CN111978248A - 一种多位点可修饰聚集诱导发光喹啉腈衍生物、制备方法及其应用 - Google Patents
一种多位点可修饰聚集诱导发光喹啉腈衍生物、制备方法及其应用 Download PDFInfo
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- WDXARTMCIRVMAE-UHFFFAOYSA-N quinoline-2-carbonitrile Chemical class C1=CC=CC2=NC(C#N)=CC=C21 WDXARTMCIRVMAE-UHFFFAOYSA-N 0.000 title claims abstract description 23
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- RIIPFHVHLXPMHQ-UHFFFAOYSA-N [4-(dimethylamino)phenyl]boronic acid Chemical compound CN(C)C1=CC=C(B(O)O)C=C1 RIIPFHVHLXPMHQ-UHFFFAOYSA-N 0.000 description 1
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
技术领域
本发明属于精细化工技术领域,具体涉及对喹啉腈氮乙基末端以及喹啉腈的6位引入不同取代基增加喹啉腈母体的可修饰位点,构建水溶性荧光探针实现对血清蛋白的实时、快速、线性响应。
背景技术
香港科技大学唐本忠院士在2001年,发现了聚集诱导发光(AIE)现象化合物(Chem.Commun.,2001,1740-1741)HPS,其表现出与传统荧光分子截然相反的发光性质,自此AIE现象被广泛应用于各种领域,尤其是生物成像领域(Angew.Chem.Int.Ed.2020,59,9812-9825)。朱为宏课题组通过合理设计将传统苯并吡喃腈的氧原子改变成氮乙基基团获得了新性AIE母体喹啉腈(QM)(ACS Appl.Mater.Interfaces 2013,5,192-198),并且通过Knoevenagel反应合成了一些列不同波长、形貌可调喹啉腈衍生物应用于各种生物成像(Angew.Chem.Int.Ed.2015,54,7275-7280)。然而由于喹啉腈本身的结构特性导致其可修饰位点紧缺,难以进行功能化修饰和拓展。同时传统聚集诱导发光化合物在水中容易发生聚集,产生荧光导致其在生物体系应用极大受限(Chem.Sci.,2019,10,398–405.Angew.Chem.Int.Ed.2020,59,2-12)。
血清白蛋白作为血浆中最丰富的蛋白质之一,在维持血液的渗透压方面起着非常重要的作用,并且还充当许多脂肪酸,代谢产物和药物的载体。低白蛋白血症是指血液中人血清蛋白(HSA)浓度低(<35g/L)的健康状况,通常是由于白蛋白产量降低或损失增加所致(Angew.Chem.Int.Ed.2020,59,3131-3136)。因此如何实时快速准确检测血液中HAS的含量至关重要。
发明内容
针对上述现有技术存在的问题,本发明的目的是为了克服现有技术的不足,提供一种多位点取代的喹啉腈衍生物,并实现对含有疏水空腔的蛋白(比如血清蛋白)的体外线性响应。
本发明提出一种多位点可修饰聚集诱导发光喹啉腈衍生物,其为式I所示化合物
式Ⅰ中,
R1为N,N-二甲基-4-(噻吩-2-基)苯胺或N,N-二苯基-4-(噻吩-2-基)苯胺中的任意一种;
R2为羟基或卤素或二甲氨基或三甲胺或羧基的任意一种;
R3为卤素或二甲氨基或三甲胺基或N,N-二甲苯胺或三苯胺或吡啶或羧基或醛基的任意一种。
本发明还提供一种合成上述喹啉腈衍生物的方法,其步骤是以6-取代-2甲基喹啉衍生物为起始原料,一次经过与相应碘乙基取代物进行反应(季铵盐化反应)、与丙二腈进行Michael加成消除、及响应的芳醛进行Knoevenagel缩合反应得到目标物(式I化合物)
本发明另一目的在于提供上述多位点可修饰喹啉腈衍生物荧光染料用于体外实时快速检测血清蛋白(包括牛血清蛋白BSA和人血清蛋白HSA)的含量。
附图说明
图1.染料I-1的核磁氢谱。
图2.染料I-2的单晶结构图谱。
图3.染料I-3的核磁氢谱。
图4.染料I-3在乙醇和水混合溶剂中不断增加水含量的紫外吸收光谱(10-5mol/L)。
图5.染料I-3在乙醇和水混合溶剂中不断增加水含量的荧光发射光谱(10-5mol/L)。
