CN117466885A - 一种基于吩噻嗪结构有机染料及其合成方法和应用 - Google Patents
一种基于吩噻嗪结构有机染料及其合成方法和应用 Download PDFInfo
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Abstract
本发明属于荧光探针及光动力(PDT)治疗应用领域,具体涉及一种基于吩噻嗪结构有机染料及其合成方法和应用。本发明以吩噻嗪及4,4'‑二甲氧基三苯胺为电子供体,甲基吡啶盐为电子受体,以吩噻嗪为反应位点合成了一种基于吩噻嗪结构用于检测次氯酸根及肿瘤光动力治疗的有机染料,该染料为本发明首次合成,原料易得,过程简单,可产业化。且该染料对次氯酸根的检测具有高选择性和高灵敏度,能够实现对次氯酸根的快速检测,并伴随有荧光开启的现象,能对肿瘤细胞,如HeLa细胞,特异性成像,同时该染料在光照条件下产生活性氧(ROS),可用于荧光成像引导的肿瘤光动力治疗效果,其在生物医学领域的次氯酸根信号分子的检测和肿瘤光动力治疗中具有广泛的价值。
Description
技术领域
本发明属于荧光探针及光动力治疗应用领域,具体涉及一种基于吩噻嗪结构有机染料及其合成方法和应用。
背景技术
次氯酸或次氯酸盐(HClO/ClO-),是由过氧化氢和氯离子在髓过氧化物酶(MPO)的催化作用下产生的,是生物体内存在的活性氧物质之一。同时它作为一种炎症物质,高浓度存在于肿瘤细胞中。ClO-的异常积聚与肿瘤的发病机制密切相关。因此,实现生物体内尤其是肿瘤细胞内ClO-含量的检测具有十分重要的意义。目前已经提出了多种传统ClO-检测方法,例如碘量滴定、电化学分析、电位分析、色谱法、和比色化学传感器等。其中,荧光分析法相比于传统的检测方法具有选择性好,较高的时间空间分辨率和高灵敏度等优势而受到了广泛关注。
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。光动力疗法是一种开创性的有效抗癌模式,它依赖于光活化光敏剂(PSs)来产生细胞毒性活性氧。PDT用于癌症治疗,具有低副作用、高选择性,在临床应用中具有广阔前景。因此,开发有效的用于癌症诊断及治疗的方法具有重要意义。
相较于正常细胞,肿瘤细胞中,如宫颈癌(HeLa)细胞,含有相对更高浓度的ClO-。因此可利用该特征实现正常细胞与肿瘤细胞的区分及成像。迄今为止,已经报道了一些有机小分子荧光探针用于ClO-的分析检测,然而此类有机小分子探针仅可用细胞成像而很少被用于成像引导的PDT,同时大部分PSs不具备对肿瘤细胞特异性成像的能力。
吩噻嗪是一种非平面“蝴蝶”型结构的杂环化合物,作为荧光团母核具有易于官能团化、斯托克斯位移大等优点。吩噻嗪母核中硫原子容易被ClO-氧化成亚砜(S=O)。因此,可通过该特性设计并合成一类基于吩噻嗪结构的荧光探针,合成出的探针既具有特异性识别ClO-并成像肿瘤细胞,同时兼有荧光成像引导的肿瘤光动力治疗能力。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足,而提供一种基于吩噻嗪结构有机染料及其合成方法和应用。
本发明的第一个方面是提供一种基于吩噻嗪结构的有机染料,该有机染料的结构通式为:
其中,X为S或O,R为H或卤素或C1~C20的直链烷氧基或C1~C20的支链烷氧基。
优选的,其中R为OCH3,X为S。
本发明的第二个方面是提供如上所述的基于吩噻嗪结构的有机染料的合成方法,包括以下步骤:
(1)化合物1和化合物3反应得到化合物2;
(2)将化合物2与1,4-二甲基吡啶-1-鎓碘化物反应得到如权利要求1或2所述的基于吩噻嗪结构的有机染料。
化合物1的结构式为:
化合物3的结构式为:
化合物2的结构式为:
