CN105017298A - 一种氟硼吡咯类化合物及其应用 - Google Patents
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Abstract
本发明涉及用于检测亚硝酰氢(HNO)的荧光探针，具体的说是一种氟硼吡咯类化合物及其应用。氟硼吡咯类化合物如通式Ⅰ所示，并以所述氟硼吡咯类化合物作为HNO的荧光探针。本发明HNO荧光探针的这类化合物，在HNO存在下对应的荧光强度发生变化，可用于HNO的检测，并可大大降低外部检测条件的干扰，提高检测精度。这类化合物作为荧光探针可用于细胞内外HNO水平的检测，不仅对阐明HNO细胞内原位生成机制具有重要的科学意义，而且为治疗心力衰竭新药的发现奠定理论基础，为心力衰竭的治疗提供一种可行性选择。
Description
技术领域
本发明涉及用于检测亚硝酰氢(HNO)的荧光探针，具体的说是一种氟硼吡咯类化合物及其应用。
背景技术
亚硝酰氢(nitroxyl,HNO)是一氧化氮(NO)的单电子还原并质子化的衍生物，但是其所具有的生物和药理作用特征与NO迥然不同。亚硝酰氢可与细胞内抗氧化清除剂硫醇直接发生反应，抑制乙醛脱氢酶的活性；可激活哺乳动物的血管系统中电压控制的K+通道；最新研究表明，HNO可增加正常及心力衰竭(cardiac failure)时心肌的收缩力，同时改善心肌舒张功能。心力衰竭以心肌收缩力下降为主要特征，临床尚缺乏理想的治疗药物，因此HNO这种具有潜在的药理学活性使其成为当前研究的热点。探索亚硝酰氢在正常和心力衰竭状态下的产生、分布和生理功能不仅对阐明其细胞信号传导机制有着重要意义，而且对阐明心力衰竭疾病的发生，对用于心力衰竭新药、新靶标的发现和新药理学治疗策略奠定理论基础，进而为心力衰竭的治疗提供一种可行的选择。
尽管越来越多的实验证据表明HNO在生物医学领域中的重要性，但对其在细胞靶位的产生、分布、浓度差异和迁移路径的研究却受到了瓶颈式的制约。这是因为：HNO存在寿命短，可自发快速二聚化((κ＝8×106M-1s-1)，最终生成一氧化二氮(N2O)和水。目前检测细胞内HNO的常用方法仍为利用通过气相色谱法对其二聚化脱水产物N2O的定量检测，该方法不适于生物体内复杂环境的检测，而且也不能排除其它的N2O生成生理机制。血红素可与HNO生成FeII-NO配合物，可被紫外-可见分光光度计和电子顺磁共振检测。但这种方法存在着FeII-NO配合物在生物体内形成途径较多，并且此产物对氧不稳定等问题。最近基于CuII荧光配合物检测的HNO的探针也被报道。然而该类探针仍易受到细胞内源性还原剂的干扰，而且NO可能会严重干扰检测。虽然上述每一种方法在一定条件下都是可行的，但是关于生命体中HNO的研究所遇到的瓶颈是缺少灵敏而又专一地检测生命系统中HNO靶向浓度变化的检测工具，由此可见，开发一种新的能够实现对生命体内HNO水平进行靶向检测的生物医学工具将是该研究领域的突破点。
发明内容
本发明的目的在于提供一种氟硼吡咯类化合物及其应用。
为实现上述目的，本发明采用的技术方案为：
一种氟硼吡咯类化合物，氟硼吡咯类化合物如通式Ⅰ所示，
通式Ⅰ中，
R1为2-(二苯基膦)苯甲酰基团；
R2为2-(二苯基膦)苯甲酰基团、丁基三苯基鏻基团、N-丙基吗啉基团或C1-25的烷基；
X为N或C；
Y为N或O；
Z为H或卤素；
