CN108484590A - 一种基于咔唑的双光子粘度荧光探针及其制备方法和用途 - Google Patents
一种基于咔唑的双光子粘度荧光探针及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种基于咔唑的双光子粘度荧光探针及其制备方法和用途,其中基于咔唑的双光子粘度荧光探针是以咔唑为母体,其结构式如下:本发明双光子荧光探针分子针对不同有机溶剂体系,仅在粘度溶剂中(甘油),其荧光出现了显著的增强。通过调节甲醇和甘油的比例,改变体系粘度,测试发现本荧光探针分子对粘度响应有好的线性关系。细胞毒性测试表明该探针对于细胞几乎没有什么毒副作用,双光子共聚焦荧光显微成像实验表明该探针对细胞膜渗透性好,能适用于定性检测细胞线粒体内的粘度变化。
Description
技术领域
本发明涉及一种基于咔唑的双光子粘度荧光探针及其制备方法和用途,以实现双光子共聚焦成像定性检测细胞线粒体内的粘度。该探针具有较大的共轭体系和双光子吸收截面、对粘度响应灵敏专一、细胞毒性低和生物相容性好等优点。
背景技术
细胞粘度是细胞正常与否的一项重要指标。细胞粘度影响着细胞内物质的运输,信号的传递,蛋白质、核酸、多糖等大分子之间的相互作用和各种活性代谢产物(如活性氧ROS和活性氮RNS)在细胞内的扩散。粘度能够控制生命活动中不同物质之间的传递速率及多相液体之间物质的转移传递。例如,细胞内的粘度能影响细胞生命过程中参与的营养物质及细胞代谢产生的代谢物的运输,同样也会影响细胞内外信号物质之间的转换。而且,亚细胞层面上的细胞微环境粘度同样也会影响亚细胞器正常生理过程。异常的细胞微环境粘度变化已经被证实与众多的疾病相关,如阿兹海默症、动脉粥样硬化、糖尿病,甚至是细胞恶性肿瘤等。因此,在生物体的微观环境中,对粘度的精确测量是至关重要的。目前,粘度的检测方法,如毛细管粘度计、落球粘度计和旋转粘度计等,均不能在细胞水平上提供有效的粘度检测。具有细胞膜通透性的小分子荧光探针可原位作用于细胞,从而实现有效实时地监测细胞内微小的粘度变化。因此开发性能优良的小分子荧光探针对细胞内及亚细胞层面的粘度研究具有重要的意义,同样对了解细胞生命过程也有着重大的意义。
线粒体是哺乳动物细胞中至关重要的一个细胞器,它在细胞凋亡的调控中(细胞程序性死亡)和某些疾病如癌症细胞凋亡异常反应特征中起重要作用。另外,线粒体中的微环境粘度通过影响分子之间作用的渗透压,进而影响其中的呼吸作用状态及ATP的转换等线粒体代谢过程。
荧光探针由于具有灵敏度高、选择性好、易合成、廉价以及良好的生物应用等特点,已成为生命科学和环境科学中主要的检测工具。目前,检测细胞中粘度的荧光探针很多是单光子荧光探针,单光子荧光探针一般具有自荧光干扰大,激发波长小导致对细胞的光毒性大,容易发生荧光自淬灭等缺点。与单光子荧光探针相比,双光子荧光探针具有很多明显的优点,如:细胞光毒性小,不会引起荧光自淬灭,时间空间分辨率高和组织渗透深度大。因此双光子荧光探针已经作为科学家们研究的一个重要课题。咔唑作为一种经典的荧光团,不仅具有大的共轭体系和共平面性能,而且具有良好的光稳定性、低毒性。现如今,以咔唑为荧光团的线粒体靶向的双光子粘度探针文献报道相对较少。
发明内容
本发明旨在提供一种基于咔唑的双光子粘度荧光探针及其制备方法和用途,所要解决的技术问题是通过分子设计得到一种合适的荧光探针结构,以实现通过双光子共聚焦成像定性检测细胞线粒体内的粘度变化。该探针具有较大的共轭体系和双光子吸收截面、对粘度响应灵敏专一、细胞毒性低和生物相容性好等优点。
本发明基于咔唑的双光子粘度荧光探针,是以咔唑为母体,简记为MCB,其结构式如下:
本发明基于咔唑的双光子粘度荧光探针的制备方法,包括如下步骤:
步骤1:中间体MC的合成
将3-碘-6-甲酰基-N-乙基咔唑(1.048g,3mmol)、碘化亚铜(0.029g,0.15mmol)和三苯基膦二氯化钯(0.063g,0.09mmol)加入到施耐克瓶中,充放氩气三次,再用注射器加入溶剂四氢呋喃(THF)和三乙胺(6mL),常温下搅拌反应30min,再注入THF溶解的4-甲氧基苯乙炔(0.4757g,3.6mmol),45℃反应1天;反应结束后冷却至室温,并将反应液用滤纸出去多余的盐,滤液旋蒸除去THF及少量的三乙胺,通过硅胶柱层析分离(洗脱液为石油醚:乙酸乙酯=20:1(v/v))得到中间体MC——3-对甲氧基苯乙炔基-6-甲酰基-N-乙基咔唑,0.6574g,产率62%;
步骤2:荧光探针MCB的合成