优选的,步骤(1)中,在惰性气体保护下,将化合物1和化合物3溶解在1,4-二氧六环中,加入Cs2CO3和催化剂,反应液在惰性气体保护下搅拌反应,反应结束后,萃取干燥,分离提纯得到化合物2。
优选的,化合物1、化合物3、Cs2CO3和催化剂的摩尔比为1:2.1:3:0.05。
优选的,所述催化剂为Pd(PPh3)4。
优选的,步骤(2)中,在惰性气体保护下,以无水乙醇为溶剂,加入化合物2、1,4-二甲基吡啶-1-鎓碘化物、哌啶,加热至回流搅拌反应,反应结束并冷却,浓缩提纯后得到所述基于吩噻嗪结构的有机染料。
优选的,化合物2、1,4-二甲基吡啶-1-鎓碘化物的摩尔比为1:3。
本发明的第三个方面提供了一种如上所述的一种基于吩噻嗪结构的有机染料用于检测次氯酸根的应用,所述吩噻嗪结构有机染料与次氯酸根作用之后,出现荧光开启现象。
本发明的第四个方面提供了一种如上所述的有机染料用于制备肿瘤光动力治疗药物的应用,所述的吩噻嗪型结构有机染料能够通过光照杀死肿瘤细胞,所述的肿瘤细胞包括宫颈癌细胞和肝癌细胞。
本发明的有益效果体现在:
(1)本发明以吩噻嗪及4,4'-二甲氧基三苯胺为电子供体,甲基吡啶盐化合物为电子受体,以吩噻嗪为反应位点合成了一类新型用于次氯酸根检测的有机染料。该有机染料为本发明首次合成,原料易得,过程简单,可产业化,具有较强的商业价值。
(2)本发明提供的有机染料在EtOH/H2O(v/v=1/1)溶液中与ClO-作用之后,紫外可见吸收光谱和荧光发射光谱都发生了明显的变化,因此该类有机染料可以实现对次氯酸根的可视化检测。
(3)本发明提供的有机染料对次氯酸根的检测具有良好的选择性和抗干扰能力,H2O2,·OH,tBUOO-,tBUOOH,1O2,NO,谷胱甘肽(GSH),半胱氨酸(Cys),高半胱氨酸(Hcy),谷氨酸(Glu),组氨酸(His),K+,Na+,Fe2+,Mg2+,SO4 2-,S2O5 2-,HSO3 -,F-,Cl-等离子、生物硫醇和氨基酸都不会对该染料对ClO-的检测造成干扰。
(4)本发明提供的有机染料对次氯酸根的检测具有很高的灵敏度,达到了纳摩尔级别,这为细胞内源性次氯酸根的检测提供了支持。
(5)本发明提供的有机染料能够快速的进入细胞,并实现HeLa细胞中内外源性ClO-的检测。
(6)本发明提供的有机染料具很强的ROS产生效率,显示出比商业染料RoseBengal更强的ROS产生效率,另外在细胞内也可以明显检测到ROS的产生;
(7)本发明提供的有机染料具有较低的细胞暗毒性,而在白光照射下显示出了很强的光毒性,说明这类光敏剂生物安全性高,光动力治疗效果优异;
综上所述,本发明提供一种基于吩噻嗪结构的有机染料,该有机染料制备简单,对次氯酸根的检测具有高选择性和高灵敏度,能够实现对次氯酸根的快速检测,并伴随有荧光开启的现象,能对肿瘤细胞特异性成像。同时该染料在被次氯酸根响应前后均可在光照条件下产生ROS,即具有光动力能力,可起到荧光引导的光动力以杀灭肿瘤细胞的治疗效果,其在生物医学领域的次氯酸根信号分子的检测和肿瘤及光动力治疗中具有广泛的应用价值。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,根据这些附图获得其他的附图仍属于本发明的范畴。
图1为实施例1的合成路线图;
图2A为实施例1中所合成的有机染料在EtOH/H2O(v/v=1/1)溶剂中(染料浓度:10μM)与ClO-(100μM)响应前后的紫外可见吸收光谱图,图2B为染料在EtOH/H2O(v/v=1/1)溶剂中(染料浓度:10μM)与ClO-(100μM)响应前后的荧光发射光谱图;
