三个产品在THF溶液的最大吸收波长分别为470、515和563nm,发射波长分别为590、630和677nm,斯托克斯(Stokes)位移分别为120nm(2TPA-BI)、115nm(2TPA-T-BI)和144nm(2TPA-2T-BI),此大的斯托克斯位移和长的波长发射的特性,作为生物荧光检测技术所需的探针,有利于减弱背景的干扰、降低自吸收的比率,以及提高检测的灵敏度等成像优点。根据扭曲的分子内电荷转移(TICT)特性,此类型分子对溶剂的极性相当敏感,如图5所示,以2TPA-BI为例子,在低极性的正己烷(Hex)溶剂放射波长为559nm,在高极性的二甲基亚砜(DMSO)溶剂放射波长为620nm,因溶剂的极性增加而红位移了61nm。在热稳定性的测试中,如图6所示,裂解温度高达400度以上,三个产品表现出来的高热稳定性,也相当具有作为有机分子发光器件的潜力。
(2)聚集诱导发光特性的研究
利用不同体积比的水和四氢呋喃(THF)溶液环境对2TPA-BI和2TPA-T-BI两个产品进行聚集诱导发光(AIE)特性的研究,以及利用不同体积比的二甲基亚砜(DMSO)和二氧六环溶液环境对2TPA-BI和2TPA-2T-BI产品进行聚集诱导发光(AIE)特性的研究,如图7-12所示,随着不良溶剂(水或二氧六环)体积比率的增加,三个分子因本身的扭曲的分子内电荷转移(TICT)特性,相对的荧光强度先呈现下降,后因聚集诱导发光(AIE)特性,相对荧光强度开始呈现增强现象,这是典型的TICT和AIE相结合的现象,作为荧光探针的设计策略而言,有利于调控出适合体内成像所需的红光及近红外光荧光探针材料,提升体内荧光标记和成像的效果。
(3)荧光寿命测量的研究
荧光材料的荧光寿命与自身的结构、所处微环境的极性、粘度等条件有关,因此通过荧光寿命测定可以直接了解材料在溶液下的单分子状态,以及不良溶剂或固态粉末下的分子聚集状态所发生的变化。如图13和14所示,以2TPA-BI和2TPA-T-BI为例子,两个分子在THF溶液环境分别得到1.80和4.28纳秒的荧光寿命,在固态粉末环境分别得到6.91和3.10纳秒的荧光寿命。研究结果表示,2TPA-T-BI产品在高极性的水环境中,因分子本身过强的TICT效应导致固体荧光寿命稍微低于THF溶液环境的荧光寿命;相较之下,2TPA-BI产品在聚集状态拥有较长的荧光寿命,作为生物荧光探针靶向或堆积在重要细胞器时,分子将因聚集而表达出高的荧光寿命和讯号,相较于溶液下单分子状态的荧光强度,具有较高的检测讯号,这也是典型的AIE特性探针所具备的重要特色,相当具有应用于生物荧光探针的潜值。
(4)固态发光的研究
以2TPA-BI为例子,将产品通过THF和正己烷进行晶体培养,晶体结构如图15-18和表1所示,从晶体数据中观察到:(a)分子构型主要由四苯乙烯(TPE)的给电子基团、醌式的苯并咪唑吸电子基团,以及具有立体位阻的环己烷取代基所构成;(b)晶体单元分别以单斜晶系(monoclinic)构成;(c)分子间主要受分子间π…H(键长为2.613-2.653)和N…H(键长为2.743)的氢键作用力,限制了分子的运动,减弱激发态分子的无辐射能量损失,使得分子以辐射方式释放能量(即荧光或磷光发射),展现出较佳的固态或聚集态发光特性;(d)受到四苯乙烯(TPE)和环己烷所构成的空间位阻效应,分子间以4.489的距离规则排列,无明显的分子间π-π堆积,以至于激发态分子不易因聚集而导致荧光猝灭(ACQ)。如图19-20所示,此数据与分子理论仿真的数据相吻合。这也证明了,拥有环己烷取代的醌式型2TPA-BI产品能在固体或聚集型态展现独特发光特性,相当适合应用于生物成像所需的荧光探针材料。
表1:2TPE-BI的晶体数据汇总。
(5)理论分子模拟的研究
为了深入了解三个产品本身推电子基团和拉电子基团所造成的电子密度分布的状况,以含时间密度泛函理论(TD-DFT)对分子进行理论模拟研究。如图21-26所示,最高被占用分子轨道(HOMO)的电子密度从四苯乙烯(TPE)分布到中心的醌式吸电子基团,相较之下,分子最低空余轨道(LUMO)的电子密度主要集中在中心的醌式吸电子基团,由此证明本发明所提出的醌式吸电子基团具有相当好的拉电子能力,搭配不同的给电子基团和间隔基团,容易对分子进行吸收与发射波长的调控,藉此得到具有更长波长发射的材料。
实施例3:产品在体外癌细胞和体内肿瘤组织标记和成像的应用
(1)聚集诱导发光型纳米颗粒(AIE dots)的制备
如图27所示,将能放射出近红外光的2TPE-2T-BI产品、两性化合物DSPE-PEG,以及带有生物正交反应的DBCO官能基的DSPE-PEG-DBCO分子,于磷酸缓冲盐溶液(PBS)环境进行纳米粒子成型(Nanoprecipitation)而得到具有生物正交反应能力的DBCO-AIEdots纳米粒子。如图28所示,DBCO-AIEdots纳米探针的吸收和发射波长分别从572和710nm延伸至近红外光区域,其最大的斯托克斯位移为138nm。此外,如图29-30所示,DBCO-AIEdots纳米粒子的粒径大小介在85纳米,相当适合应用于体内标记与成像的血液循环过程。
(2)细胞培养