将中间体MC(0.3534g,1mmol)加入100mL圆底烧瓶中,加入15mL乙醇,加热搅拌至溶解后加入2,3-二甲基苯并噻唑-3-鎓碘化物(0.2911g,1mmol),并滴加2-3滴哌啶,80℃回流反应8-12小时,静置冷却,分层后过滤得到红色粗产物,通过硅胶柱层析分离(洗脱液为二氯甲烷:甲醇=100:1(v/v))得到目标产物0.5012g,产率80%。
本发明基于咔唑的双光子粘度荧光探针MCB的合成过程如下:
本发明基于咔唑的双光子粘度荧光探针的用途,是在定性检测细胞线粒体内的粘度变化时作为检测试剂使用,检测方法如下:
将本发明双光子荧光探针溶DMSO中配制2mM的母液,配得5mL,各取15μL母液于3mL不同比例甲醇-甘油(v/v)体系中,检测到其紫外吸收峰在480nm处,在480nm波长激发下,其荧光发射峰在566nm处,与此同时,随着甘油含量的提高,荧光逐渐增强,且荧光强度与粘度值成一定线性关系。为了进一步验证本发明双光子荧光探针的粘度响应特性,在480nm波长激发下,检测了甲醇-甘油(10/90,v/v)在不同温度下的荧光,随着温度的降低,荧光逐渐增强,此结果与理论相符:随着温度的降低,甲醇-甘油(10/90,v/v)溶剂体系粘度增大,分子旋转阻力增大,荧光增强。
本发明的双光子荧光探针结构简单,易于合成。该分子在咔唑母体上引入2,3-二甲基苯并噻唑-3-鎓碘化物,而由于粘度的增加会限制苯并噻唑鎓碘盐与咔唑相连的碳碳单键的旋转,使探针MCB对粘度有响应,其次探针MCB的苯噻唑鎓碘盐,能使MCB靶向线粒体和增加细胞膜通透性,从而很容易进入细胞。
附图说明
图1是10μM探针MCB在不同有机溶剂中的荧光发射光谱图。
图2是10μM探针MCB在不同比例甲醇-甘油粘度体系下的荧光发射光谱图。
图3是10μM探针MCB在不同粘度下与荧光强度的线性关系图。
图4是10μM探针MCB在甲醇-甘油(10/90,v/v)粘度体系下,不同温度的荧光发射光谱图。
图5是0.1mM探针MCB的有效双光子吸收截面。
图6是0.1mM探针MCB在840nm激发波长下的双光子验证图。
图7是不同浓度的探针MCB(0μM、10μM、20μM、30μM)下的HeLa细胞存活率图。
图8是10μM探针MCB在HeLa细胞中分别在不同温度下双光子细胞成像。图8b,8f,8j是探针MCB分别在4℃,25℃和37℃温度下的红色通道发射,图8a,8e,8i分别是商品化线粒体染色剂MitoTracker Green FM在4℃,25℃和37℃下的绿色通道。图8c是8a和8b的叠加,图8g是8e和8f的叠加,图8k是8i和8j的叠加。图8d,8h和8l分别是4℃,25℃和37℃下HeLa细胞的明场。
图9是10μM探针分子在HeLa细胞的线粒体定位成像照片。其中图9a,图9b分别为绿色通道和红色通道下的荧光共聚焦成像。图9c是HeLa细胞的明场,图9d是图9a和9b的叠加,图9e是图9d中单个细胞的荧光强度剖面图,图9f是MCB和MitoTracker Green FM强度的相关性分布图,重叠系数为0.95。
具体实施方式
下面通过实施例对本发明做进一步说明。
实施例1:中间体MC的合成
将3-碘-6-甲酰基-N-乙基咔唑(1.048g,3mmol),碘化亚铜(0.029g,0.15mmol),三苯基膦二氯化钯(0.063g,0.09mmol)加入到施耐克瓶中,充放氩气三次,再用注射器加入适量的溶剂四氢呋喃(THF)和三乙胺(6mL),常温下,搅拌30分钟,再注入4-甲氧基苯乙炔(0.4757g,3.6mmol)THF溶液,并在45℃反应1天。反应结束后,冷却至室温,并将反应液用滤纸出去多余的盐,滤液置于圆底烧瓶中,旋转蒸发除去THF和少量的三乙胺,制样,通过硅胶柱层析分离(洗脱液为石油醚:乙酸乙酯=20:1(v/v))得到目标产物0.6574g。产率62%。1HNMR(400MHz,CDCl3,ppm):δ10.12(s,J=2.3Hz,1H),8.62(s,J=3.7Hz,1H),8.35(s,J=3.8Hz,1H),8.06(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.53(dd,J=12.0Hz,3H),7.44(d,J=8.0Hz,1H),6.93(d,J=8.0,Hz,2H),4.43(dd,J=12.0Hz,2H),3.87(s,J=2.2Hz,3H),1.51(t,J=16.0Hz,3H).13C NMR(400MHz,CDCl3,ppm):δ191.58,159.50,143.93,140.12,132.96,130.20,129.00,127.36,124.31,124.14,123.15,122.84,115.76,115.46,114.06,109.17,108.99,88.71,88.20,77.21,55.33,38.13,13.86.