进一步的说，所述通式Ⅰ中R1为2-(二苯基膦)苯甲酰基团；R2为丁基三苯基鏻基团或N-丙基吗啉基团；X为N；Y为O；Z为H。
一种氟硼吡咯类化合物的应用，以通式Ⅰ所示的所述氟硼吡咯类化合物作为亚硝酰氢的荧光探针。
一种荧光探针，荧光探针为通式Ⅰ所示的以BODIPY)染料作为荧光母体，并在母体R2位置上引入对具备线粒体、溶酶体、内质网定位功能团的季磷盐、吗啉、C1-25烷基碳链或2-(二苯基膦)苯甲酰基团。
所述荧光探针用于定性/定量的检测生理环境下、细胞或生物体内外的亚硝酰氢。
本发明的有益效果：
本发明用于作为HNO荧光探针的化合物，其在HNO存在下对应的荧光强度发生变化，进而可用于水体系、模拟生理环境和细胞内HNO水平的检测。本发明HNO荧光探针的这类化合物，在HNO存在下对应的荧光强度发生变化，可用于HNO的检测，并可大大降低外部检测条件的干扰，提高检测精度。这类化合物作为荧光探针可用于细胞内外HNO水平的检测，不仅对阐明HNO细胞内原位生成机制具有重要的科学意义，而且为治疗心力衰竭新药的发现奠定理论基础，为心力衰竭的治疗提供一种可行性选择。
附图说明
图1为本发明实施例提供的采用的荧光探针对HNO检测前后荧光变化。
图2为本发明实施例提供的所采用的荧光探针对HNO的选择性示意图；其中，横坐标从左至右依次为：亚硝酰氢、一氧化氮、亚硝酸根、硝酸根、过氧化亚硝酰阴离子、双氧水、次氯酸跟、谷胱甘肽、抗坏血酸。
具体实施方式
氟硼吡咯类化合物通式为：
式Ⅰ中，
R1为2-(二苯基膦)苯甲酰基团；
R2为2-(二苯基膦)苯甲酰基团、丁基三苯基鏻基团、N-丙基吗啉基团或C1-25的烷基链；
X为N或C；
Y为N或O；
Z为H或卤素；
优选：通式Ⅰ中X为N；Y为O；Z为H时，所述氟硼吡咯类化合物的通式为：
通式II中：
R1为2-(二苯基膦)苯甲酰基团；
R2为2-(二苯基膦)苯甲酰基团、丁基三苯基鏻基团或N-丙基吗啉基团；
将通式Ⅰ与待测定水体、模拟生理环境或生物体内外的HNO反应从而导致荧光强度的改变，所得通式III结构的化合物；
将通式II结构应用于检测HNO时，其是与HNO作用后，生成具有通式IV结构的化合物，从而导致荧光强度的改变；
通式II可对HNO进行定性、定量的检测。
本发明中使用的术语“烷基”包括直链烷基和支链烷基。如提及单个烷基如“丙基”，则只特指直链烷基，如提及单个支链烷基如“异丙基”，则只特指支链烷基。例如，“C1-6烷基”包括C1-4烷基、C1-3烷基、甲基、乙基、正丙基、异丙基和叔丁基。类似的规则也适用于本说明书中使用的其它基团。
本发明中使用的术语“卤素”包括氟、氯、溴和碘。
本发明中使用的术语“苄基”是指-CH2-Ph基团。当用“任选取代”修饰苄基时，指该苄基可以未取代的形式存在，或者可被合适的取代基在任何合适的位置取代。合适的取代基包括但不限于H、C1-18烷基、CN、COOH、NH2、NO2、OH、SH、C1-6烷氧基、C1-6烷基氨基、C1-6酰氨基、卤素、或C1-6卤代烷基等，只要最终形成的化合物具有本发明期望的性质。优选苄基由COOH、NH2、OH、C1-6烷氧基、卤素任选取代。
具体实施方式
实施例用于进一步说明本发明，但本发明不限于实施例。
实施例1.氟硼吡咯类化合物的制备：
通式Ⅰ中所示氟硼吡咯类化合物由市售对羟基苯乙酮和苯甲醛反应起，合成响应的荧光团BODIPY，然后在荧光团相应的位置分别修饰上不同的定位基团。最后将修饰定位基团的荧光团与2-(二苯基膦)苯甲酸在二氯甲烷溶剂中，由DMAP和EDC催化反应生成相应的氟硼吡咯类化合物。具体实施例如下：
