CN115232145B - 一种aie型有机光敏剂及其合成方法和应用 - Google Patents
一种aie型有机光敏剂及其合成方法和应用 Download PDFInfo
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
本发明属于有靶向能力的有机光敏剂技术领域,公开了一种AIE型有机光敏剂及其合成方法和应用,本发明以三苯胺为电子供体,吡啶盐为电子受体,噻吩为电子π桥,合成了一系列新型的生物素受体和线粒体双靶向的AIE型有机光敏剂。生物素基团的引入能够有效地增强光敏剂对肿瘤细胞的选择性,另一方面,带正电的吡啶盐离子基团的存在可以使光敏剂进入癌细胞后主动靶向线粒体这一重要细胞器,进而提高了光敏剂的光动力治疗作用。综合这两方面的作用,使得其在肿瘤光动力治疗药物中有很好的应用前景。
Description
技术领域
本发明属于有靶向能力的有机光敏剂技术领域,具体涉及一种AIE型有机光敏剂及其合成方法和应用。
背景技术
癌症作为高死亡率、高侵袭率、高复发率的疾病,威胁到了越来越多人们的生命健康。手术、化疗和放疗作为传统的治疗手段在治疗效果上仍然很糟糕,并伴有不可避免的副作用。因此,开发有效的癌症治疗方法具有重要意义,同时也具有挑战性。光动力疗法(PDT)是近年来出现的一种很有前途的癌症治疗方法,具有无创性、低毒性、无初始耐药性等优点。
PDT采用光激发光敏剂(PSs),通过I型(电子转移)或II型(能量转移)光化学机制产生高细胞毒性活性氧(ROS),ROS能迅速与生物物质相互作用,诱导癌细胞死亡,从而产生治疗作用。Ⅰ型PDT通过超氧化物歧化酶和芬顿反应产生具有细胞毒性的O2-·和OH·,还可以原位产生额外的氧气,有效改善肿瘤缺氧环境;Ⅱ型PDT则是光敏剂将吸收来的能量传递给周围环境中的氧,生成高毒性的单线态氧,是一种高度依赖氧气的治疗方式。线粒体作为真核细胞中重要的能量工厂,不仅参与细胞内的氧化磷酸化循环,还参与细胞信号传递、细胞生长、细胞自噬以及细胞凋亡等。线粒体损伤或杀死宿主至少有三种主要机制,即通过产生ROS或促炎信号或通过线粒体膜通透性。有趣的是,线粒体作为能量来源,对PDT产生的ROS更加敏感,在PDT诱导细胞凋亡的早期就会受到损伤。
荧光成像技术在生物体内的应用极为广泛,凭借其快速响应、出色的时间分辨率、卓越的灵敏度、操作简单和良好的重现性等优点成为不可缺少的可视化分析工具。与可见光相比,近红外(NIR)荧光成像被认为更利于生物成像,对细胞的光损伤更小,光散射更低,穿透深度更深,信噪比更高。而常见的有机小分子荧光探针(如卟啉、酞菁等)因其平面刚性π共轭结构和较差的水溶性导致聚集荧光猝灭(ACQ)和ROS产生不足,极大的影响了它们在光动力治疗中的应用。由唐本忠院士提出的AIE分子因其在聚集态下表现出明亮的荧光发射和优秀的ROS产生能力,很好的解决了荧光猝灭和ROS产生能力不足的问题。
传统的有机光敏剂还存在着靶向性不足的问题,对于正常细胞和癌细胞没有区分能力,生物素受体在快速增殖的癌细胞表面常表现为过度表达。因此在光敏剂分子结构中引入生物素基团,可以与肿瘤细胞表面过表达的受体相结合,达到增强光敏剂靶向能力的效果。
因此,为了开发具有优异光动力治疗效果的光敏剂,本发明人设计并合成一类基于生物素受体和线粒体双靶向的AIE型有机光敏剂。
发明内容
本发明旨在解决现有技术中存在的技术问题,本发明的目的是提供一种AIE型有机光敏剂及其合成方法和应用。
为达到上述目的,本发明采用如下技术方案:一种AIE型有机光敏剂,其结构通式如下:
其中:X为S,R为H、卤素、C1~C20的直链烷氧基或C1~C20的支链烷氧基。
一种AIE型有机光敏剂,包括如下合成方法:步骤1,在氩气保护下,将1摩尔份化合物1、1.5摩尔份5-醛基-2-噻吩硼酸频那醇酯溶解在1,4-二氧六环中,加入3摩尔份K2CO3水溶液和5%的催化剂Pd(PPh3)4,得反应液,反应液在惰性气体氩气保护下于100℃搅拌反应12小时,反应结束并冷却至室温后,向反应液中加入水,用DCM萃取,合并有机相并用水洗多次,加无水硫酸镁干燥,减压旋蒸浓缩,粗产物通过柱层析分离提纯,制得化合物2;