图6.染料I-3在乙醇和水混合溶剂中不断增加水含量荧光强度在720nm处的变化(10-5mol/L)。I0:纯水中720nm处的荧光强度。
图7.染料I-3(10-5mol/L)在PBS中随着牛血清蛋白(BSA)增加的紫外吸收光谱。
图8.染料I-3(10-5mol/L)在PBS中随着牛血清蛋白(BSA)增加的荧光光谱。
图9.染料I-3(10-5mol/L)在PBS中随着牛血清蛋白(BSA)增加荧光强度在720nm处的变化。I0:纯水中720nm处的荧光强度。
图10.染料I-3(10-5mol/L)在PBS中随着人血清蛋白(HSA)增加的紫外吸收光谱。
图11.染料I-3(10-5mol/L)在PBS中随着人血清蛋白(HSA)增加的荧光光谱。
图12.染料I-3(10-5mol/L)在PBS中随着人血清蛋白(HSA)增加的荧光增加荧光强度在720nm处的变化。I0:纯水中720nm处的荧光强度。
具体实施方式
下面通过实施例对本发明作进一步的阐述,其目的仅在于更好地理解本发明的内容。因此,所举之例并不限制本发明的保护范围:
实施例1
(1)染料I-1的合成:
在50mL单口烧瓶中加入溴甲基喹啉(1g,4.5mmol),碘乙醇(1.42g,8.3mmol),乙醇(20mL),氮气保护下60℃加热24h,冷却至室温,通过减压旋蒸,得到黑绿色固体(1.6g,4.0mmol),产率:89.9%,直接用于下步反应。
在50mL单口烧瓶中上一步产物(1.6g,4.0mmol),丙二腈(0.528g,8.0mmol),乙醇钠(0.54g,8.0mmol)乙醇(20mL),氮气保护下60℃加热20h,冷却至室温,通过减压旋蒸去除溶剂,通过柱层析分离得到产物(0.4g,1.2mmol)产率:30%。
1H-NMR(400MHz,DMSO-d6,ppm):δ9.0(S,1H,Ar-H),8.0(d,J=4.4Hz,1H,Ar-H),6.8(S,1H,Ar-H),5.0(S,1H,OH),4.5(S,2H,CH2CH2),3.7(S,2H,CH2CH2)2.6(S,3H,CH3)。(图1)
(2)染料I-2的合成:
在50mL单口烧瓶中上一步产物(2.5g,8.0mmol),5-三苯胺基噻吩-2甲醛(2.8g,8.0mmol),吡啶(40mL),氮气保护下70℃加热24h,冷却至室温,通过减压旋蒸去除溶剂,通过柱层析分离得到产物(1.9g,2.9mmol)产率:36.3%。结构通过单晶表征(图2)。
(3)染料I-3的合成:
在50mL单口烧瓶中上一步产物(30.0mg,0.07mmol),5-苯环二甲氨基噻吩-2甲醛(32.0g,0.14mmol),吡啶(10mL),氮气保护下70℃加热24h,冷却至室温,通过减压旋蒸去除溶剂,通过柱层析分离得到产物(24.0mg,0.04mmol)产率:54.2%。
1H-NMR(400MHz,DMSO-d6,ppm):δ8.9(d,J=8.4Hz,1H,Ph-H),8.0(d,J=8.4Hz,1H,Ph-H),7.9-8.0(t,J=7.8Hz,1H,thiophene-H),7.6-7.7(m,2H,one for alkene-H,onefor thiophene-H),7.5(t,J=6.6Hz,3H,Ph-H),7.3(d,J=3.6Hz,1H,Ph-H),7.0-7.1(d,J=15Hz,1H,alkene-H),7.0(s,1H,Ph-H),6.7(d,J=8.5Hz,3H,Ph-H),5.0(t,J=7.3Hz,2H,CH2CH2NMe3),3.8(s,2H,CH2CH2NMe3),3.3(s,9H,NMe3),2.9(s,6H,NMe2).(图3)
(4)染料I-4的合成:
在50mL圆底烧瓶中加入6-二甲氨基-2-甲基喹啉(400.1mg,2.15mmol),碘乙烷(2.9g,18.63mmol),乙醇(15mL)60℃搅拌12h,冷却至室温,旋干,柱色谱分离(DCM:MeOH=10:1),得粗产品320.7mg,0.94mmol,产率:43.72%。用于下一步反应。
1H-NMR(400MHz,DMSO-d6,ppm):δ8.71(d,J=8.48Hz 1H,Ar-H),8.34(m,1H,Ar-H),7.85(t,J=8.60Hz,2H,Ar-H),7.76(q,J1=9.80Hz,J2=2.96Hz Ar-H),7.26(t,J=2.96Hz,1H,Ar-H)4.89(m,2H,CH2CH3),3.12(s,6H,NMe2),1.49(m,3H,CH2CH3).
