CN111285866B - 一种检测Hg2+/ClO-的双通道小檗碱基荧光探针及其制备方法和应用 - Google Patents
一种检测Hg2+/ClO-的双通道小檗碱基荧光探针及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种检测Hg2+/ClO‑的双通道小檗碱基荧光探针及其制备方法和应用。本发明利用小檗碱为原料，制备出双通道检测Hg2+/ClO‑的小檗碱类荧光探针。盐酸小檗碱1经脱甲氧基和氯离子得到酮类化合物2；化合物2经酸化异构得到酚类化合物3；化合物3经Duff醛基化反应得到对羟基醛类化合物4；化合物4与氨基硫脲缩合得到缩氨基硫脲类席夫碱化合物5。化合物5能专一性识别Hg2+和ClO‑，在365nm紫外光照射下，在Hg2+存在下探针发出橙红色荧光；在ClO‑存在下探针则发出绿色荧光，而其他阴离子和金属离子的存在则不发生荧光。因此化合物5可作为双通道荧光探针，具有很好的应用价值。
Description
技术领域
本发明属于精细有机合成技术领域和新型光致发光材料合成技术领域，涉及一种可同时检测Hg2+/ClO-的新型双通道小檗碱基荧光探针及其制备方法和应用。
背景技术
在各种金属离子中，Hg2+被认为是最危险的重金属离子之一，可破坏人体细胞功能，引起心脏病、肝功能衰竭、DNA损伤、肾衰竭、神经系统损伤等疾病，甚至危及生命；HOCl和ClO-作为消毒剂广泛应用于医药卫生领域，然而，过量的次氯酸盐会损害人体DNA和蛋白质，导致许多疾病，如风湿、心血管疾病、动脉粥样硬化、帕金森症和癌症等疾病。因此，对Hg2+和ClO-进行高选择性的实时检测具有重要的意义。相对于传统的化学分析方法，有机荧光探针法具有快速、灵敏度高等优点，已被广泛应用于各种有毒有害物质的检测中。
小檗碱，又名黄连素，是一种天然异喹啉类生物碱，主要存在于毛莨科、罂粟科、小檗科等植物中，具有抗菌、抗炎、解热、镇痛、抗心律失常、抗血小板聚集、降压等生理活性。
近年来，关于小檗碱的研究主要集中在生物医学方面。Wiegrebe等对小檗碱的8位进行修饰，得到了一系列小檗碱衍生物，并对其抗菌活性进行了测定；Hayashi等发现，小檗碱能在病毒侵入宿主细胞后和病毒复制前起作用，抑制人巨细胞病毒的复制；JunYin等对肥胖鼠小鼠研究过程中发现小鼠空腹胰岛素及胰岛素抵抗指数分别下降了46％和48％；Kim等将小檗碱与哌嗪连接合成了小檗碱类的Mannich碱，以考察其抗氧化和抗癌活性，取得了较好地研究效果；宋丹青等设计、合成了一系列小檗碱酯类和醚类前药，并研究了其降低胆固醇的生物利用度。
作为一种具有π-π共轭体系的季铵盐化合物，小檗碱具有一定的荧光性能，是合成荧光探针等光学材料的重要前体。黄志纾等通过对小檗碱的9位进行修饰和改造，得到一系列小檗碱衍生物，这些衍生物与G－四链体的结合能力更髙，且随着DNA浓度增强，荧光逐渐增强；乔江鹏等研究了10种常见小檗碱类化合物的荧光性质实验，发现多数小檗碱类化合物荧光性较弱，但当加入β-环糊精或者十二烷基硫酸钠时，荧光明显增强；陈金香等合成了小檗碱的二聚体，并通过与荧光素标记的单链DNA结合，形成荧光猝灭的化合物，当其与癌症指示相关的RNA结合后，荧光恢复。
小檗碱虽可作为合成有机荧光探针的前体，但由于其在水溶液中荧光性能较弱，需要通过添加包合物或荧光素来实现荧光的指示变化。本发明通过对小檗碱的结构进行化学修饰，首次合成了在甲醇和水的混合溶剂中具有一定荧光性能的缩氨基硫脲类席夫碱，并成功用于Hg2+/ClO-的检测。
发明内容
针对现有技术中存在的不足，本发明的目的在于提供一种检测Hg2+/ClO-的新型双通道小檗碱基荧光探针，能满足使用需求。本发明的另一目的是提供一种检测Hg2+/ClO-的新型双通道小檗碱基荧光探针的制备方法。
