CN113150575B - 一种近红外的萘酰亚胺染料及其制备方法与应用 - Google Patents
一种近红外的萘酰亚胺染料及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于分析化学领域,具体涉及一种近红外的萘酰亚胺染料及其制备方法和应用,其是以含有醛基及羟基的萘酰亚胺衍生物、2‑(3,5,5‑三甲基环己‑2‑烯‑1‑亚基)丙二腈和4‑溴丁酰氯为原料制得所述近红外的萘酰亚胺染料。该近红外的萘酰亚胺染料具有很好的稳定性及优异的光学性能,尤其是引入的丙二腈、4‑溴丁基基团可增强染料的荧光发射。将该近红外的萘酰亚胺染料用于人血清白蛋白(HSA)的检测时,人血清白蛋白可与染料分子相互结合,引发染料吸收光谱和荧光光谱的改变,从而可作为HSA检测的荧光探针,用于尿液中HSA的荧光检测,并具有很好的检测灵敏度。
Description
技术领域
本发明属于分析化学领域,具体涉及一种近红外的萘酰亚胺染料及其制备方法与其在人血清白蛋白的荧光检测上的应用。
背景技术
人血清白蛋白(HSA)是人血浆中的主要载体蛋白,在促进各种药物,脂肪酸和代谢产物的运输中起着至关重要的作用。体液中HSA的含量通常被视为可靠的健康指标,正常尿液中的HSA浓度小于30mg L-1,而在血清中,HSA浓度的正常范围约为35-55g L-1。例如,血清中低水平的HSA被称为低蛋白血症,这可能表明肝衰竭、肝硬化或慢性肝炎。相反,尿液中存在过多的HSA,会导致微量白蛋白尿,可能表明患有肾脏疾病、心血管疾病和糖尿病。因此,由于其高临床和生物相关性,开发有效的HSA检测方法具有重要意义。
如今,已经有文献报道过利用比色技术(Handbook of Lipoprotein Testing,ed.N.Rifai,G.R.Warnick and M.H.Dominiczak,AACC Press,Washingon,DC,USA,2ndedn,2000,pp.298–304;ABC of Kidney Disease,ed.B.Afzali,S.Jayawardene andD.Goldsmith,Blackwell Publishing Ltd.,Oxford,UK,2007,pp.1–10)、免疫测定(Weissleder R,Ntziachristos V.Shedding light onto live molecular targets[J].Nature medicine,2003,9(1):123-128;Pogue B W,Poplack S P,McBride T O,etal.Quantitative hemoglobin tomography with diffuse near-infraredspectroscopy:pilot results in the breast[J].Radiology,2001,218(1):261-266;Xiong J,Cao X,Yang S,et al.Fluorescent probes for detection of protein:frombench to bed[J].Protein and peptide letters,2018,25(6):548-559;Fan J,Sun W,Wang Z,et al.A fluorescent probe for site I binding and sensitivediscrimination ofHSA from BSA[J].Chemical Communications,2014,50(67):9573-9576.)、表面增强拉曼散射(Gomes V S D,H M R,Boto R E F,etal.Barbiturate squaraine dyes as fluorescent probes for serum albuminsdetection[J].Journal of Photochemistry and Photobiology A:Chemistry,2020,400:112710.),芯片电泳法(V J,Yang K L.Using liquid crystals as a readoutsystem in urinary albumin assays[J].Analyst,2011,136(16):3307-3313;Ding X,Yang K L.Antibody-free