CN108484650B - 一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物及其制备方法和应用 - Google Patents
一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种3,5‑二苯并咪唑基‑8‑对甲基苯基氟硼荧类衍生物,属于氟硼荧衍生物技术领域。所述氟硼荧类衍生物具有下述式Ⅰ所示结构:
Description
技术领域
本发明属于氟硼荧衍生物技术领域,具体为一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物及其制备方法和应用。
背景技术
内质网是真核细胞内非常重要的多功能细胞器,细胞内蛋白质的合成、折叠、修饰,脂类和固醇合成是以内质网为场所而进行的。在完成这些基本生理功能的同时,内质网凭借其庞大的膜结构成为协调信号转导的枢纽平台,维持细胞内环境的稳定。当遗传或环境损伤引起内质网应激,内质网应激过强或持续时间过久可引起细胞凋亡,从而引发一些列的疾病[参见:J.E.Vance,Traffic,2015,16,1.],专一性跟踪检测细胞内内质网的形态及分布有利于深入了解和研究许多相关的生理活动[参见:Z.Yang,Y.He,J.H.Lee,W.-S.Chae,W.X.Ren,J.H.Lee,C.Kang and J.S.Kim,Chem.Commun.,2014,50,11672.]。
近年来,对于标记内质网的靶向试剂有一些报道,但具体靶向定位标记的机理并不十分明确。我们需要更多的研究来设计可靠的内质网标记靶向试剂,目前常用的是将靶向基团与荧光团相结合来构筑新型的内质网靶向试剂[参见:W.Xu,Z.Zeng,J.-H.Jiang,Y.-T.Chang and L.Yuan,Angew.Chem.,Int.Ed.2016,55,13658]。
在众多荧光染料中,氟硼络合的二吡咯甲烷类荧光染料又称氟硼荧具有较高的摩尔消光系数、荧光量子产率高、稳定的光谱性质、高的光热及化学稳定性、分子量小和较低的细胞毒性等优点,作为生物分子、离子等荧光探针和细胞器成像荧光试剂等已被广泛应用[参见:(a)S.Arai,S.-C.Lee,D.Zhai,M.Suzuki and Chang,Y.T.Sci.Rep.2014,4,6701;(b)X.Kong,F.Su,L.Zhang,J.Yaron,F.Lee,Z.Shi,Y.Tian and Meldrum,D.R.Angew.Chem.,Int.Ed.2015,54,12053;(c)L.Yang,Y.-J.Ji,J.-F.Yin,Y.Wu,H.Fan,Y.Zhang and G.-C.Kuang,Soft Matter,2016,12,8581.]。有很多基于氟硼荧骨架的标记分子已经被广泛做为细胞器的标准标记试剂在市场上流通,如LysoTrackerTM Red、LysoTrackerTM Green、ER-TrackerTM Red和ER-TrackerTM Green[参见:I.Johnson,M.T.Z.Spence,The Molecular Probes Handbook,A Guide to Fluorescent Probes andLabeling Technologies,11th Ed.;Molecular Probes:Eugene,OR,2010.]。但是,这些常见的市售内质网靶向试剂结构复杂,合成不方便,价格昂贵。
因此,提供一种以用于内质网标记的荧光分子,结构简单,合成简便,生产成本低,成为了本领域技术人员亟待解决的问题。
发明内容
本发明的目的在于提供一种可以用于内质网标记的氟硼荧类衍生物小分子,将本发明氟硼荧类衍生物用于内质网荧光标记,可以有效解决现有技术中内质网靶向试剂结构复杂,合成不方便,价格昂贵的问题。
本发明还提供该氟硼荧类衍生物的制备方法及应用。
本发明目的通过以下技术方案来实现:
一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物,具有下述式Ⅰ所示结构:
其中:R1,R2,R3为氢、氘、烷基、烷氧基、羰基、酯基、卤素、取代芳基或取代杂芳基中的一种或两种。进一步,所述烷基、烷氧基、酯基或羰基的碳链为碳个数为0~40的直链、支链或环链。
进一步,所述取代芳基和取代杂芳基中的取代基团为烷基、烷氧基或羰基中的一种或几种。更进一步,所述烷基、烷氧基或羰基的碳链为碳个数为0~40的直链、支链或环链。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的一个具体实施例,具有下述式Ⅱ所示结构:
一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的制备方法,包括:
1)将8-对甲基苯基氟硼荧与苯并咪唑类衍生物,氧化剂和溶剂混合均匀,随后在无水无氧条件下反应,反应式如下:
2)反应完成后,冷却至室温,移除溶剂后加入二氯甲烷将反应体系溶解,再经硅藻土过滤,并用二氯甲烷洗涤,合并滤液,减压移去溶剂,剩余物用硅胶柱层析分离纯化,真空干燥即可制得式Ⅰ化合物。
进一步,上述步骤1)中,所述无水无氧条件可以采取惰性气体保护的方式,更进一步可以优选为氮气气氛下反应。
本发明制备方法所用合成路线为C–H/N–H直接氧化偶联反应,与传统的氟硼荧氨化制备技术相比较,缩短了较为冗长的有机合成步骤,避免了底物预活化的繁琐过程,提高了反应的兼容性,增加了合成反应总产率。