技术方案：为了实现上述发明目的，本发明采用的技术方案为：
新型双通道小檗碱基荧光探针，结构式如下：
所述的新型双通道小檗碱基荧光探针的制备方法，反应式为：
具体包括如下工艺步骤如下：
1)盐酸小檗碱经脱甲氧基化、酸异构化得到的酚类化合物3，在乌洛托品(HMTA)/三氟乙酸(TFA)作用下发生Duff醛基化反应得到化合物4。具体的制备方法包括：
(1)在50mL的圆底烧瓶中加入1.0g化合物3，10～20mLTFA，0.5～1.0g HMTA，回流反应6～10h后冷却，滴加5～15mL 3.0M HCl,继续回流反应1～3h；
(2)将反应液迅速倒入20～40mL冰水中，用60～100mL的乙酸乙酯萃取3次，合并有机相，采用蒸馏水和饱和食盐水洗涤，蒸去溶剂后得到粗产物，经柱层析(硅胶300～400目，溶剂：CH2Cl2：CH3OH＝10:1)纯化，得红色固体化合物4。
2)化合物4与氨基硫脲缩合得到缩氨基硫脲类席夫碱化合物5。具体制备方法包括：
(1)在25mL的圆底烧瓶中加入0.1g化合物4，10～20mL乙醇，0.2～0.4g氨基硫脲，滴加1～5滴三乙胺，室温搅拌8h；
(2)反应液经蒸馏脱除乙醇后，蒸馏剩余物用甲醇重结晶，得红色固体颗粒状物质，即为化合物5。
所述的双通道小檗碱基荧光探针在检测检测Hg2+和/或ClO-中的应用。
化合物5能专一性识别Hg2+和ClO-，在365nm紫外光照射下，在Hg2+存在下探针发出橙红色荧光；在ClO-存在下探针则发出绿色荧光，而其他阴离子和金属离子的存在则不发生荧光。化合物5可作为双通道荧光探针应用于水体中Hg2+和ClO-的检测。
有益效果：与现有的研究成果相比，本发明的优点在于：化合物5能专一性识别Hg2+和ClO-，在365nm紫外光照射下，在Hg2+存在下探针发出橙红色荧光；在ClO-存在下探针则发出绿色荧光，而其他阴离子和金属离子的存在则不发生荧光。化合物5可作为双通道荧光探针应用于水体中Hg2+和ClO-的检测。
附图说明
图1是新型双通道小檗碱基荧光探针分别与Hg2+和ClO-反应的日光下颜色对比图；
图2是新型双通道小檗碱基荧光探针与不同被测物质产生的荧光吸收光谱图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
实施例1新型双通道小檗碱基荧光探针的制备
反应式为：
具体步骤如下：
10-甲氧基-5,6-二氢-9H-[1,3]间二氧杂环戊烯并[4,5-g]异喹啉并[3,2-α]异喹啉-9-酮(化合物2)的制备：在250mL的圆底烧瓶中加入20.0g盐酸小檗碱，并将圆底烧瓶置于油浴中，将磨口抽气接头一端连接圆底烧瓶，另一端连接循环真空水泵，缓慢升温至185℃，待黄色的小檗碱完全转化为红色的小檗红碱，实验结束，反应时间为30～60min；反应体系用无水甲醇重结晶3次，得到红色固体小檗红碱，得率为75.7％；1H NMR(400MHz,Methanol-d4)δ:9.24(s,1H),7.96(s,1H),7.50(d,J＝8.0Hz,1H),7.40(s,1H),6.85(d,J＝9.0Hz,2H),6.05(s,2H),4.60(t,J＝6.0Hz,2H),3.88(s,3H),3.13(t,J＝6.0Hz,2H)；13CNMR(400MHz,Methanol-d4)δ:164.35,151.06,150.82,149.43,147.26,135.47,133.65,130.63,124.08,122.85,121.63,119.62,109.20,108.26,105.79,103.25,56.75,55.54,28.94；ESI-MS(m/z):322.1095[M+H]+。