detection of human chorionic gonadotropin by use ofliquid crystals[J].Analytical chemistry,2013,85(22):10710-10716;V J,SimP H,Choy W T,et al.Detecting proteins in microfluidic channels decorated withliquid crystal sensing dots[J].Langmuir,2012,28(50):17571-17577;WangY R,FengL,Xu L,et al.Arapid-response fluorescent probe for the sensitive andselective detection of human albumin in plasma and cell culture supernatants[J].Chemical Communications,2016,52(36):6064-6067.)等方法检测细胞、血浆和尿液中HSA的含量。虽然这些技术具有高选择性和高灵敏度等优点,但是也具有不稳定性等缺点,且需要昂贵的仪器和耗时的操作。相比之下,基于荧光探针的HSA检测分析则具有简单、灵敏度高、选择性高等优点。
萘酰亚胺染料有着刚性的平面结构和共轭π键结构,萘环上的N位或者4号位上分别含有两个性质不同的反应位点,可以设计不同功能的基团分别引入N位或者4号位上来调节其光物理特性或者给予其特定的功能,例如靶向性、疏水性、亲水性、生物兼容性和生物可降解性等。该类化合物的显著特征是色泽鲜艳、在可见光至近红外区有狭窄而强的吸收带和较好的光稳定性。相对于其它有机染料而言,萘酰亚胺染料由于其优异的荧光发射性能、良好的光学稳定性及易修饰等特点,拥有更广的应用前景。
本发明通过对萘酰亚胺染料的结构进行优化,合成了近红外的萘酰亚胺染料,增强了荧光发射,并实现了其在HSA荧光检测中的应用,具有良好的发展前景。
发明内容
本发明的目的在于提供一种近红外的萘酰亚胺染料及其制备方法与其在HSA荧光检测中的应用。
为了实现上述目的,本发明采用如下的技术方案:
一种近红外的萘酰亚胺染料,其结构式如下:
所述近红外的萘酰亚胺染料的制备方法包括以下步骤:
(2)减压除去溶剂,得粗产品;
(3)经硅胶柱层析纯化,得到所述的近红外萘酰亚胺染料;
其中,步骤(1)中所用溶剂为干燥的二氯甲烷溶液,所述反应的温度为室温,时间为2小时;
步骤(3)所述硅胶柱层析采用体积比为3:1的石油醚和乙酸乙酯的混合溶液作为洗脱剂。
进一步地,所述萘酰亚胺衍生物的合成方法包括如下步骤:
(2)冷却至室温,减压除去溶剂,得粗产品;
(3)经硅胶柱层析纯化,得到所述的萘酰亚胺衍生物;
其中,步骤(1)中所用溶剂为无水乙醇,催化剂为哌啶,所述反应的温度为78℃,时间为12小时;
步骤(3)所述硅胶柱层析采用体积比为10:1的二氯甲烷和甲醇的混合溶液作为洗脱剂。
进一步地,所述含有醛基及羟基的萘酰亚胺衍生物的合成方法包括如下步骤:
(2)冷却至室温,析出固体并过滤,得粗产品;
(3)粗产品经硅胶柱层析纯化,得到所述的含有醛基及羟基的萘酰亚胺衍生物;
其中所用溶剂为三氟乙酸;
所述回流反应的温度为80℃,时间为12小时;
所述硅胶柱层析采用体积比为30:1的二氯甲烷和甲醇的混合溶液为洗脱剂。
进一步地,所述含有羟基的萘酰亚胺衍生物的合成方法包括如下步骤:
(2)冷却至室温,析出固体并过滤,得粗产品;
(3)粗产品经硅胶柱层析纯化,得到所述的含有羟基的萘酰亚胺衍生物;
其中所用溶剂为47wt%的氢碘酸;
所述回流的温度为130℃,时间为12小时;
所述硅胶柱层析采用体积比为100:1的二氯甲烷和甲醇的混合溶液为洗脱剂。
进一步地,所述含有甲氧基的萘酰亚胺衍生物的合成方法包括如下步骤:
(2)冷却至室温,减压除去溶剂,得粗产品;
(3)粗产品经硅胶柱层析纯化,得到所述的含有甲氧基的萘酰亚胺衍生物;其中,步骤(1)中所用溶剂为甲醇,催化剂为硫酸铜,所述反应的温度为65℃,时间为12小时;
步骤(3)所述硅胶柱层析采用体积比为4:1的石油醚和乙酸乙酯的混合溶液作为洗脱剂。
进一步地,所述溴代萘酰亚胺衍生物的合成方法包括如下步骤:
(2)冷却至室温,减压除去溶剂,得粗产品;
(3)粗产品经硅胶柱层析纯化,得到所述的溴代萘酰亚胺衍生物;