步骤2,在氩气保护下,以无水乙醇为溶剂,加入1摩尔份化合物2,1摩尔份化合物3,0.2mL哌啶,加热至回流搅拌反应24小时,反应结束并冷却至室温后,减压旋蒸浓缩,粗产物通过氧化铝柱层析分离提纯,制得化合物4;
步骤3,在氩气保护下,以N,N-二甲基甲酰胺为溶剂,加入1摩尔份化合物4,2摩尔份羧烷基取代的生物素,5摩尔份缩合剂HATU,3摩尔份碳酸铯,常温搅拌反应12小时,反应结束后,得合成液,往合成液中加入水,用DCM萃取,合并有机相并用水洗多次,加无水硫酸镁干燥,减压旋蒸浓缩,粗产物通过柱层析分离提纯,得到AIE型有机光敏剂。
一种AIE型有机光敏剂的应用,将AIE型有机光敏剂应用于制备肿瘤光动力治疗药物。
一种AIE型有机光敏剂的应用,将AIE型有机光敏剂应用于制备靶向肿瘤细胞及靶向细胞器线粒体的靶向药物。
在本发明的一种优选实施方式中,所述的R=H,X=S。
在本发明的一种优选实施方式中,AIE型有机光敏剂具有近红外聚集诱导发光性质,且AIE型有机光敏剂在白光照射下能产生活性氧。
本发明的有益效果以及原理:1、光敏剂中具有螺旋桨结构的三苯胺转子的存在使得该类分子具有典型的AIE特性。
2、本发明所述的光敏剂显示出近红外荧光发射性能,对于深层组织的成像和光动力治疗都有较好的帮助。
3、相比于无生物素受体靶向的有机光敏剂,通过引入生物素基团构建的生物素受体和线粒体双靶向的AIE型光敏剂具有对生物素受体高表达肿瘤细胞有更好的选择性,可以减弱光敏剂对正常细胞造成的杀伤作用。
4、本发明所述的光敏剂能够进入细胞发出红色荧光并靶向线粒体。
5、本发明所述的光敏剂具很强的ROS产生效率。
6、该类光敏剂的细胞暗毒性可忽略不计,在LED白光灯的照射条件下显示出很强的光毒性,说明该类光敏剂安全性高,光动力治疗效果好。
7、本发明所述的光敏剂的原料易得,合成简单。未见报道类似的用于光动力治疗的光敏剂,具有较强的商业价值。
与商业化的用于肿瘤光动力治疗的光敏剂和已报道的一些有机光敏剂相比,本发明具有如下优点和技术效果:通过在分子中引入生物素基团可以起到选择性靶向肿瘤细胞增强光敏剂对肿瘤细胞杀伤作用的效果,提高了该类光敏剂的光动力治疗效果。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1为本发明的有机光敏剂的合成路线图;
图2中a)为实施例中所合成的染料TSPy-B在DMSO/toluene溶剂中不同DMSO/toluene体积比下的荧光发射图,b)为实施例中所合成的染料TSPy-CH3在相同条件下的荧光发射图,c)为不同DMSO/toluene体积比下的相对荧光强度变化图,d)为αAIE(Iaggr,max/Isolu);
图3中a)为实施例中所合成的染料在DMSO溶剂中的液体紫外吸收光谱图,b)为实施例中所合成染料在DMSO/toluene=1/99体系中的聚集态荧光发射光谱图;
图4中a)为实施例中合成的染料TSPy-B在白光灯照射下使ROS指示剂DCFH-DA的荧光强度增强图,b)为实施例中合成的染料TSPy-CH3在相同条件使DCFH-DA的荧光增强图片,c)为商业染料Rose Bengal在相同条件使DCFH-DA的荧光增强图片;
图5为实施例中合成的染料TSPy-B在HeLa细胞内与线粒体商业染料MitoTrackerGreen的共定位荧光图;
图6为实施例中合成的染料TSPy-B和TSPy-CH3在HeLa细胞和COS-7细胞中的光毒性及暗毒性数据图;
图7为实施例中合成的染料TSPy-B和TSPy-CH3在HepG2细胞和COS-7细胞中的共孵育摄取实验数据图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作进一步地详细描述。
