CN113527350B - 一类近红外溶酶体荧光指示剂及应用 - Google Patents
一类近红外溶酶体荧光指示剂及应用 Download PDFInfo
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Abstract
一类近红外溶酶体荧光指示剂及应用,属于精细化工领域。该近红外溶酶体荧光指示剂独创性的将亲水性小分子基团引入至亲脂性BODIPY母体结构中,成功得到一系列最大发射波长在600‑750 nm之间连续可调的两亲性近红外BODIPY衍生物。该设计使染料分子在水溶液中因为聚集而无荧光,在酸性脂类环境中因为解聚集而恢复荧光。同时,该类化合物易于透过细胞膜,快速靶向溶酶体,且仅在进入细胞之后发出荧光,相较其他溶酶体靶向荧光染料,具有免洗及背景荧光弱的优势。另外,该化合物使用低至纳米级浓度即可准确的标记溶酶体中,并能够用于长时间的荧光成像研究,对溶酶体的运动和形态变化进行长时间实时跟踪。
Description
技术领域
本发明涉及一类近红外溶酶体荧光指示剂及应用,属于精细化工领域。
背景技术
溶酶体在细胞各种生命活动,如物质代谢、细胞膜循环、细胞凋亡中发挥着重要作用。溶酶体具有高度动态的性质,可不断地改变其形态和空间分布。可视化追踪溶酶体,并对其活性物种、特定微环境及关键生理过程进行检测,不仅有助于理解溶酶体参与生命活动的分子机制,而且对疾病的治疗具有重要的指导意义。为了实现其上述功能需要发光性质优越、溶酶体特异性高、并且对溶酶体生理功能干扰小的荧光探针。近年来,较多靶向溶酶体的荧光指示剂被相继报道,但是大部分荧光染料的发射峰的位置处于可见光范围内(400-650nm),其中紫外光区的荧光指示剂与细胞内的自发荧光相重叠,不利于准确成像;而多数近期报道的溶酶体探针,以及商品化溶酶体指示剂集中在可见区,探针之间光谱重叠度高,难于满足双色及更多颜色的多通道荧光成像。近红外荧光团由于其吸收及发射波长长,生物相容性优于可见区荧光团、成像深度大于可见区荧光团、可提供额外的成像波段配合其他染料实现多色荧光成像。
基于上述原因,开发光谱区分度高,覆盖可见区至近红外区、靶向性能稳定、发光亮度强的溶酶体荧光探针具有重要意义,能够解决目前活细胞溶酶体相关研究的诸多难题,具有很高的实用性意义。
发明内容
本发明提供一类以BODIPY为母体的两亲性近红外溶酶体荧光指示剂及应用,该指示剂具有两亲性的特点,可低浓度、快速靶向溶酶体,并可长期稳定的停留于溶酶体中。该化合物具有如下结构通式:
其中,RR1,R2各自独立的为H、Cl、Br或者I;
所述的一类近红外溶酶体荧光指示剂的制备方法,该方法的反应式和采用的反应步骤如下:
i)用分水器除水,化合物A、B、哌啶和冰醋酸在有机溶剂中加热反应,反应混合物浓缩,并用CH2Cl2萃取,萃取后的有机相用盐水洗涤干燥浓缩,硅胶柱提纯得到化合物C;
ii)氩气保护下,化合物Y-N3加入有机溶剂中,再加入溶于H2O的CuSO4·5H2O,和抗坏血酸钠,将化合物C溶解在有机溶剂中,滴加到上述反应液中,室温下搅拌反应,反应混合物浓缩,并用CH2Cl2萃取,萃取后的有机相用盐水洗涤干燥浓缩,硅胶柱提纯得到化合物D。
其中,R1、R2、R3、X2和Y的定义同结构通式中的定义。
所述的步骤i中的有机溶剂为苯、甲苯、二甲苯、氯苯、二氯苯、二氧六环、氮甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜、六甲基磷酰胺、环丁砜和苯甲腈中的一种或几种,反应温度为90-150℃;步骤ii的反应温度为室温,溶剂为水、二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜、氮甲基吡咯烷酮和乙腈中的一种。
本发明的有益效果:一类近红外溶酶体荧光指示剂及应用,该近红外溶酶体荧光指示剂独创性的将亲水性小分子基团引入至亲脂性BODIPY母体结构中,成功得到一系列最大发射波长在600-750nm之间连续可调的两亲性近红外BODIPY衍生物。该设计调节了分子的亲水亲脂性,使染料分子在水溶液中因为聚集而无荧光,在酸性脂类环境中因为解聚集而恢复荧光。同时,该类化合物易于透过细胞膜,快速靶向溶酶体,且仅在进入细胞之后发出荧光,相较其他溶酶体靶向荧光染料,具有免洗及背景荧光弱的优势。另外,该化合物的摩尔消光系数及荧光量子产率高,发光亮度强,且不易被漂白,使用低至纳米级浓度即可准确的标记溶酶体中,并能够用于长时间的荧光成像研究,对溶酶体的运动和形态变化进行长时间实时跟踪。
附图说明
图1是化合物D1、D2、D25、D26在不同溶剂中的发射光谱图。
图2是化合物D1、D6、D22、D25的活细胞溶酶体共定位成像图。
图3是化合物D15、D20、D46、D51的活细胞溶酶体共定位成像图。
图4是化合物D25的免洗条件下活细胞溶酶体成像图。
图5是化合物D25的氯喹刺激条件下活细胞溶酶体成像图。
具体实施方式
为使本发明的技术方案更加清楚,以下结合技术方案和附图详细完整叙述本发明的具体实施例。本发明用以下实例加以说明但不局限于此,其中除非另有说明,所有的份数和百分数均以重量计。
实施例1
i)A1(1.27mmol),B(1.27mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C1。
ii)在氩气条件下,化合物C1(82μmol),Y1(164μmol),CuSO4·5H2O(82μmol),抗坏血酸钠(164μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C1反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D1。
实施例2
化合物D2、D3和D4的合成方法参照实施例1。
实施例3
i)A2(1.27mmol),B(1.27mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C2。