实施例2:荧光探针分子MCB的合成
将3-对甲氧基苯乙炔基-6-甲酰基-N-乙基咔唑(0.3534g,1mmol)加入100mL圆底烧瓶中,加入15mL乙醇,加热搅拌至原料溶解后,再加入2,3-二甲基苯并噻唑-3-鎓碘化物(0.2911g,1mmol),并滴加2-3滴哌啶,80℃回流过夜。静置冷却,分层后过滤得到红色粗产物,制样,通过硅胶柱层析分离(洗脱液为二氯甲烷:甲醇=100:1(v/v))得到目标产物0.5012g。产率80%。1H NMR(400MHz,DMSO-d6,ppm):δ9.04(s,1H),8.44(t,J=12.8Hz,2H),8.37(s,1H),8.22(t,J=17.6Hz,2H),8.07(d,J=15.6Hz,1H),7.87(t,J=12.0Hz,2H),7.79(dd,J=8.0Hz,2H),7.71(d,J=8.8Hz,1H),7.54(d,J=8.4Hz,2H),7.03(d,J=8.8Hz,2H),4.55(dd,J=14.6Hz,2H),4.38(s,3H),3.82(s,3H),1.40(t,J=14.2Hz,3H).13C NMR(400MHz,DMSO-d6,ppm):δ172.33,159.82,150.61,143.07,142.49,140.35,133.22,130.29,129.70,129.42,128.57,127.92,126.16,124.62,124.20,123.88,123.05,122.93,117.02,115.15,114.93,114.67,111.08,110.98,110.87,89.35,88.60,55.78,38.14,36.61,14.38.
实施例3:荧光探针分子的光谱测试
将本发明双光子荧光探针溶于DMSO中制得2mM的母液,配得5mL,取15μM母液于3mL样品管,配制检测液为10μM,在480nm波长激发下,在各种有机溶剂中,在甘油中荧光发射峰(566nm处)强度显著增强,在其它溶剂中其发射峰强度无明显变化(图1)。为了说明该探针分子对粘度的响应,测试了不同比例甲醇-甘油(v/v)下的荧光光谱:在566nm处的荧光强度随着甘油体积比的增多,探针MCB的荧光增强,且荧光强度和粘度值呈一定的线性关系(图2和图3)。此外,为了进一步证明探针MCB响应粘度,测试了该分子在甲醇-甘油(10-90(v/v))低温荧光光谱:随着温度的降低,在566nm处的荧光增强(图4)。
实施例4:荧光探针分子的双光子性能测试
利用双光子诱导荧光测量技术,测试探针MCB在不同粘度值下(甲醇/甘油,v/v:0/99,20/80,40/60)的双光子有效吸收截面,从图5可以看出,双光子激发波长在840nm时,探针MCB的双光子有效吸收截面达到最大,其值分别是80.45GM,62.16GM和50.33GM。说明探针MCB具有双光子吸收的性能,并有望应用于双光子生物成像。图6是MCB双光子验证图,以99%的纯甘油为测试液,波长设定为840nm,改变入射激发光的能量(0.3~0.8mW),测试了不同入射光强度下的双光子荧光光谱,数据显示荧光输出能量(Iout)和输入能量(Iin)之间有很好的平方关系,斜率为1.9929,这充分说明了MCB具有双光子吸收性质。
实施例5:细胞毒性测试
MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐)实验是根据已报道的文章操作进行细胞毒性测试。分别在同一批细胞中加入0μM、10μM、20μM、30μM的荧光探针分子,条件是在37℃、含5%CO2的细胞培养箱中孵育24小时,根据细胞存活度的公式:细胞存活率%=OD570(样品)/OD570(对照组)×100,可算得细胞存活率(图7)。从图7中我们可以看出,浓度为20μM时,细胞存活率还有92%左右,当探针浓度达到30μM时,细胞存活率仍然有约86%,说明了本发明荧光探针分子对细胞无明显毒性作用,因此可以用来检测细胞中线粒体内的粘度。
