新型Ca~（2+）荧光探针的设计、合成及胞内信使作用研究
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摘要
Ca~(2+)作为细胞内的信息传递物质,它起着调节许多重要细胞功能的作用。作为第二信使,Ca~(2+)参与生物信号的跨膜传递,介导细胞对外界刺激的应答等等,因此,准确测定活体细胞内游离Ca~(2+)的浓度及其动态变化已成为化学、生命科学及基础临床医学研究中的一个非常重要的研究领域。
80年代以来Tsien等人合成的具有EGTA、BAPTA螫合母体的Ca~(2+)荧光探针,广泛地应用于细胞内游离Ca~(2+)浓度的测定。这种方法灵敏性高,响应时间短,并且可以通过显微镜成像来提高空间解析度,从而为细胞内Ca~(2+)的研究提供一条简便、高效的途径。因此,Ca~(2+)荧光探针的设计、合成也成为有机合成化学的热点问题。目前广泛应用的Ca~(2+)荧光探针上要以荧光素类和吲哚型为主。其中,荧光素类Ca~(2+)荧光探针属于可见光激发的荧光探针,主要通过荧光强度的变化来测定胞内Ca~(2+)的浓度:吲哚型Ca~(2+)荧光探针属于紫外光激发的荧光探针,在结合了Ca~(2+)后,激发波长或发射波长会发生较大位移.可应用双波长比率法进行Ca~(2+)浓度的测定。然而,目前商业化应用的Ca~(2+)荧光探针的数目极为有限。
为了满足不同浓度范围Ca2~(2+)的测试,改善探针的生物亲和性以及荧光强度,本文围绕新型Ca~(2+)荧光探针的设计、合成及其胞内信使作用展开研究.主要内容有以下几个方面:
1.通过对目前广泛应用的Ca~(2+)荧光探针的螫合母体BAPTA结构的分析,设计、合成了五种新型BAPTA结构的衍生物,并对这五种化合物进行了结构表征.
2.设计、合成了三种未见文献报道的新型荧光素类Ca~(2+)荧光探针,并对这三种新型荧光素类Ca~(2+)荧光探针的甲酯形式进行了结构表征。报道了这三种新型荧光素类Ca~(2+)荧光探针甲酯的荧光光谱。
3.设计、合成了五种未见文献报道的新型含氯荧光素类Ca~(2+)荧光探针,并对这五种新型荧光素类Ca~(2+)荧光探针的甲酯形式进行了结构表征.报道了这五种新型荧光素类Ca~(2+)荧光探针甲酯的荧光光谱。同时,从理论计算角度获得了Ca~(2+)荧光探针分子设计的有用结果。
4.设计、合成了五种未见文献报道的新型吲哚型Ca~(2+)荧光探针,并对这五种新型吲哚犁Ca~(2+)荧光探针的甲酯形式进行了结构表征。报道了这五种新型吲哚型Ca~(2+)荧光探针的荧光光谱。
5.对设计、合成的新型荧光素类Ca~(2+)荧光探针Fluo-3M的荧光光谱进行了研究,结果表明,Fluo-3M在与Ca~(2+)结合后,荧光强度明显增强。其最大激发波长和发射波长与Fluo-3类似,所有可应用于Fluo-3的荧光成像仪器均适用于这种新型探针,为Fluo-3M的商品化应用奠定了基础。
6.对设计、合成的新型荧光素类Ca~(2+)荧光探针Fluo-3M的离解平衡常数-K_d进行了测定,结果表明,Fluo-3M是一种具有较高亲和力(低K_d值)的Ca~(2+)荧光探针,适用于细胞膜附近的Ca~(2+)浓度的测定。
7.将设计、合成的新型荧光素类Ca~(2+)荧光探针Fluo-3M的乙酸甲酯形式-Fluo-3MAM负载入人胚肾细胞及中国仓鼠卵巢细胞中,应用Olympus IX71型倒置研究级荧光显微镜进行活体细胞中胞内自由Ca~(2+)的检测和成像。结果表明:Fluo-3M具有优良的荧光性能和生物亲和性,可应用于活体细胞的连续测定,是一种性能优良的Ca~(2+)荧光探针。
Ca~(2+) acts as a universal messenger in a variety of cells. Numerous functions of all types of cells are regulated by calcium to a greater or lesser degree. Serving as an intracellular second messenger and mediator,Ca~(2+) plays a very important role in intracellular signal transduction as well as extracellular. Consequently, the measurement of cytosolic Ca~(2+) has become an important investigation area in chemical, biological and medical research.