作为本分发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的制备方法的一个具体实施例,所述氧化剂为一水合醋酸铜、醋酸铜、氯化铜、溴化铜、三氟乙酸酮、三氟甲烷磺酸铜(Ⅱ)、乙酰丙酮铜、碳酸银、氧化银、醋酸银、硝酸银、六氟锑酸银、氧气、醋酸碘苯、苯醌、二氯二氰苯醌、过二硫酸钠、过二硫酸铵、过二硫酸钾、二叔丁基过氧化物中的一种或多种。
作为本分发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的制备方法的一个具体实施例,所述溶剂为甲醇、乙醇、四氢呋喃、二氯甲烷、三氯甲烷、乙醚、二甲基亚砜、苯、邻二氯苯、氯苯、甲苯、二甲苯、均三甲苯、环己烷、石油醚、叔戊醇、1,4-二氧六环、1,2-二氯乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或多种。
作为本分发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的制备方法的一个具体实施例,所述8-对甲基苯基氟硼荧的反应浓度为0.0001~10mol/L。进一步优选为0.1~8mol/L,0.5~5mol/L,1~3mol/L。
作为本分发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的制备方法的一个具体实施例,所述8-对甲基苯基氟硼荧,苯并咪唑类衍生物,氧化剂的摩尔比为1:(0.01~50):(0.01~100)。进一步优选为1:(0.1~40):(10~80),1:(5~30):(20~60)。
作为本分发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的制备方法的一个具体实施例,所述步骤1)的反应温度为-40~160℃,进一步优选为20~100℃,40~80℃;时间为0.1~720h,进一步优选为10~30h。
本发明还提供所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用,其在细胞内质网专一性荧光显影和荧光标记中的应用。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用的一个具体实施例,包括以下步骤:
步骤1:将细胞于培养基中培养;
步骤2:将培养后的细胞去除培养基,加入3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的缓冲液,培养;
步骤3:步骤2培养结束后,将培养玻底皿经荧光共聚焦显微镜成像。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用的一个具体实施例,所述细胞为HepG2细胞。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用的一个具体实施例,所述培养基为含有10%胎牛血清的DMEM(H)培养基。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用的一个具体实施例,所述3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的缓冲液浓度为2.5μM的磷酸盐缓冲液。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用的一个具体实施例,步骤1中的培养条件为37℃下培养24小时。
作为本发明所述一种3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的应用的一个具体实施例,包括以下步骤:
向含有10%胎牛血清的DMEM(H)培养基中通入5%CO2,将HepG2细胞于37℃下培养24小时;将培养基去除,加入2.5μM化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的磷酸盐缓冲液,培养30分钟;待培养结束后,取出培养玻底皿,用磷酸盐缓冲液清洗2~3次后,将培养玻底皿经荧光共聚焦显微镜成像。
与现有技术相比,本发明具有以下有益效果:
与现有的市售内质网荧光标记试剂相比,本发明3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物,合成路线更加简洁、高效、环境友好,产物价格低廉、容易大量获取。具体表现为:
1、本发明所用合成路线为C–H/N–H直接氧化偶联反应,与传统的氟硼荧氨化制备技术相比较,缩短了较为冗长的有机合成步骤,避免了底物预活化的繁琐过程,提高了反应的兼容性,增加了合成反应总产率。
2、与市售的内质网标记试剂ER-Tracker Red和ER-Tracker Green相比,本发明化合物合成简单,价格低廉。ER-Tracker Red和ER-Tracker Green的价格高达4863元/100μg(Thermo Fisher Scientific公司),而我们的产物则相对的便宜很多,合成原料中,即使是氧化剂用最为昂贵的AgOAc,其成本价格也才289元/25g(安耐吉公司),而其它合成原料都是市场上便宜易得的化合物,本申请氟硼荧类衍生物价格大概在2000~5000元/1g。同时在本发明的反应条件下,产率可以达到80%以上。所以采用本发明氟硼荧类衍生物作为内质网荧光标记的成本将远低于市售的标记试剂。