实施例6:低温成像测试
HeLa细胞由DEME(invitrogen)培养液培养,成像前一天,HeLa细胞放于玻底培养皿中,再向HeLa细胞中加入10μMMCB置于含5%CO2的细胞培养箱中分别在37℃、25℃、4℃下孵育0.5小时,用PBS缓冲溶液充分洗涤3次后,继续加入0.5μM的MitoTracker Green FM,最后用PBS缓冲溶液充分洗涤3次后,用双光子荧光共聚焦成像。通过改变细胞孵育温度来获得细胞内不同粘度,从图8b,8f,8j所示,随着细胞内温度的降低,红色通道(580-620nm)的荧光逐渐增强,这是由于细胞内粘度随着温度的降低而增加。图8(a,e,i)分别是商品化线粒体染色剂MitoTracker Green FM在4℃,25℃和37℃下,绿色通道(500-540nm)的荧光发射。图8c是8a和8b的叠加,图8g是8e和8f的叠加,图8k是8i和8j的叠加,从图8c,8g,8k可以看出,即使温度改变,荧光探针MCB仍然很好的定位在线粒体。图8d,8h和8l分别是4℃,25℃和37℃下HeLa细胞的明场。
实施例7:细胞定位测试
HeLa细胞由DEME(invitrogen)培养液培养,成像前一天,HeLa细胞放于激光共聚焦皿中,再向HeLa细胞中加入10μMMCB置于37℃、含5%CO2的细胞培养箱中孵育0.5小时,用中性的PBS缓冲溶液洗涤3次后,再往培养皿中加入0.5μM商品化线粒体染色剂MitoTrackerGreen FM溶液继续孵育0.5小时,用中性的PBS缓冲溶液洗涤3次后,用双光子荧光共聚焦成像,设置商品化线粒体染色剂MitoTracker Green FM为绿色通道(500-540nm,λex=488nm,图9a);探针MCB为红色通道(580-620nm,λex=568nm,图9b)。图9c是HeLa细胞的明场,图9d是9a和9b的叠加,图9e是9d中单个细胞的荧光强度剖面图,图9f是MCB和MitoTracker GreenFM强度的相关性分布图,重叠系数为0.95。从图9d可以看出,MCB绝大多数定位在线粒体内,表明其可用于检测细胞线粒体内的粘度。
Claims (5)
1.一种基于咔唑的双光子粘度荧光探针,是以咔唑为母体,其特征在于其结构式如下:
2.一种权利要求1所述的基于咔唑的双光子粘度荧光探针的制备方法,其特征在于包括如下步骤:
步骤1:中间体MC的合成
将3-碘-6-甲酰基-N-乙基咔唑3mmol、碘化亚铜0.15mmol和三苯基膦二氯化钯0.09mmol加入到施耐克瓶中,充放氩气三次,再用注射器加入溶剂四氢呋喃和三乙胺6mL,常温下搅拌反应30min,再注入THF溶解的4-甲氧基苯乙炔3.6mmol,45℃反应1天;反应结束后冷却至室温,并将反应液用滤纸出去多余的盐,滤液旋蒸除去THF及少量的三乙胺,通过硅胶柱层析分离得到中间体MC——3-对甲氧基苯乙炔基-6-甲酰基-N-乙基咔唑;
步骤2:荧光探针MCB的合成
将中间体MC 1mmol加入100mL圆底烧瓶中,加入乙醇,加热搅拌至溶解后加入2,3-二甲基苯并噻唑-3-鎓碘化物1mmol,并滴加2-3滴哌啶,80℃回流反应8-12小时,静置冷却,分层后过滤得到红色粗产物,通过硅胶柱层析分离得到目标产物。
3.根据权利要求2所述的制备方法,其特征在于:
步骤1中,硅胶柱层析分离的洗脱液为石油醚和乙酸乙酯按体积比20:1混合构成。
4.根据权利要求2所述的制备方法,其特征在于:
步骤2中,硅胶柱层析分离的洗脱液为二氯甲烷和甲醇按体积比100:1混合构成。
5.一种权利要求1所述的基于咔唑的双光子粘度荧光探针的用途,其特征在于:是在定性检测细胞线粒体内的粘度变化时作为检测试剂使用。
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