制备式一化合物：
在氩气保护下，BODIPY荧光团(52.9mg，0.1mmol)及2-(二苯基膦)苯甲酸(61.2mg，0.2mmol)、DMAP(24.4mg，0.2mmol)、EDCI(19.2mg，0.1mmol)溶于盛有20ml干燥的二氯甲烷的50ml烧瓶中，常温条件下搅拌24h，TLC追踪。粗产品由氢溴酸中和后由NaBr的饱和溶液洗涤至中性，二氯甲烷萃取，硫酸钠干燥有机层后旋蒸。采用柱层析分离法对产品进行分离，洗脱剂比例(乙酸:甲醇＝3:1v/v)。收集绿色组分，蒸干溶剂后得到式一所示化合物*22mg,收率:20％。
化合物式一的1H NMR(500MHz,CDCl3-D1)δ(ppm):6.73(s,1H),6.90(s,1H),7.16-7.65(m,44H),8.12(d,2H).LC-MS(API-ES):m/zC70H48BF2N3O4P2Calcd1105.3181,found[M]1105.3181.
制备式二化合物：
在氩气保护下，取连有三苯基膦基团的荧光团(84.6mg，0.1mmol)及2-(二苯基膦)苯甲酸(30.6mg，0.1mmol)、DMAP(12.2mg，0.1mmol)、EDCI(9.6mg，0.05mmol)于盛有20ml干燥的二氯甲烷的50ml烧瓶中，常温下搅拌24h，TLC追踪。粗产品由氢溴酸中和后，用NaBr的饱和溶液洗涤至中性，二氯甲烷萃取，硫酸钠干燥有机层后旋蒸。所得固体用二氯甲烷溶解后，用硅胶柱色谱(200-300目)分离。洗脱剂为乙酸乙酯和甲醇(3:1/v/v)，收集绿色组分，蒸干溶剂后得到式二所示化合物28.4mg,收率:25％。
式二化合物的1H NMR(500MHz,CDCl3-D1)δ(ppm):1.31-1.56(m,6H),3.37(t,2H),6.60(s,1H),6.86(s,1H),7.06-8.03(m,46H),8.40(s,1H).LC-MS(API-ES):m/z C73H57BF2N3O3P2 +Calcd1134.3931,found[M+].
制备式三化合物：
取已制备的连有线粒体定位基团的荧光团(84.6mg，0.1mmol)及2-(二苯基膦)苯甲酸(30.6mg，0.1mmol)、4-二甲氨基吡啶DMAP(12.2mg，0.1mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI(9.6mg，0.05mmol)溶于盛有20ml干燥的二氯甲烷的50ml烧瓶中，常温条件下搅拌24h，TLC追踪。粗产品由氢溴酸中和后由NaBr的饱和溶液洗涤至中性，二氯甲烷萃取，硫酸钠干燥有机层后旋蒸。采用柱层析分离法对产品进行分离，洗脱剂比例(乙酸:甲醇＝3:1v/v)。收集绿色组分，蒸干溶剂后得到式三所示化合物17mg,收率:18％。
式三化合物的1H NMR(500MHz,CDCl3-D1)δ(ppm):1.80(m,2H),2.36-2.47(m,6H),3.65(t,4H),4.07(t,2H),5.10(s,2H),7.06-8.03(m,31H),8.50(s,1H).LC-MS(API-ES):m/z C58H48BF2N4O4P Calcd944.3474,found[M+H]+945.3554.