附图说明
图1为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物的结构通式。
图2为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧核磁图谱H谱。
图3为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧核磁图谱C谱。
图4为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的紫外可见光吸收光谱和荧光发射光谱。
图5为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧标记细胞内质网的细胞成像图。
图6为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧在HepG2细胞中的CCK8细胞毒性实验结果。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明实施例中,HepG2细胞株采购于ATCC(American Type CultureCollection)公司,10%胎牛血清采购于Hyclone公司,DMEM(H)(Dulbecco’s modifiedessential medium)培养基采购于美国Gibco。内质网染料ER-TrackerTM Green采购于Thermo Fisher Scientific公司。
实施例1
3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的合成
将8-对甲基苯基氟硼荧(14.1mg,0.05mmol),苯并咪唑(23.6mg,0.20mmol),AgOAc(33.4mg,4.0equiv),二甲基亚砜(1.0mL)加入反应管,在氮气条件下搅拌均匀后加热到80℃,反应12小时;具体反应式如下:
反应完成后,将反应管冷却至室温,移除溶剂后加入10mL二氯甲烷将反应体系溶解,再经硅藻土过滤并用10~20mL的二氯甲烷洗涤,合并滤液,减压移去溶剂,剩余物用硅胶柱层析(二氯甲烷/石油醚/乙酸乙酯=10:10:1,v/v/v)分离纯化,真空干燥后得到黑色固体目标产物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧21.3mg,产率83%。
本实施例产物二苯并咪唑基-8-对甲基苯基氟硼荧核磁图谱H谱和C谱分别如图2及图3所示,结构数据表征如下:
1H NMR(400MHz,CDCl3)δ=2.53(s,3H),6.75(d,J=4.4Hz,2H),7.15(d,J=4.4Hz,2H),7.30-7.36(m,4H),7.42(d,J=8.0Hz,2H),7.46-7.49(m,2H).7.55(d,J=8.0Hz,2H),7.85-7.87(m,2H),8.60(s,2H).13C NMR(100MHz,CDCl3)δ=21.7,111.2,114.3,121.2,123.9,124.4,129.7,130.1,132.4,133.0,133.9,142.1,143.4,143.5,143.6,143.8,146.3,146.5.HRMS(ESI+):计算值C30H21BF2N6Na[M+Na]+:537.1781,实测值537.1780。
实施例2
实施例1制备得到的化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的紫外-可见-近红外吸收光谱图和荧光发射谱图
将化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧溶于二氯甲烷中,配成1×10- 5mol/L,取2.5mL放入比色皿中,测定紫外-可见-近红外吸收以及荧光发射光谱。
图4为化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的紫外可见光吸收光谱和荧光发射光谱,其中黑色实线表示紫外可见光吸收光谱,黑色虚线表示荧光发射光谱。从图4中可以看出,化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的吸收光谱最大吸收峰位于546nm;荧光发射光谱最大吸收峰位于576nm,斯托克斯位移为30nm。
实施例3
实施例1制备得到的化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧与市售内质网染色剂ER-TrackerTM Green在HepG2细胞中的荧光共聚焦共成像
首先,向含有10%胎牛血清的DMEM(H)培养基中通入5%CO2,将HepG2细胞于37℃下培养24小时。将培养基去除,加入2.5μM化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的磷酸盐缓冲液,随后加入1μM市售内质网染色剂ER-TrackerTM Green于37℃下共同培养30分钟。待培养结束后,取出培养玻底皿,用磷酸盐缓冲液清洗2~3次后,将培养玻底皿经荧光共聚焦显微镜成像。