Fluorescent indicators with the structure of EGTA、BAPTA were developed by Tsien and his colleagues in the 1980's for cytosolic Ca~(2+) detection. Fluorescence probes, which are sensitive, fast-responding and capable of affording high spatial resolution via microscopic imaging, provide a new method in the research of intracellular calcium. Therefore, the design and synthesis of new fluorescence probes for cytosolic Ca~(2+) have arisen much more attention. Among the fluorescent Ca~(2+) probes synthesized, fluorescein-based calcium fluorescent probes and fluorescent probes with an indole structure, which are excitated by visible light and UV light respectively, have been widely used. Nevertheless, the fluorescence probes for Ca~(2+) which can be used widely and commercially are quite limited nowadays.
In order to test the Ca~(2+) in different concentration, improve the biological affinity to Ca~(2+)and the fluorescence intensity, the investigations on the design, synthesis and function test of new fluorescence probes for Ca~(2+) are carried out, mainly including the following several aspects:
1.According to the analysis of the structure of BAPTA,five kinds of novel derivates of BAPTA were synthesized successfully. Furthermore, the structures of these compounds were all confirmed.
2.Have designed and synthesized three novel fluorescein-based calcium fluorescent probes. The methyl ester forms of the new probes were confirmed. The fluorescent spectrum of the novel compounds were reported.
3.Have designed and synthesized five novel fluorescein-based calcium fluorescent probes linked chlorine. The methyl ester forms of the new probes were confirmed. The fluorescent spectrum of the novel compounds were reported. Simultaneously, very useful results about designing of the new probes were obtained from theoretic calculation.
4.Have designed and synthesized five novel calcium fluorescent probes with an indole structure.The methyl ester forms of the new probes were confirmed. The fluorescent spectrum of the novel compounds were reported.
5.The fluorescent spectrum of the novel fluorescein-based calcium fluorescent probe Fluo-3M were investigated. The experimental result shows that the fluorescence intensity enhanced obviously after bonded with Ca~(2+).The fluorescence excitation and emission wavelength maxima for Fluo-3M are nearly the same as those reported for Fluo-3. Thus, fluorescence microscopy applications are applicable for detection of Fluo-3M as well.
6.Have calculated the K_d of the novel fluorescent probe Fluo-3M. The data shows that Fluo-3M has a relatively high affinity to calcium. It can be used to measure the Ca~(2+) distributed near the membrane of the cell.
7.Fluo-3M was injected into HEK-293 cells and CHO cells, the OlympusⅨ71 fluorescent microscope was used for detecting the intracellular calcium and the imaging of the cell. The experimental results show that Fluo-3M which has a high fluorescence intensity and biological affinity can be used in vivo.
80年代以来Tsien等人合成的具有EGTA、BAPTA螫合母体的Ca~(2+)荧光探针,广泛地应用于细胞内游离Ca~(2+)浓度的测定。这种方法灵敏性高,响应时间短,并且可以通过显微镜成像来提高空间解析度,从而为细胞内Ca~(2+)的研究提供一条简便、高效的途径。因此,Ca~(2+)荧光探针的设计、合成也成为有机合成化学的热点问题。目前广泛应用的Ca~(2+)荧光探针上要以荧光素类和吲哚型为主。其中,荧光素类Ca~(2+)荧光探针属于可见光激发的荧光探针,主要通过荧光强度的变化来测定胞内Ca~(2+)的浓度:吲哚型Ca~(2+)荧光探针属于紫外光激发的荧光探针,在结合了Ca~(2+)后,激发波长或发射波长会发生较大位移.可应用双波长比率法进行Ca~(2+)浓度的测定。然而,目前商业化应用的Ca~(2+)荧光探针的数目极为有限。
为了满足不同浓度范围Ca2~(2+)的测试,改善探针的生物亲和性以及荧光强度,本文围绕新型Ca~(2+)荧光探针的设计、合成及其胞内信使作用展开研究.主要内容有以下几个方面:
1.通过对目前广泛应用的Ca~(2+)荧光探针的螫合母体BAPTA结构的分析,设计、合成了五种新型BAPTA结构的衍生物,并对这五种化合物进行了结构表征.