实施例1
本发明提供了一种AIE型有机光敏剂,其结构通式如下:
其中:X为S或O,R为H、卤素、C1~C20的直链烷氧基或C1~C20的支链烷氧基。
实施例2
一种AIE型有机光敏剂(TSPy-B)的合成方法,包括如下步骤:
步骤1,在氩气的保护下,取一个50mL的二口圆底烧瓶,加入20mL 1,4-二氧六环(1,4-Dioxane)作为溶剂,并将324mg(1.0mmol)化合物1和394mg(1.2mmol)5-醛基-2-噻吩硼酸频那醇酯,3mL 2M的K2CO3水溶液加入其中,然后再加入60mg的Pd(PPh3)4作为催化剂。将反应液均匀混合后升温至100℃反应12h。反应结束,得反应液,将反应液冷却至室温,往反应液中加入30mL去离子水,并用二氯甲烷萃取多次。萃取合并所得有机相,加入无水硫酸镁干燥后过滤,旋蒸除去有机溶剂,得到粗产物。粗产物以(正己烷/乙酸乙酯,v/v=5/1)为流动相,用硅胶柱层析进行分离提纯,得到0.51g红色固体化合物2,产率为74%。制得化合物2。核磁:1H NMR(400MHz,CDCl3)δ9.89(s,1H),7.74(d,J=3.9Hz,1H),7.55(d,J=3.9Hz,1H),7.34(t,J=7.8Hz,5H),7.20–7.09(m,9H)。本实施例中,化合物1结构通式,如下:
化合物2的分子式,如下:
化合物2的合成化学式如下:
步骤2,在氩气的保护下,取一个50mL的二口圆底烧瓶,加入20mL无水乙醇作为溶剂,将355mg(1mmol)化合物2,294mg(1.2mmol)化合物3和0.2mL哌啶加入其中。将反应液均匀混合后,升温至80℃反应24h。反应结束,待反应液降至常温,得到粗产物。粗产物以(二氯甲烷/甲醇v/v=10/1)作为流动相,用中性氧化铝柱层析分离提纯,得到326mg深红色化合物4。产率为63%。核磁:1H NMR(400MHz,DMSO-d6)δ8.90(d,J=5.9Hz,2H),8.18(t,J=12.7Hz,3H),7.60(d,J=8.2Hz,2H),7.48(s,2H),7.32(t,J=7.4Hz,4H),7.15–7.02(m,7H),6.95(d,J=8.2Hz,2H),4.45(t,J=6.5Hz,2H),2.58(d,J=5.7Hz,2H),2.02–1.82(m,2H),1.37(dd,J=12.6,6.4Hz,2H)。
本实施例中,化合物3的分子式如下:
本实施例中,化合物4的分子式如下:
本实施例中,化合物4的合成化学式如下:
步骤3,在一个50mL的圆底烧瓶中,依次加入,将582.6mg(1mmol)化合物3,488mg(2.0mmol)的生物素、1.9g(5.0mmol)的HATU以及978mg(3mmol)的碳酸铯加入其中,用20mLN,N-二甲基甲酰胺(DMF)作为溶剂。将合成液均匀混合后,常温反应24h。反应结束,向合成液中加入30mL去离子水,并用二氯甲烷萃取多次。萃取合并所得有机相,加入无水硫酸镁干燥后过滤,旋蒸除去有机溶剂,得到粗产物。粗产物用(二氯甲烷/甲醇v/v=25/1)作为流动相,用中性氧化铝柱层析分离提纯,得到417mg深红色光敏剂TSPy-B。产率为75%。核磁:1HNMR(400MHz,DMSO-d6)δ8.89(d,J=6.8Hz,2H),8.20(t,J=12.1Hz,3H),7.90(t,J=5.7Hz,1H),7.62(d,J=8.7Hz,2H),7.50(q,J=3.9Hz,2H),7.35(t,J=7.9Hz,4H),7.18–7.04(m,8H),6.98(d,J=8.7Hz,2H),6.39(d,J=16.4Hz,2H),4.48(t,J=7.1Hz,2H),4.36–4.23(m,1H),4.15–4.06(m,1H),3.07(dd,J=12.5Hz,3H),2.80(dd,J=12.4Hz,1H),2.56(d,J=12.4Hz,1H),2.05(t,J=7.3Hz,2H),1.86(dd,J=14.8Hz,2H),1.60–1.26(m,8H)。