ii)在氩气条件下,化合物C2(82μmol),Y2(164μmol),CuSO4·5H2O(82μmol),抗坏血酸钠(164μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C2反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D5。
实施例4
化合物D6、D7和D8的合成方法参照实施例3。
实施例5
i)A3(1.27mmol),B(1.27mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C3。
ii)在氩气条件下,化合物C3(82μmol),Y3(164μmol),CuSO4·5H2O(82μmol),抗坏血酸钠(164μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C3反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D9。
实施例6
化合物D10、D11和D12的合成方法参照实施例5。
实施例7
i)A4(1.27mmol),B(1.27mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C4。
ii)在氩气条件下,化合物C4(82μmol),Y4(164μmol),CuSO4·5H2O(82μmol),抗坏血酸钠(164μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C4反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D13。
实施例8
化合物D14、D15和D16的合成方法参照实施例7。
实施例9
i)A5(1.27mmol),B(1.27mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C5。
ii)在氩气条件下,化合物C5(82μmol),Y5(164μmol),CuSO4·5H2O(82μmol),抗坏血酸钠(164μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C5反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D17。
实施例10
化合物D18、D19和D20的合成方法参照实施例9。
实施例11
i)A6(1.27mmol),B(1.27mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C6。
ii)在氩气条件下,化合物C6(82μmol),Y6(164μmol),CuSO4·5H2O(82μmol),抗坏血酸钠(164μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C6反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D21。
实施例12
化合物D22、D23和D24的合成方法参照实施例11。
实施例13
i)A1(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C7。
ii)在氩气条件下,化合物C7(66μmol),Y1(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C7反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D25。
实施例14
化合物D26、D27和D28的合成方法参照实施例13。
实施例15
i)A7(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C8。
ii)在氩气条件下,化合物C8(66μmol),Y2(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C8反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D29。
实施例16
化合物D30、D31和D32的合成方法参照实施例15。
实施例17
i)A8(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C9。
ii)在氩气条件下,化合物C9(66μmol),Y3(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C9反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D33。
实施例18
化合物D34、D35和D36的合成方法参照实施例17。
实施例19
i)A9(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C10。
ii)在氩气条件下,化合物C10(66μmol),Y7(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C10反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D37。
实施例20
化合物D38、D39和D40的合成方法参照实施例19。
实施例21
i)A10(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C11。
ii)在氩气条件下,化合物C11(66μmol),Y5(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C11反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D41。
实施例22
化合物D42、D43和D44的合成方法参照实施例21。
实施例23
i)A11(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C12。