其中,步骤(1)中所用溶剂为无水乙醇,所述反应的温度为78℃,时间为12小时;
步骤(3)所述硅胶柱层析采用体积比为12:1的石油醚和乙酸乙酯的混合溶液作为洗脱剂。
(2)冷却至室温,倒入冰水析出固体并过滤,得粗产品;
(3)粗产品经硅胶柱层析纯化,得到所述的含有甲氧基的萘酰亚胺衍生物;其中,步骤(1)中所用溶剂为无水乙醇,催化剂为哌啶,所述反应的温度为78℃,时间为12小时;
步骤(3)所述硅胶柱层析采用体积比为8:1的石油醚和乙酸乙酯的混合溶液作为洗脱剂。
所得近红外的萘酰亚胺染料可制成荧光响应的HSA探针,用于尿液中HSA的荧光检测。
本发明将2-(3,5,5-三甲基环己-2-烯-1-亚基)丙二腈连接到含有醛基及羟基的萘酰亚胺骨架上,通过酯键再接上4-溴丁酰基氯,得到了一种近红外的萘酰亚胺染料。其中,由于分子内旋转染料分子在水中没有荧光,在加入HSA后,通过染料分子特异性的***到HSA的疏水腔中,使染料分子无法内旋转,分子荧光释放,从而可实现对HSA的检测。
相对于现有技术的显著优点在于:
本发明所得萘酰亚胺染料荧光探针水溶性较好,稳定性好,光学性能优异,将其用于尿液中HSA的荧光检测能表现出很好的特异性和检测灵敏度。经检测,该染料探针在PBS缓冲液中对HSA具有很好的特异性,对其它金属离子(Na+、K+、Ca2+等)、氨基酸(脯氨酸、组氨酸、半胱氨酸、精氨酸等)和酶(胰蛋白酶、脂肪酶、糜蛋白酶等)无响应,其检测限为14.09μgL-1(0.21nM)。
附图说明
图1为近红外的萘酰亚胺染料(5μM)的PBS缓冲液中滴加不同浓度HSA(0-0.20mgmL-1)时的荧光光谱图(λex=520nm,λem=670nm,slit=10nm/10nm,PMT=600V)。
图2为近红外的萘酰亚胺染料(5μM)在670nm处的荧光强度与HSA浓度(0-0.05mgmL-1)的线性关系图(λex=520nm,slit=10nm/10nm,PMT=600V)。
图3为近红外的萘酰亚胺染料(5μM)在不同pH(3-10)的水溶液中对HSA(0.15mgmL-1)的响应情况图。
图4为500W氙灯照射3小时条件下近红外的萘酰亚胺染料(5μM)与HSA(0.15mg mL-1)作用的荧光稳定性。
图5为近红外的萘酰亚胺染料(10μM)对不同离子的荧光光谱响应情况图。
图6为近红外的萘酰亚胺染料(10μM)对不同氨基酸和酶的荧光光谱响应情况图。
图7为近红外的萘酰亚胺染料(5μM)在实际尿液中对HSA的荧光光谱响应情况图。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
实施例1
于50mL两口圆底烧瓶中,将1.90g(13.7mmol)异佛尔酮,1.36g(20.6mmol)丙二腈和0.45mL哌啶溶于25mL乙醇中,在氮气的保护下于78℃回流12小时。反应结束后,将混合物溶液倒入50mL冰水中,将沉淀物过滤,用水洗涤并真空干燥,硅胶柱提纯,洗脱剂为PE:EA=8:1(v:v),得到无色晶体1.52g,产率59%。
1H NMR(400MHz,CDCl3)δ6.62(s,1H),2.51(s,2H),2.17(s,2H),2.03(s,3H),1.01(s,6H)
实施例2
在250mL圆底烧瓶中,将1.00g(3.61mmol)4-溴-1,8-萘二甲酸酐和1.30mL正丁胺(13.0mmol)溶于100mL乙醇中,于78℃回流12小时。反应结束后,减压除去溶剂乙醇,硅胶柱提纯,洗脱剂为PE:EA=12:1(v:v),得到白色固体0.84g,产率70%。
1H NMR(400MHz,CDCl3)δ8.65(d,J=7.2Hz,1H),8.56(d,J=8.5Hz,1H),8.41(d,J=7.9Hz,1H),8.04(d,J=7.8Hz,1H),7.84(t,J=7.9Hz,1H),4.17(t,J=7.5Hz,2H),1.75-1.68(m,2H),1.50-1.40(m,2H),0.98(t,J=7.3Hz,3H);13C NMR(100MHz,CDCl3)δ163.44,163.41,133.00,131.85,131.04,130.97,130.41,130.03,128.78,127.96,123.03,122.16,40.35,30.14,20.37,13.84;HRMS(ESI):Calcd for C16H14NO2Br([M+H]+):332.0286,Found:332.0290.