本实施例中,有机光敏剂TSPy-B的合成化学式,如下:
无生物素受体靶向的AIE型有机光敏剂TSPy-CH3的合成方法,如下:
光敏剂TSPy-CH3的合成
在一个50m L的圆底烧瓶中,依次加入,将5 82.6mg(1m m o l)化合物3,1 20mg(2.0mmol)的醋酸、1.9g(5.0mmol)的HATU以及978mg(3mmol)的碳酸铯加入其中,用20mL N,N-二甲基甲酰胺(DMF)作为溶剂。将反应液均匀混合后,常温反应24h。反应结束,往反应液中加入30mL去离子水,并用二氯甲烷萃取多次。萃取合并所得有机相,加入无水硫酸镁干燥后过滤,旋蒸除去有机溶剂,得到粗产物。粗产物用(二氯甲烷/甲醇v/v=100/1)作为流动相,用硅胶柱层析分离提纯,得到366mg深红色光敏剂TSPy-CH3。产率为79%。核磁:1H NMR(400MHz,DMSO-d6)δ8.82–8.78(m,1H),8.20(t,J=11.1Hz,3H),7.90(s,1H),7.63(d,J=8.6Hz,2H),7.51(dd,J=8.0,3.8Hz,2H),7.36(t,J=7.8Hz,4H),7.20–7.07(m,7H),6.99(d,J=8.6Hz,2H),4.47(t,J=7.3Hz,2H),3.06(dd,J=12.8,6.5Hz,2H),1.96–1.85(m,2H),1.79(s,3H),1.38(td,J=14.5,7.3Hz,2H。
实施例3
对实施例1的光敏剂TSPy-B和TSPy-CH3进行了AIE性能测试,如图2所示。基于生物素受体和线粒体双靶向的AIE型有机光敏剂TSPy-B和无生物靶向的AIE型有机光敏剂TSPy-CH3在DMSO/toluene中测试了它们的AIE性能。从图2中a)、b)和c)中可以看出随着toluene体积的增加,溶液的荧光强度逐渐增强。在图2中d)中可以看到,TSPy-B荧光强度最大增强了196.7倍;TSPy-CH3增加了358倍。这说明两个光敏剂具有很好的AIE性能。
实施例4
对实施例1的光敏剂TSPy-B和TSPy-CH3进行了液体紫外和聚集态荧光测试。如图3所示。染料TSPy-B和TSPy-CH3在DMSO中的紫外可见吸收光谱如图3中a)所示,TSPy-B和TSPy-CH3的最大吸收波长为480nm,吸收光谱覆盖了大部分的可见光区。图3中b)为染料TSPy-B和TSPy-CH3在DMSO/toluene=1/99体系中的聚集态荧光发射光谱图,染料的荧光发射峰在630nm,具有很好的荧光发射性能。
实施例5
对实施例1的光敏剂TSPy-B和TSPy-CH3进行了ROS产生能力的检测实验,如图4所示。DCFH-DA是ROS的指示剂,从图4中a)和b)中可以发现染料TSPy-B和TSPy-CH3在光照条件下使溶液在525nm处的荧光快速增强。图4中c)为商业化染料Rose Bengal在光照条件下使DCFH-DA荧光增强的图片。比较图4中a)、b)和c)图,很明显光敏剂TSPy-B和TSPy-CH3的ROS产生效率要高于商业染料Rose Bengal,这说明光敏剂TSPy-B和TSPy-CH3显示出了优异的ROS产生性能。
实施例6
对实施例1的光敏剂TSPy-B进行了细胞成像和线粒体靶向染料的荧光共定位实验,如图5所示。用2μM的TSPy-B孵育HeLa细胞30分钟,并用线粒体商业染料MitoTrackerGreen进行共定位确认光敏剂的靶向位置。从图5中A中可以发现,光敏剂TSPy-B能够很好的进入HeLa细胞并发射红色荧光。从图5中D中可以发现,光敏剂TSPy-B和线粒体商业染料的荧光重叠度高,这说明光敏剂TSPy-B能很好的靶向细胞器线粒体。
实施例7