图5为化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的荧光成像图(激发波长:553nm,发射波长收集范围:550-650nm)。通过与市售内质网染色剂ER-TrackerTM Green的荧光成像图(激发波长:488nm,发射波长收集范围:450-550nm)相对比可以直观地看出,化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧在细胞中的分布和市售内质网染色剂ER-TrackerTM Green基本一致,corresponding Pearson’s系数达到0.96,说明化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧具有优异的内质网示踪效果,能专一性标记细胞内的内质网。
实施例4
实施例1制备得到的化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的CCK8细胞毒性实验
将处于对数生长期的HepG2细胞接种于96孔培养板中,每孔接种3000个细胞,在37℃下用通入5%CO2的含有10%胎牛血清的DMEM(H)培养基中培养过夜。待细胞完全贴壁后,向其中加入不同浓度的化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧,每组浓度另设3个复孔和空白对照孔。加样后继续培养细胞24小时,使用CCK8检测法检测细胞存活率。
图6为3,5-二苯并咪唑基-8-对甲基苯基氟硼荧在HepG2细胞中的CCK8细胞毒性实验结果。如图6所示,在0.25~4μM的浓度范围内,化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧的细胞存活率均非常高(存活率超过90%),在8μM时存活率才会明显降低(存活率小于40%),表明化合物3,5-二苯并咪唑基-8-对甲基苯基氟硼荧在我们的标记工作浓度内毒性是很小的,可以忽略不计。
实施例5
在实施例1的制备方法中,分别采用氘、烷基、烷氧基、羰基、酯基、卤素、取代芳基或取代杂芳基代替R1,R2和R3中的氢。其它条件不变,成功制备出了一系列能实现细胞内质网专一性荧光显影和荧光标记的3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物。其中以实施例1中制备的产品在细胞内质网荧光显影和荧光标记效果最好。
实施例6
在实施例1或5的制备方法中,调整相关参数进行系列实验:
在步骤1)中分别选择-40℃,-20℃,0℃、20℃、40℃、60℃、100℃、120℃、140℃、160℃代替80℃;反应时间控制在0.1~720h;
分别控制8-对甲基苯基氟硼荧类衍生物,苯并咪唑类衍生物,氧化剂的摩尔比为1:(0.01~50):(0.01~100);
用一水合醋酸铜、醋酸铜、氯化铜、溴化铜、三氟乙酸酮、三氟甲烷磺酸铜(Ⅱ)、乙酰丙酮铜、碳酸银、氧化银、硝酸银、六氟锑酸银、氧气、醋酸碘苯、苯醌、二氯二氰苯醌、过二硫酸钠、过二硫酸铵、过二硫酸钾、二叔丁基过氧化物代替醋酸银;
用甲醇、乙醇、四氢呋喃、二氯甲烷、三氯甲烷、乙醚、苯、邻二氯苯、氯苯、甲苯、二甲苯、均三甲苯、环己烷、石油醚、叔戊醇、1,4-二氧六环、1,2-二氯乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺代替二甲基亚砜。
通过实验参数筛选发现上述各条件下均可成功制备出能实现细胞内质网专一性荧光显影和荧光标记的3,5-二苯并咪唑基-8-对甲基苯基氟硼荧类衍生物。其中以实施例1中制备的产品在细胞内质网荧光显影和荧光标记效果最好。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
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US5274113A (en) * | 1991-11-01 | 1993-12-28 | Molecular Probes, Inc. | Long wavelength chemically reactive dipyrrometheneboron difluoride dyes and conjugates |
CN102923696A (zh) * | 2011-08-10 | 2013-02-13 | 中国科学院理化技术研究所 | 一种光催化制备石墨烯的方法 |
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US5274113A (en) * | 1991-11-01 | 1993-12-28 | Molecular Probes, Inc. | Long wavelength chemically reactive dipyrrometheneboron difluoride dyes and conjugates |
CN102923696A (zh) * | 2011-08-10 | 2013-02-13 | 中国科学院理化技术研究所 | 一种光催化制备石墨烯的方法 |
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基于C-H/N-H氧化偶联快速构筑BODIPY-唑类荧光分子库;章华星等;《中国化学会第四届卟啉与酞菁学术研讨会》;20170706;第20页 * |
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