实施例3
于100mL圆底烧瓶中,将0.66g(1.98mmol)实施例2制备的溴代萘酰亚胺衍生物0.86g(15.9mmol)甲醇钠和0.01g无水合硫酸铜溶于50mL甲醇中,于65℃回流12小时。反应结束后,减压除去溶剂甲醇,硅胶柱提纯,洗脱剂为PE:EA=4:1(v:v),得到浅黄色固体0.53g,产率94%。
1H NMR(400MHz,CDCl3)δ8.57(d,J=7.3Hz,1H),8.52(d,J=8.3Hz,2H),7.67(t,J=7.8Hz,1H),7.01(d,J=8.3Hz,1H),4.16(t,J=7.5Hz,2H),4.12(s,3H),1.75-1.68(m,2H),1.50-1.40(m,2H),0.98(t,J=7.4Hz,3H);13C NMR(100MHz,CDCl3)δ163.72,163.10,159.98,132.55,130.64,128.39,127.73,125.25,122.57,121.67,114.40,104.62,55.84,39.72,30.05,20.28,13.74;HRMS(ESI):Calcd for C17H18NO3([M+H]+):284.1287,Found:284.1289.
实施例4
于50mL圆底烧瓶中,将0.11g(0.39mmol)实施例3制备的含有甲氧基的萘酰亚胺衍生物和20mL 47wt%氢碘酸的混合物于130℃回流12小时。反应结束后,冷却并减压抽滤,将收集的固体用水洗涤(5mL×3)并真空干燥,硅胶柱提纯,洗脱剂为DCM:MeOH=100:1(v:v),得到黄色针状固体93mg,产率90%。
1H NMR(400MHz,d6-DMSO)δ8.52(d,J=8.3Hz,1H),8.45(d,J=7.2Hz,1H),8.35(d,J=8.2Hz,1H),7.75(t,J=7.8Hz,1H),7.15(d,J=8.2Hz,1H),4.02(t,J=7.4Hz,2H),1.64-1.56(m,2H),1.39-1.30(m,2H),0.92(t,J=7.3Hz,3H);13C NMR(100MHz,d6-DMSO)δ164.12,163.45,160.69,133.99,131.56,129.60,129.32,126.04,122.83,122.26,113.07,110.41,30.21,20.29,14.19;HRMS(ESI):Calcd for C16H16NO3([M+H]+):270.1130,Found:270.1129.
实施例5
于50mL两口圆底烧瓶中,将160mg(0.59mmol)实施例4制备的含有羟基的萘酰亚胺衍生物和250mg(1.77mmol)六亚甲基四胺溶于15mL三氟乙酸中,在氮气的保护下于80℃回流12小时。反应结束后,将混合物溶液倒入100mL冰水中,将沉淀物过滤,用水洗涤并真空干燥,硅胶柱提纯,洗脱剂为DCM:MeOH=30:1(v:v),得到黄色固体143mg,产率82%。
1H NMR(400MHz,d6-DMSO)δ10.39(s,1H),8.73(d,J=8.3Hz,1H),8.71(s,1H),8.59(d,J=7.3Hz,1H),7.88(t,J=7.8Hz,1H),4.05(t,J=7.4,2H),1.62(dd,J=14.8,7.7Hz,2H),1.38(dd,J=14.9,7.4Hz,2H),0.95(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ196.59,165.87,163.86,163.20,135.04,134.28,131.95,130.51,127.19,123.04,122.98,115.30,115.05,40.44,30.32,20.49,13.97;HRMS(ESI):Calcd for C17H16NO4([M+H]+):298.1074,Found:298.1074.
实施例6
于50mL两口圆底烧瓶中,将148mg(0.49mmol)实施例5制备的含有醛基及羟基的萘酰亚胺衍生物94.0mg(0.50mmol)实施例1制备的2-(3,5,5-三甲基环己-2-烯-1-亚基)丙二腈和5滴哌啶溶于10mL乙醇中,在氮气的保护下于78℃回流12小时。反应结束后,减压除去溶剂乙醇,硅胶柱提纯,洗脱剂为DCM:MeOH=10:1(v:v),得到黑色晶体228mg,产率98%。
1H NMR(400MHz,CDCl3:MeOD=10:1(v:v))δ8.76(s,1H),8.62(d,J=8.4Hz,1H),8.56(d,J=7.3Hz,1H),7.71(dd,J=14.8,6.7Hz,2H),7.23(d,J=15.9Hz,1H),6.92(s,1H),4.16(dd,J=15.8,8.3Hz,2H),2.63(s,2H),2.58(s,2H),1.80-1.63(m,2H),1.45(dd,J=14.9,7.4Hz,2H),1.12(s,6H),0.99(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3:MeOD=10:1(v:v))δ169.66,164.64,164.07,154.86,131.70,131.06,130.94,130.18,129.69,129.40,126.09,123.98,123.35,122.53,119.58,114.06,113.61,112.73,77.96,43.01,40.17,39.23,32.00,30.18,29.65,27.88,20.31,13.76;HRMS(ESI):Calcd for C29H28N3O3([M+H]+):466.2125,Found:466.2123.