人乳腺癌细胞(MCF-7)由ATCC提供。MCF-7细胞在10%热灭活的胎牛血清(FBS)和1%青霉素的改性型培养基(MEM)培养基中培养,并且在37℃含有5%CO2的湿化孵化器中保持。在实验前,细胞预先培养至达到融合。MCF-7细胞在增补10%FBS和青霉素的MEM培养基中的盖玻片上生长。
(3)体外细胞的代谢标记
将MCF-7细胞置放于含有50μM化学修饰后的非天然葡萄糖(Ac4ManNAz)的8孔板,并且在37℃含有5%CO2的湿化孵化器中孵育三天。此外,另外培养一组不含Ac4ManNAz的MCF-7细胞作为参比。
(4)荧光探针染色和细胞成像
使用磷酸缓冲盐溶液(PBS)冲洗细胞两次,细胞在DBCO-AIEdots纳米探针的MEM培养基中再培养30分钟,接着,将荧光标记的细胞安装在标准的安装介质上,通过共聚焦激光扫描显微镜进行细胞成像。DBCO-AIEdots产品所选择的激发波长皆为575nm,发射长波通滤波器波长为600–750nm;商业细胞核探针(DAPI)的激发波长条件为488nm,发射长波通滤波器波长为490–600nm。如图31–32所示,只有经过Ac4ManNAz处理过的MCF-7细胞才能与DBCO-AIEdots纳米探针进行生物正交反应,于细胞核周围出现荧光讯号,参见图31,未经Ac4ManNAz处理过的MCF-7细胞则无荧光讯号,参见图32。初步验证,DBCO-AIEdots纳米探针于体外具有对Ac4ManNAz标记的MCF-7癌细胞进行生物正交反应(Biorthogonal reaction)的能力。
(5)体内肿瘤组织的标记与成像研究
雌性BALB/c裸鼠主要由北京维通利华实验动物技术有限公司所提供,该实验工作由中国科学院深圳先进技术研究院协助完成。将MCF-7细胞植入裸鼠,进行大约两周的肿瘤接种。当肿瘤生长到大约50平方毫米后,于裸鼠的尾静脉连续四天注射化学修饰后的非天然葡萄糖(Ac4ManNAz),同时,另外一组参比的裸鼠则注射相同体积的生理盐水。三天后,从裸鼠的尾静脉注射DBCO-AIEdots纳米探针,并且于小动物荧光成像仪检测不同时间的体内荧光讯号。如图33–34所示,经过24小时后,只有注射过Ac4ManNAz的裸鼠肿瘤组织出现明显的DBCO-AIEdots荧光讯号,参见图33,未注射Ac4ManNAz的裸鼠肿瘤组织则无荧光讯号,参见图34。进一步将肿瘤组织和重要器官(心脏、肝脏、脾脏、肺脏、肾脏)进行小动物荧光成像仪检测,如图35–36所示,注射过Ac4ManNAz的裸鼠的肿瘤组织明显呈现较强的荧光讯号,参见图35。
本发明的基于醌式吸电子基团型化合物所构成的DBCO-AIEdots纳米探针产品,能透过生物正交反应,成功在体外或体内对癌细胞和肿瘤组织进行标记与成像,此外,由于DBCO-AIEdots纳米探针主要由近红外发射能力的2TPE-2T-BI分子所构成,有助于提升体内荧光监测的深度组织穿透、高信躁比和较少的生物光损伤。此外,本发明在材料制备上具有简易的优点,更能突显本发明的醌式吸电子基团型荧光探针具有相当大的竞争力。
本发明仅以MCF-7细胞为实施例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进或变换都应属于本发明所附权利要求的保护范围内,内容包含对其它肿瘤细胞(如HeLa细胞或MDA-MB-231细胞)或正常细胞(如COS-7细胞或MDCK-II细胞)进行标记成像、对淡水或咸水类海藻的进行标记成像,或是采用醌式吸电子基团型化合物包覆成纳米探针在生物学上的应用。此外,考虑到该类化合物良好的固态发光性质,可作为发光层,有望用于有机发光二极管装置。
本发明所包含的信息,在未脱离下述权利要求的精神和保护范围下,本发明各种偏离精确的描述,对于与本发明相关的本领域技术人员来说是显而易见的。本发明并不认为限制在所定义的程序、性质或组成的范围内,因为优选的实施例和其他描述只用于说明目前提供发明的特定方面。对于在化学、生物化学或相关领域的技术人员来说,实现本发明于各种修改的描述模式,都应属于本发明所附权利要求的保护范围内。
应当理解的是,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进或变换都应属于本发明所附权利要求的保护范围之内。
Claims (4)
2.权利要求1所述的化合物在搭配生物正交反应的官能基团制备用于聚集诱导发光型纳米探针的应用以及在搭配生物正交反应的官能基团制备用于标记癌细胞或肿瘤组织的生物荧光探针中的应用;所述生物正交反应的官能基团包括八元环炔基、含氟原子的八元环底物和双苯并八元环炔。
3.权利要求1所述的化合物在制备聚集诱导发光型纳米探针中的应用以及在制备用于标示肿瘤细胞、正常细胞、淡水藻、咸水类海藻、辨识细菌的荧光探针、发光二极管、光电放大器、光信息存储器、液晶显示器、光波导材料、生物传感器或逻辑门、无损读出的生物探针中的应用。
4.权利要求1所述的化合物在制备用于肿瘤组织标记的聚集诱导发光型纳米探针中的应用以及在制备用于预防和治疗肿瘤疾病的生物医学领域的诊疗一体化的药物和/或药物组合物中的应用。
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