对实施例1的光敏剂TSPy-B和TSPy-CH3进行了光毒性和暗毒性研究,分别采用了生物素受体高表达的HeLa细胞和生物素受体低表达的COS-7细胞,如图6所示。96孔板分别用图6所示浓度的光敏剂孵育HeLa细胞和COS-7细胞24小时,细胞分为四组,一组为HeLa细胞白光照射10分钟,一组为HeLa细胞无光照;另外两组为COS-7细胞白光照射10分钟和COS-7细胞无光照。从图中可以发现光敏剂TSPy-B和TSPy-CH3在暗态下均具有很小的细胞毒性,而在光照条件下则显示出了很高的光毒性,其中对于生物素受体高表达的HeLa细胞,相同浓度下TSPy-B的毒性高于TSPy-CH3;而对于生物素受体低表达的COS-7细胞,相同浓度下TSPy-CH3的毒性高于TSPy-B,实验说明光敏剂TSPy-B可以更有效的杀伤生物素受体高表达的肿瘤细胞,减少对正常细胞的毒性,具有很好的肿瘤光动力治疗效果。
实施例8
对实施例1的光敏剂TSPy-B和TSPy-CH3进行了不同细胞的共孵育摄取实验,分别采用了生物素受体高表达的HepG2细胞和生物素受体低表达的COS-7细胞,如图7所示。将HepG2细胞铺板于共聚焦小皿中的爬片上培养24h,次日将COS-7细胞加进爬片上培养24h,将5μM TSPy-B和TSPy-CH3分别孵育2h。从图7中a)中可以看到HepG2细胞和COS-7细胞对TSPy-CH3的摄取没有差别;而在图7中b)中可以看到HepG2细胞和COS-7细胞对TSPy-B的摄取有显著的区别,HepG2细胞对TSPy-B的摄取要显著高于COS-7对TSPy-B的摄取。实验说明TSPy-B对生物素受体高表达的细胞有更高的选择性。
以上所述的仅是本发明的实施例,方案中公知的具体结构和/或特性等常识在此未作过多描述。应当指出,对于本领域的技术人员来说,在不脱离本发明结构的前提下,还可以作出若干变形和改进,这些也应该视为本发明的保护范围,这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准,说明书中的具体实施方式等记载可以用于解释权利要求的内容。
Claims (4)
1.一种AIE型有机光敏剂,其特征在于:结构如下:
2.一种根据权利要求1所述的AIE型有机光敏剂的合成方法,其特征在于:
步骤1,在氩气保护下,将1摩尔份化合物1、1.5摩尔份5-醛基-2-噻吩硼酸频那醇酯溶解在1,4-二氧六环中,加入3摩尔份K2CO3水溶液和5%的催化剂Pd(PPh3)4,得反应液,反应液在惰性气体氩气保护下于100℃搅拌反应12小时,反应结束并冷却至室温后,向反应液中加入水,用DCM萃取,合并有机相并用水洗多次,加无水硫酸镁干燥,减压旋蒸浓缩,粗产物通过柱层析分离提纯,制得化合物2;
其中,化合物1的结构如下:
其中,化合物2的结构如下:
步骤2,在氩气保护下,以无水乙醇为溶剂,加入1摩尔份化合物2,1摩尔份化合物3,0.2mL哌啶,加热至回流搅拌反应24小时,反应结束并冷却至室温后,减压旋蒸浓缩,粗产物通过氧化铝柱层析分离提纯,制得化合物4;
其中,化合物3的结构如下:
其中,化合物4的结构如下:
步骤3,在氩气保护下,以N,N-二甲基甲酰胺为溶剂,加入1摩尔份化合物4,2摩尔份羧烷基取代的生物素,5摩尔份缩合剂HATU,3摩尔份碳酸铯,常温搅拌反应12小时,反应结束后,得合成液,往合成液中加入水,用DCM萃取,合并有机相并用水洗多次,加无水硫酸镁干燥,减压旋蒸浓缩,粗产物通过柱层析分离提纯,得到权利要求1所述的AIE型有机光敏剂。
3.一种AIE型有机光敏剂的应用,其特征在于:将权利要求1所述的AIE型有机光敏剂应用于制备肿瘤光动力治疗药物。
4.一种AIE型有机光敏剂的应用,其特征在于:将权利要求1所述的AIE型有机光敏剂应用于制备靶向肿瘤细胞及靶向细胞器线粒体的靶向药物。
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