ii)在氩气条件下,化合物C12(66μmol),Y6(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C12反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D45。
实施例24
化合物D46、D47和D48的合成方法参照实施例23。
实施例25
i)A12(1.27mmol),B(3.81mmol)于30mL干燥的甲苯(使用前用分子筛除水)中搅拌,加入哌啶1mL和冰醋酸1mL催化,150℃加热回流,反应过程中产生的水份用分水器除去。用TLC监测反应直至反应结束。冷却至室温后,减压除去反应液中的大部分甲苯,所得液体用二氯甲烷稀释后用水洗涤并浓缩。粗产物经硅胶柱色谱(二氯甲烷/石油醚=1/3)提纯得固体C13。
ii)在氩气条件下,化合物C13(66μmol),Y8(198μmol),CuSO4·5H2O(66μmol),抗坏血酸钠(132μmol)加入到甲苯、乙醇和水的混合溶液(v/v/v=12/4/1),在室温下搅拌反应,用TLC监测反应直至化合物C13反应完全。将反应混合物浓缩后经硅胶柱色谱提纯得固体D49。
实施例26
化合物D50、D51和D52的合成方法参照实施例25。
实施例27
将化合物D1、D2、D25、D26进行性质研究。将D1、D2、D25、D26溶解在DMSO中以获得1mM的储备溶液。将储备溶液用乙腈进一步稀释为1μM测试溶液,并加入1μL三氟乙酸(体积含量0.1%)。将这些测试溶液进行吸收、发射光谱、量子产率和摩尔消光系数的测试。吸收光谱通过Agilent 8453紫外可见分光光度计进行测量,荧光光谱通过Agilent光谱仪测量。表1列出了化合物D1、D2、D25、D26在乙腈中的最大吸收波长(λab)、最大发射波长(λem)、摩尔消光系数(ε)和荧光量子产率(Φ1)。从表中数据可知,化合物D1、D2、D25、D26最大发射波长在600-750nm之间,同时具有较高的摩尔消光系数和荧光量子产率。
表1.D1、D2、D25、D26乙腈中光谱性质
实施例28
将化合物D1、D2、D25、D26进行性质研究。将D1、D2、D25、D26溶解在DMSO中以获得1mM的储备溶液。将储备溶液用2mM CTAB(pH 3),ddH2O(pH 7)进一步稀释为1μM测试溶液。将这些测试溶液进行吸收、发射光谱的测试。光谱性质的测试方法同实施例13。
如图1所示,a、b、c、d分别是D1、D2、D25、D26(1μM)在pH 3的CTAB(2mM)、ddH2O(pH7)中的发射光谱。CTAB(十六烷基三甲基溴化铵)是一种阳离子表面活性剂,其临界胶束浓度(cmc)为0.9mM,2mMCTAB(pH 3)水溶液中CTAB以胶束的形态存在,不仅对染料分子起到助溶的作用,且模拟了溶酶体的酸性微环境。从图中可以看出,在pH为3的2mM CTAB中,四种化合物处于类似溶酶体的微环境中均呈现出稳定的发射光,而在pH为7的H2O对照组中均无荧光,可见四种化合物在细胞外无荧光特性,仅在细胞内表现出稳定且强烈的荧光,初步判定此类化合物无需PBS清洗可直接进行共聚焦成像,可用于溶酶体荧光标记。
实施例29
化合物D6、D15、D20、D22、D46、D51的光谱性质以下表的形式给出,测试条件同实施例14和实施例15。从表2中数据可以看出,化合物D6、D15、D20、D22、D46、D51最大发射波长在600-750nm之间,同样具有较高的摩尔消光系数和荧光量子产率。在pH为3的2mM CTAB中,六个化合物处于类似溶酶体的微环境中均呈现出稳定的发射光,而在pH为7的H2O中均无荧光,可见,此类化合物无需PBS清洗可直接进行共聚焦成像,可用于溶酶体荧光标记。
表2.D6、D15、D20、D22、D46、D51的光谱性质
实施例30
对化合物D1、D6、D22、D25进行荧光成像实验,将RAW 264.7细胞在37℃,5%的CO2细胞孵育箱中孵育24小时后,分别使用1μM的D1、D6染色孵育5分钟,1μM的D22、D25染色孵育60分钟,再使用1μM的DND-26绿色溶酶体探针染色孵育5分钟,PBS洗三次,进行共聚焦成像。
如图2所示,第一排为DND-26共聚焦成像图片,第二排从左至右分别为D1、D6、D22、D25共聚焦成像图片,通过共聚焦成像图片可以清楚观察到化合物D1、D6、D22、D25特异性靶向溶酶体。
实施例31
对化合物D15、D20、D46、D51进行荧光成像实验,将RAW 264.7细胞在37℃,5%的CO2细胞孵育箱中孵育24小时后,分别使用1μM的D15、D20染色孵育5分钟,1μM的D46、D51染色孵育60分钟,再使用1μM DND-26绿色溶酶体探针染色孵育5分钟,PBS洗三次,进行共聚焦成像。
图3是化合物D15、D20、D46、D51的细胞成像共定位图,如图3所示,通过共聚焦成像图片可以清楚观察到化合物D15、D20、D46、D51特异性靶向溶酶体。
实施例32
对化合物D25进行荧光成像实验,将RAW 264.7细胞在37℃,5%的CO2细胞孵育箱中孵育24小时后,使用100nM的D25染色孵育60分钟,直接进行共聚焦成像。如图4所示,通过共聚焦成像图片可以清楚观察到化合物D25在免洗的条件下仍能够用于溶酶体成像研究。
实施例33
对化合物D25进行荧光成像实验,将RAW 264.7细胞在37℃,5%的CO2细胞孵育箱中孵育24小时后,使用1μM的D25染色孵育60分钟,再使用1μMDND-26绿色溶酶体探针染色孵育5分钟,PBS洗三次,再加入20μM氯喹,进行共聚焦成像。氯喹可以导致质子从溶酶体中逃逸出来,用来提高溶酶体的pH值。
如图5所示,在与DND-26共染色的条件下,加入20μM氯喹后,DND-26的荧光强度在5min内明显减弱,而化合物D25的荧光仅有轻微的改变。可见,化合物D25的荧光强度稳定,与溶酶体pH变化无关,可正确指示溶酶体的位置和形态。
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