实施例7
于25mL两口圆底烧瓶中,将50.0mg(0.10mmol)实施例6制备的萘酰亚胺衍生物和15.0mg(0.15mmol)干燥的三乙胺溶于5mL干燥的二氯甲烷中,逐滴滴入4-溴丁酰氯(24.0mg,0.02mL,0.12mmol),氮气条件下室温反应2小时反应结束后,减压除去溶剂乙醇。硅胶柱提纯,洗脱剂为PE:EA=3:1(v:v),得到黄色絮状固体27.4mg,产率41%。
1H NMR(400MHz,CDCl3)δ8.86(s,1H),8.61(d,J=7.1Hz,1H),8.09(d,J=8.2Hz,1H),7.80(t,J=7.8Hz,1H),7.28(d,J=10.3Hz,1H),7.16(d,J=16.1Hz,1H),6.97(s,1H),4.19(t,J=4.0Hz,2H),3.64(t,J=6.0Hz,2H),3.16(t,J=6.6Hz,2H),2.63(s,2H),2.50(s,2H),2.43-2.38(m,2H),1.78-1.67(m,2H),1.45(dd,J=14.9,7.4Hz,2H),1.11(s,6H),0.99(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ170.38,168.69,163.74,163.25,152.19,148.89,133.89,131.88,129.10,129.02,128.29,127.85,127.46,126.97,126.05,125.56,123.35,121.51,113.19,112.28,80.84,43.04,40.48,39.37,32.58,32.16,31.82,30.26,28.13,27.05,20.41,13.91;HRMS(ESI):Calcd for C33H33BrN3O4([M+H]+):614.1649,Found:614.1650.
应用实施例
1.在含有5μM实施例7所得近红外萘酰亚胺染料的PBS缓冲液中,进行HSA的荧光滴定实验,结果见图1、2。
由图1可见,在PBS缓冲液中,近红外萘酰亚胺染料溶液的荧光处于淬灭状态,当向体系中加入HSA时,670nm处的荧光强度逐渐增强,当加入HSA的浓度为0.20mg mL-1时,荧光强度大约有95倍的增强。
如图2所示,HSA的浓度在0-0.05mg mL-1范围内,溶液的荧光强度与HSA浓度呈现良好的线性关系(R2=0.9998,k=7.442×103)。根据公式3σ/k,计算得其检测限为14.09μg L-1(0.21nM)。
2.环境中的pH值会有一定的变化范围,因此在不同pH(3、4、5、6、7、8、9、10)下进行了HSA的荧光滴定实验,结果见图3。
由图3可见,在不同pH下,近红外萘酰亚胺染料的荧光都处于猝灭状态,加入HSA(0.15mg mL-1)后,荧光强度增强,染料在pH值7-10荧光强度都很强且恒定,表明染料探针可以在很宽的pH值范围内对HSA的检测几乎没有影响,有很好的稳定性。
3.对所得近红外萘酰亚胺染料自身对HSA响应稳定性做了考察,结果见图4。由图可知,用500W辐照灯超过3小时,萘酰亚胺染料本身的荧光强度没有明显变化几乎保持不变,显示出非常好的光稳定性。
4.考察近红外萘酰亚胺染料对体系中存在的一些金属离子、氨基酸,蛋白酶等的荧光光谱响应情况见图5、6。
由图5、6可见,所述近红外萘酰亚胺染料仅对HSA有明显响应,而对一些金属离子(Na+、K+、Ca2+等)、氨基酸(脯氨酸、组氨酸、半胱氨酸、精氨酸等)和酶(胰蛋白酶、脂肪酶、糜蛋白酶等)均无响应,因此,该探针可用于尿液中HSA含量的快速检测。
5.在实际样品尿液中对HSA的检测,荧光光谱响应情况见图7。
如图7所示,在尿液中探针荧光强度随着HSA浓度增加而增强,该染料探针可用于检测实际尿液中的HSA。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (10)
3.根据权利要求2所述的制备方法,其特征在于:步骤(1)中所用溶剂为干燥的二氯甲烷溶液,所述反应的温度为25℃,时间为2小时。
10.一种如权利要求1所述的近红外萘酰亚胺染料在人血清白蛋白HSA荧光检测中的应用,其特征在于:将所述近红外的萘酰亚胺染料制成响应HSA的荧光探针。
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