另外，通式Ⅰ所示的其它化合物按照上述的记载制备获得。
现以式二所指化合物为例说明测定过程，以下实施例中涉及到的探针化合物均为式二所指化合物：
实施例2
将制备所得式二化合物作为探针应用于水体系、模拟生理环境和细胞内进行对HNO的检测，模拟生理条件，以下各项实验均在pH＝7.4条件下进行(HEPES缓冲溶液，浓度为40mM)，探针浓度采用10μM。
上述制备所得式二化合物对HNO的光谱响应；于10ml比色管中加入10μM式二化合物，再加入40mM HEPES，然后加入10μM HNO，超纯水定容到10ml，摇匀溶液平衡10min后，将上述工作液加入荧光皿中测定荧光光谱。荧光光谱变化如图1所示。由图1所示该化合物可用于实现生物体内的HNO检测。同时，本发明实施例提供的探针与硫化氢反应后产物结构如下；
实施例3
式二化合物对硫化氢的选择性
测试液pH采用HEPES缓冲溶液控制。取多个10ml比色管，并在每个10ml比色管中加入10μM式二化合物，再加入HEPES缓冲液，然后分别加入如图2所示，待测物依次为：亚硝酰氢、一氧化氮、亚硝酸根、硝酸根、过氧化亚硝酰阴离子、双氧水、次氯酸跟、谷胱甘肽、抗坏血酸。最后用超纯水定容到10ml。摇匀溶液，25℃下平衡10min后，将各个比色管中工作液分别倒入到荧光皿中测定荧光光谱。式二化合物对HNO的选择性如图2所示。并由图可知lysoSeOBOD对硫化氢具有很好的选择性，与NHO作用后，式二化合物对应的荧光增强。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。作为荧光染料是本发明新化合物的一种用途，不能认定本发明的化合物仅用于荧光染料，对于本发明所属技术领域的普通技术人员来说，在基于本发明化合物用作荧光染料的相同作用机理的考虑下，还可以做出若干简单推理，得出本发明的化合物的其他应用用途，都应当视为属于本发明的保护范围。
Claims (5)
1.一种氟硼吡咯类化合物，其特征在于：氟硼吡咯类化合物如通式Ⅰ所示，
通式Ⅰ中，
R1为2-(二苯基膦)苯甲酰基团；
R2为2-(二苯基膦)苯甲酰基团、丁基三苯基鏻基团、N-丙基吗啉基团或C1-25的烷基；
X为N或C；
Y为N或O；
Z为H或卤素。
2.按权利要求1所述的氟硼吡咯类化合物，其特征在于：所述通式Ⅰ中R1为2-(二苯基膦)苯甲酰基团；R2为丁基三苯基鏻基团或N-丙基吗啉基团；X为N；Y为O；Z为H。
3.一种权利要求1所述的氟硼吡咯类化合物的应用，其特征在于：以通式Ⅰ所示的所述氟硼吡咯类化合物作为亚硝酰氢的荧光探针。
4.一种荧光探针，其特征在于：
荧光探针为通式Ⅰ所示的以BODIPY)染料作为荧光母体，并在母体引入对具备线粒体、溶酶体、内质网定位功能团的季磷盐、吗啉、C1-25烷基碳链或2-(二苯基膦)苯甲酰基团。
5.按权利要求4所述的荧光探针，其特征在于：所述荧光探针用于定性/定量的检测生理环境下、细胞或生物体内外的亚硝酰氢。
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| CN108342190B (zh) * | 2018-01-09 | 2020-05-26 | 湖北大学 | 一种比值式检测hno的纳米荧光探针及其制备方法和应用 |
| US11339175B2 (en) | 2018-11-06 | 2022-05-24 | The Board Of Trustees Of The University Of Illinois | Thiol-based fluorescent probe for reactive species |
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