(5)染料I-4的合成:
在50mL圆底烧瓶中加入6-二甲氨基-2-甲基喹啉(320.7mg,0.94mmol),丙二腈(123.81g,1.87mmol),乙醇(5mL),加醇钠(127.25,1.87mmol),常温搅拌过夜,用二氯甲烷进行柱色谱分离,得黄色产物(84.2mg,0.30mmol),产率32.18%。
1H-NMR(400MHz,DMSO-d6,ppm):δ7.98(d,J=2.84Hz,1H,Ar-H),7.91(d,J=9.72Hz,1H,Ar-H),7.46(d,J1=9.92Hz,J2=9.92Hz,1H,Ar-H),6.93(s,Ar-H),4.53(d,J=6.92Hz,2H,CH2CH3),3.70(s,9H,NMe3),2.71(s,3H,Me),1.34(m,3H,CH2CH3).
(6)染料I-5的合成:
将6-二甲氨基喹啉腈(82.3mg,0.3mmol),碘甲烷(425.8mg,3.0mmol)加入50mL圆底烧瓶中,加入DMF 15mL,室温搅拌20h。旋干溶剂,柱色谱分离,得黄色化合物(22.5mg,产率17.8%)。
1H-NMR(400MHz,DMSO-d6,ppm):δ9.25(d,J=2.88Hz,1H,Ar-H),8.51(q,J1=9.44Hz,J1=2.84Hz,1H,Ar-H),8.30(d,J=9.92Hz,2H,Ar-H),6.93(s,Ar-H),4.53(d,J=6.92Hz,2H,CH2CH3),3.70(s,9H,NMe3),2.71(s,3H,Me),1.34(m,3H,CH2CH3)
(7)染料I-6的合成:
在50mL圆底烧瓶中加入6-溴-喹啉腈(264.1mg,0.84mmol),对二甲氨基苯硼酸(180.3g,1.09mmol),Pd(PPh3)4(48.53mg,0.042),K2CO3(5M,10mL),THF(15mL)100℃回流12h,冷却至室温,分液去除水层,旋干溶剂,柱色谱分离(DCM:PE=1:1),得黄色产品(172.9mg,0.49mmol).
1H-NMR(400MHz,DMSO-d6,ppm):δ9.15(d,J=4.5Hz 1H,Ar-H),8.19(m,1H,Ar-H),8.07(d,J=9.3Hz 1H,Ar-H),7.65(d,J=8.8Hz,2H,Ph-H),6.86(d,J=8.9Hz,1H,Ph-H),6.82(s,1H,Ar-H),4.18(q,J1=13.72Hz,J1=6.72Hz 2H,CH2CH3),2.97(s,6H,NMe2),2.67(s,3H,Me),1.37(t,J=6.8Hz 3H,CH2CH3).