图3A为实施例1中所合成的有机染料在EtOH/H2O(v/v=1/1)溶剂中(染料浓度:10μM)与ClO-(100μM)或其他测试样品(100μM)存在的荧光强度柱状图,图3B为染料在EtOH/H2O(v/v=1/1)(浓度:10μM)与ClO-(100μM)和其他测试样品(100μM)共同存在反应后的荧光强度柱状图;测试样品:H2O2(1),·OH(2),tBUOO-(3),tBUOOH(4),1O2(5),NO(6),GSH(7),Cys(8),Hcy(9),L-Glu(10),L-His(11),K+(12),Na+(13),Fe2+(14),Mg2+(15),SO4 2-(16),S2O5 2-(17),HSO3 -(18),F-(19),Cl-(20),ClO-(21),Blank(22);
图4A为实施例1中合成的有机染料(10μM)与不同浓度ClO-(0,10,,30,50,70,80,90,95,100μM)反应后的荧光光谱变化图,图4B为实施例1中合成的有机染料(10μM)的荧光强度与ClO-浓度(2-10μM)的线性关系图;
图5A为实施例1中合成的染料TPTPy在白光灯照射下使ROS指示剂DCFH-DA的荧光强度变化图,图5B为实施例1中合成的染料TPTPy在被ClO-响应后在相同条件使DCFH-DA的荧光变化图片,图5C为商业染料Rose Bengal在相同条件使DCFH-DA的荧光变化图片,图5D为仅加入ClO-在相同条件使DCFH-DA的荧光变化图片;
图6为实施例1中合成的染料TPTPy在正常人脐静脉内皮细胞细胞(HUVEC)和宫颈癌细胞(HeLa)中与内外源性ClO-反应后的荧光共聚焦图,(A1-A3)HeLa细胞用TPTPy(10μM)培养2h;(B1-B3)HeLa细胞先加NAC(100μM)培养0.5h,再加入TPTPy(10μM)培养2h;(C1-C3)HeLa细胞先加NaClO(100μM)培养0.5h,再加入TPTPy(10μM)培养2h;(D1-D3)HeLa细胞先加NAC(100μM)培养0.5h,再加入加NaClO(100μM)培养0.5h,最后加入TPTPy(10μM)培养2h,(E1-E3)HUVEC细胞用TPTPy(10μM)培养2h。
图7为实施例1中合成的有机染料在HeLa细胞中由白光灯照射不同时间使ROS指示剂DCFH-DA增强的荧光成像图;
图8为实施例1中合成的有机染料TPTPy在HeLa细胞中的光毒性及暗毒性数据图。
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
一种基于吩噻嗪结构有机染料用于次氯酸根的检测和肿瘤光动力治疗TPTPy的合成。
(1)化合物2的合成
取一个50mL的二口圆底烧瓶,加入15mL 1,4-二氧六环(1,4-Dioxane)及5mL超纯水作为溶剂,并将658mg(1.0mmol)化合物1和499mg(2.1mmol)5-醛基-2-噻吩硼酸频那醇酯,再加入975mg(3.0mmol)Cs2CO3加入其中,然后再加入60mg的Pd(PPh3)4作为催化剂。在氩气的保护下,将反应液均匀混合后升温至100℃反应12h。反应结束,将反应液冷却至室温,向反应液中加入30mL超纯水,并用二氯甲烷多次萃取。萃取合并所得有机相,加入无水硫酸镁干燥后过滤,减压旋蒸除去有机溶剂,得到粗产物。粗产物以(石油醚/乙酸乙酯/二氯甲烷,v/v=4/1/1)为流动相,用硅胶柱层析进行分离提纯,得到0.41g橙黄色固体化合物2,产率为57%。1H NMR(400MHz,DMSO-d6)δ9.86(s,2H),7.99(s,2H),7.63(s,2H),7.51(s,2H),7.38(d,J=7.8Hz,2H),7.21(d,J=7.0Hz,6H),6.99(d,J=7.9Hz,3H),6.92(s,3H),6.24(d,J=8.4Hz,2H),3.76(s,6H)。
(2)染料TPTPy的合成