2.设计、合成了三种未见文献报道的新型荧光素类Ca~(2+)荧光探针,并对这三种新型荧光素类Ca~(2+)荧光探针的甲酯形式进行了结构表征。报道了这三种新型荧光素类Ca~(2+)荧光探针甲酯的荧光光谱。
3.设计、合成了五种未见文献报道的新型含氯荧光素类Ca~(2+)荧光探针,并对这五种新型荧光素类Ca~(2+)荧光探针的甲酯形式进行了结构表征.报道了这五种新型荧光素类Ca~(2+)荧光探针甲酯的荧光光谱。同时,从理论计算角度获得了Ca~(2+)荧光探针分子设计的有用结果。
4.设计、合成了五种未见文献报道的新型吲哚型Ca~(2+)荧光探针,并对这五种新型吲哚犁Ca~(2+)荧光探针的甲酯形式进行了结构表征。报道了这五种新型吲哚型Ca~(2+)荧光探针的荧光光谱。
5.对设计、合成的新型荧光素类Ca~(2+)荧光探针Fluo-3M的荧光光谱进行了研究,结果表明,Fluo-3M在与Ca~(2+)结合后,荧光强度明显增强。其最大激发波长和发射波长与Fluo-3类似,所有可应用于Fluo-3的荧光成像仪器均适用于这种新型探针,为Fluo-3M的商品化应用奠定了基础。
6.对设计、合成的新型荧光素类Ca~(2+)荧光探针Fluo-3M的离解平衡常数-K_d进行了测定,结果表明,Fluo-3M是一种具有较高亲和力(低K_d值)的Ca~(2+)荧光探针,适用于细胞膜附近的Ca~(2+)浓度的测定。
7.将设计、合成的新型荧光素类Ca~(2+)荧光探针Fluo-3M的乙酸甲酯形式-Fluo-3MAM负载入人胚肾细胞及中国仓鼠卵巢细胞中,应用Olympus IX71型倒置研究级荧光显微镜进行活体细胞中胞内自由Ca~(2+)的检测和成像。结果表明:Fluo-3M具有优良的荧光性能和生物亲和性,可应用于活体细胞的连续测定,是一种性能优良的Ca~(2+)荧光探针。
Ca~(2+) acts as a universal messenger in a variety of cells. Numerous functions of all types of cells are regulated by calcium to a greater or lesser degree. Serving as an intracellular second messenger and mediator,Ca~(2+) plays a very important role in intracellular signal transduction as well as extracellular. Consequently, the measurement of cytosolic Ca~(2+) has become an important investigation area in chemical, biological and medical research.
Fluorescent indicators with the structure of EGTA、BAPTA were developed by Tsien and his colleagues in the 1980's for cytosolic Ca~(2+) detection. Fluorescence probes, which are sensitive, fast-responding and capable of affording high spatial resolution via microscopic imaging, provide a new method in the research of intracellular calcium. Therefore, the design and synthesis of new fluorescence probes for cytosolic Ca~(2+) have arisen much more attention. Among the fluorescent Ca~(2+) probes synthesized, fluorescein-based calcium fluorescent probes and fluorescent probes with an indole structure, which are excitated by visible light and UV light respectively, have been widely used. Nevertheless, the fluorescence probes for Ca~(2+) which can be used widely and commercially are quite limited nowadays.
In order to test the Ca~(2+) in different concentration, improve the biological affinity to Ca~(2+)and the fluorescence intensity, the investigations on the design, synthesis and function test of new fluorescence probes for Ca~(2+) are carried out, mainly including the following several aspects:
1.According to the analysis of the structure of BAPTA,five kinds of novel derivates of BAPTA were synthesized successfully. Furthermore, the structures of these compounds were all confirmed.
2.Have designed and synthesized three novel fluorescein-based calcium fluorescent probes. The methyl ester forms of the new probes were confirmed. The fluorescent spectrum of the novel compounds were reported.
3.Have designed and synthesized five novel fluorescein-based calcium fluorescent probes linked chlorine. The methyl ester forms of the new probes were confirmed. The fluorescent spectrum of the novel compounds were reported. Simultaneously, very useful results about designing of the new probes were obtained from theoretic calculation.
4.Have designed and synthesized five novel calcium fluorescent probes with an indole structure.The methyl ester forms of the new probes were confirmed. The fluorescent spectrum of the novel compounds were reported.
5.The fluorescent spectrum of the novel fluorescein-based calcium fluorescent probe Fluo-3M were investigated. The experimental result shows that the fluorescence intensity enhanced obviously after bonded with Ca~(2+).The fluorescence excitation and emission wavelength maxima for Fluo-3M are nearly the same as those reported for Fluo-3. Thus, fluorescence microscopy applications are applicable for detection of Fluo-3M as well.
6.Have calculated the K_d of the novel fluorescent probe Fluo-3M. The data shows that Fluo-3M has a relatively high affinity to calcium. It can be used to measure the Ca~(2+) distributed near the membrane of the cell.
7.Fluo-3M was injected into HEK-293 cells and CHO cells, the OlympusⅨ71 fluorescent microscope was used for detecting the intracellular calcium and the imaging of the cell. The experimental results show that Fluo-3M which has a high fluorescence intensity and biological affinity can be used in vivo.
引文
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