(8)染料I-7的合成
在50mL圆底烧瓶中加入6-二甲苯胺-喹啉腈(47.9mg,0.14mmol),碘甲烷(191.8mg,1.4mmol),DMF(约20mL),反应8h,旋干溶剂,柱色谱分离得黄色产品(62.2mg,0.13mmol)产率:92.9%
1H-NMR(400MHz,DMSO-d6,ppm):δ9.29(d,J=2.0Hz 1H,Ar-H),8.34(d,J=2.0Hz,1H,Ar-H),8.33(m,1H,Ar-H),8.19(d,J=9.2Hz,2H,Ph-H),8.16(d,J=8.8Hz,1H,Ph-H),8.02(d,J=9.2Hz,1H,Ph-H),6.88(s,1H,Ar-H),4.52(q,J1=13.80Hz,J1=6.80Hz 2H,CH2CH3),3.66(s,9H,NMe3),2.70(s,3H,Me),1.38(t,J=7.2Hz 3H,CH2CH3).
实施例2
染料I-3在乙醇水体系的吸收和荧光光谱
取实施例1制备的染料I-3溶于分析纯二甲基亚砜中,制成1.0×10-3M的储备液。然后制备不同比例乙醇(EtOH)/水混合溶剂2970μL。取30μL上述储备液加入到已制备的不同比例EtOH/水混合溶剂中,混合均匀后转移至光学石英比色皿(10×10mm)中测试其吸收和荧光光谱。如图4-6所示,染料I-3在400-550nm表现出宽吸收峰,且最大吸收波长位于在450nm;以450nm作为激发波长,染料I-7的最大发射峰大约位于720nm处,位于近红外区域,斯托克斯位移达到270nm;并且染料I-3在纯水中无荧光具有生物应用的潜质,在混合溶剂中随着乙醇含量增加其荧光增强,具有典型的聚集荧光增强特性。
实施例3
染料I-3对于牛血清蛋白BSA的荧光标记
为了研究染料I-3对于BSA的响应,我们首先配置不同浓度的BSA(0、40、80、120、160、200、240、480、800μg/mL)的PBS(pH=7)溶液2970μL。然后每份加入30μL实时例2中的储备液,混合均匀后迅速转移至光学比色皿中测其吸收和荧光光谱。如图7-9所示,随着BSA浓度增加,吸收光谱逐渐变宽,荧光强度逐渐上升,而且在720nm处荧光增强具有非常良好的线性关系(R2=0.996)。
实施例4
染料I-3对于牛血清蛋白BSA的荧光标记
鉴于染料对于BSA优秀的响应能力,我们进一步研究了染料I-3对于人血清蛋白的荧光标记能力。研究显示(图10-12)染料I-3对于HAS同样具有非常良好的线性响应能力,具有用于实时快速检测人体内血清蛋白浓度的能力。
综上所述,喹啉腈衍生物I-3含有水溶性季铵盐结构,在水中溶解性较好,且在水中没有荧光,具有在生物体系应用的潜力。喹啉腈衍生物I-3在不良溶剂乙醇中发生聚集表现出聚集诱导发光的性质。
喹啉腈衍生物I-5含有水溶性季铵盐结构,在水中溶解性较好,且在水中没有荧光,具有在生物体系应用的潜力。
喹啉腈衍生物I-7含有水溶性季铵盐结构,在水中溶解性较好,且在水中没有荧光,具有在生物体系应用的潜力。
Claims (5)
3.一种多位点可修饰聚集诱导发光喹啉腈衍生物的制备方法,其步骤是以6-取代-2甲基喹啉衍生物为起始原料,一次经过与相应碘乙基取代物进行季铵盐化反应、与丙二腈进行Michael加成消除、及响应的芳醛进行Knoevenagel缩合反应得到式如权利要求1所述的化合物I。
4.一种多位点可修饰聚集诱导发光喹啉腈衍生物的应用,是作为荧光染料用于体外实时快速检测血清蛋白的含量。
5.根据权利要求4所述的一种多位点可修饰聚集诱导发光喹啉腈衍生物的应用,其特征在于,所述体外实时快速检测血清蛋白的含量是牛血清蛋白BSA或人血清蛋白HAS的检测。
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