取一个50mL的二口圆底烧瓶,加入20mL无水乙醇作为溶剂,将722mg(1.0mmol)化合物2,1.17g(5.0mmol)1,4-二甲基吡啶-1-鎓碘化物和0.2mL哌啶加入其中。将反应液均匀混合后,在氩气的保护下,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532mg深紫色化合物TPTPy。产率为46%。1H NMR(400MHz,DMSO-d6)δ8.82(d,J=6.6Hz,4H),8.18(t,J=12.1Hz,6H),7.51(dd,J=17.5,3.7Hz,4H),7.44(d,J=1.8Hz,2H),7.29(m,2H),7.22(d,J=8.7Hz,6H),7.12(d,J=15.9Hz,2H),7.00(d,J=8.9Hz,4H),6.94(d,J=8.8Hz,2H),6.26(d,J=8.6Hz,2H),4.22(s,6H),3.77(s,6H)。
实施例2
对实施例1的有机染料TPTPy进行与次氯酸响应后的紫外和荧光发射光谱测试,如图2A和2B所示。TPTPy的最大吸收波长在490nm,在与ClO-作用之后,染料的最大吸收峰蓝移到了445nm。而TPTPy与ClO-反应前后的荧光强度则发生了明显的变化。TPTPy在不加入ClO-之前的荧光发射信号很弱,而在加入ClO-之后,染料溶液有明显的荧光“turn-on”现象,在585nm出现了很强的荧光信号峰。同时在加入ClO-后,我们可以通过裸眼观测溶液由原先的淡粉色变为黄色,且在365nm紫外灯照射下溶液发射出肉眼可见明显的橙红色荧光。
实施例3
对实施例1的有机染料TPTPy进行了选择性测试实验。如图3A所示,各类氧化物、氨基酸和代表性的离子的加入都不会使TPTPy的荧光发射出现明显的变化。然而ClO-的加入可以让TPTPy的荧光发生明显的“turn-on”现象。此外,如图3B所示,在其他竞争性样品存在的情况下,ClO-仍会引发TPTPy出现与图3A相似的荧光响应现象。从选择性和抗干扰实验中可以说明探针TPTPy对ClO-具有很好的选择性。
实施例4
对实施例1的有机染料TPTPy进行了荧光滴定实验,如图4A所示。探针TPTPy自身的荧光很弱,随着ClO-的加入,在585nm处的荧光发射强度逐渐增强。图4B为探针TPTPy在ClO-浓度为2-10μM范围内的荧光滴定实验,通过线性关系拟合直线并计算得到染料TPTPy对ClO-的检测限为185.38nM。结果说明TPTPy对ClO-具有很高的灵敏度。
实施例5
对实施例1的染料TPTPy与ClO-响应前后进行了ROS生成能力的检测实验,如图5所示。DCFH-DA是ROS的指示剂,图5A和5B中可以发现染料在被ClO-响应前后,在光照条件下均能使溶液在525nm处的荧光快速增强。图5C为商业化染料Rose Bengal在光照条件下使DCFH-DA荧光增强的图片。图D是仅加入DCFH-DA和ClO-光照后的荧光谱图,可以看出加入ClO-几乎不会使525nm处的荧光增强。比较A、B和C图,说明TPTPy在被ClO-响应前后均具有优异的ROS产生性能,同时TPTPy在被ClO-响应前后的ROS产生效率均要高于商业染料RoseBengal。
实施例6
实施例1的有机染料TPTPy对人脐静脉内皮细胞(HUVEC)和宫颈癌细胞(HeLa)中内外源性ClO-进行了成像检测。如图6(A1-A3)所示,由于HeLa细胞自身含有较多ClO-,故细胞孵育TPTPy后产生明显的红色荧光。图6(B1-B3)通过使用NAC清除HeLa细胞内源的ClO-,细胞再用TPTPy孵育并未发现明显的红色荧光,说明TPTPy能够被肿瘤细胞内高表达的内源性ClO-响应并点亮。如图6(C1-C3)所示,用TPTPy孵育HeLa细胞并加入外源性的ClO-显示出更加明显的红色荧光。如图6(D1-D3)所示,HeLa细胞通过孵育NAC清除细胞内源性ClO-后,再向细胞中加入外源性ClO-,最后再用细胞孵育TPTPy,能观察到明显的红色荧光。如图6(E1-E3),对于正常细胞,如人脐静脉内皮细胞,由于自身不存在高浓度的ClO-,故细胞孵育TPTPy后未产生明显红色荧光。该实验说明,有机染料TPTPy可以对细胞内外源性的ClO-进行监测,并能够特异性点亮自身ClO-高表达的肿瘤细胞。
实施例7
对实施例1的有机染料TPTPy进行了HeLa细胞内的ROS产生能力检测实验,如图7所示。DCFH-DA是ROS的指示剂,能与ROS结合产生绿色荧光。HeLa细胞经TPTPy孵育后,在无光照的条件下,细胞几乎观察不到绿色荧光。在进行2min和5min光照处理后显示出了不断增强的绿色荧光。这说明TPTPy在细胞内显示出了优异的ROS生成能力。
实施例8
对实施例1的有机染料TPTPy在HeLa细胞中进行了光毒性和暗毒性研究。如图8所示,96孔板分别用图中所示浓度的TPTPy孵育HeLa细胞2h,孵育结束后细胞分为两组,一组为白光照射10分钟组,一组为无光照组。处理后将细胞置于培养箱中继续培养24h,再进行细胞活性测试。TPTPy在暗态下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,当TPTPy浓度达到30μM时便具有良好的光动力治疗效果。
以上所揭露的仅为本发明较佳实施例而已,当然不能以此来限定本发明之权利范围,因此依本发明权利要求所作的等同变化,仍属本发明所涵盖的范围。
Claims (10)
1.一种基于吩噻嗪结构的有机染料,其特征在于,该有机染料的结构通式为:
;
其中,X为 S或O,R为H或卤素或C1~C20的直链烷氧基或C1~C20的支链烷氧基。
2.根据权利要求1所述的基于吩噻嗪结构的有机染料,其特征在于:其中R为OCH3,X为S。
3.如权利要求1或2所述的基于吩噻嗪结构的有机染料的合成方法,其特征在于,包括以下步骤:
(1)化合物1和化合物3反应得到化合物2;
(2)将化合物2与1,4-二甲基吡啶-1-鎓碘化物反应得到如权利要求1或2所述的基于吩噻嗪结构的有机染料;
化合物1的结构式为:
;
化合物3的结构式为:
;
化合物2的结构式为:
。
4.根据权利要求3所述的基于吩噻嗪结构的有机染料的合成方法,其特征在于:步骤(1)中,在惰性气体保护下,将化合物1和化合物3溶解在1,4-二氧六环中,加入Cs2CO3和催化剂,反应液在惰性气体保护下搅拌反应,反应结束后,萃取干燥,分离提纯得到化合物2。
5.根据权利要求4所述的基于吩噻嗪结构的有机染料的合成方法,其特征在于:化合物1、化合物3、Cs2CO3和催化剂的摩尔比为1:2.1:3:0.05。
6.根据权利要求4所述的基于吩噻嗪结构的有机染料的合成方法,其特征在于:所述催化剂为Pd(PPh3)4。
7.根据权利要求3所述的基于吩噻嗪结构的有机染料的合成方法,其特征在于:步骤(2)中,在惰性气体保护下,以无水乙醇为溶剂,加入化合物2、1,4-二甲基吡啶-1-鎓碘化物、哌啶,加热至回流搅拌反应,反应结束并冷却,浓缩提纯后得到所述基于吩噻嗪结构的有机染料。
8.根据权利要求3所述的基于吩噻嗪结构的有机染料的合成方法,其特征在于:化合物2、1,4-二甲基吡啶-1-鎓碘化物的摩尔比为1:3。
9.如权利要求1或2所述的一种基于吩噻嗪结构的有机染料用于检测次氯酸根的应用,其特征在于:所述吩噻嗪结构有机染料与次氯酸根作用之后,出现荧光开启现象。
10.如权利要求1或2所述的一种基于吩噻嗪结构的有机染料用于制备肿瘤光动力治疗药物的应用,其特征在于:所述的吩噻嗪型结构有机染料能够通过光照杀死肿瘤细胞,所述的肿瘤细胞包括宫颈癌细胞和肝癌细胞。
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