9-羟基-10-甲氧基-5,6-二氢-[1,3]间二氧杂环戊烯并[4,5-g]异喹啉并[3,2-α]异喹啉-7氯化物(化合物3)的制备：在150ml的圆底烧瓶中加入10.0g化合物2，60mL无水乙醇，20mL 3.0M的盐酸，在20℃下搅拌8h，反应产物经甲醇重结晶3次，得到黄色固体化合物3，得率为98％；1H NMR(400MHz,DMSO-d6)δ:11.31(s,1H),9.97(s,1H),8.88(s,1H),8.12(d,J＝8.9Hz,1H),7.82(s,1H),7.75(d,J＝8.9Hz,1H),7.10(s,1H),6.21(s,2H),4.96(t,J＝6.3Hz,2H),4.09(s,3H),3.25(t,J＝6.3Hz,2H)；13C NMR(400MHz,DMSO-d6)δ:149.58,147.61,145.70,145.30,143.75,136.52,132.39,130.33,125.43,120.56,119.80,118.03,117.58,108.32,105.29,101.94,56.99,54.89,26.48；ESI-MS(m/z):322.1074[M-Cl]+。
12-甲酰基-9-羟基-10-甲氧基-5,6-二氢-[1,3]间二氧杂环戊烯并[4,5-g]异喹啉并[3,2-α]异喹啉-7-氯化物(化合物4)的制备：在50mL的圆底烧瓶中加入1.0g化合物3，20mLTFA，525mg HMTA，80℃回流搅拌，反应时间为8h，冷却，滴加10mL 3.0M HCl,80℃下继续回流搅拌2h；将反应液迅速倒入冰水中，乙酸乙酯萃取3次，合并有机相，蒸馏水和饱和食盐水洗涤至中性，蒸去溶剂后得到的粗产物，经柱层析(300～400目硅胶，溶剂：CH2Cl2：CH3OH＝10:1)分离得到化合物4，得率为34.6％；1H NMR(600MHz,DMSO-d6)δ:10.19(s,1H),9.28(s,1H),9.08(s,1H),7.72(s,1H),7.56(s,1H),7.02(s,1H),6.15(s,2H),4.60(t,J＝6.3Hz,2H),3.77(s,3H),3.10(t,J＝6.4Hz,2H),1.24(s,1H)；ESI-MS(m/z):350.1049[M-Cl]+。
12-((硫脲亚肼基)甲基)-9-羟基-10-甲氧基-5,6-二氢-[1,3]间二氧杂环戊烯并[4,5-g]异喹啉并[3,2-α]异喹啉-7-氯化物(化合物5)的制备：在25mL的圆底烧瓶中加入100mg化合物4，10mL C2H5OH，237.0mg硫代氨基脲，滴加3滴三乙胺，室温搅拌反应8h。反应结束后，反应液经旋转蒸发除去溶剂后，加入5mL甲醇重结晶3次，得到红色固体颗粒状化合物5，得率为96.3％；1H NMR(400MHz,DMSO-d6)δ:11.07(s,1H),9.95(s,1H),9.17(s,1H),8.63(s,1H),8.57(s,1H),8.38(s,1H),8.28(s,1H),7.72(s,1H),7.03(s,1H),6.17(s,2H),4.90(t,J＝6.3Hz,2H),4.10(s,3H),3.17(d,J＝6.9Hz,2H)；ESI-MS(m/z):423.1121[M-Cl]+。
实施例2
将一定量的化合物5溶于CH3OH/PBS(V/V＝7:3)的混合溶剂中，配置成1×10-5M，溶液呈黄色透明状态，随着Hg2+(1×10-4M)和ClO-(1×10-4M)的加入，溶液体系分别迅速变为淡黄色和无色，在日光下观察如图1所示。
实施例3
将一定量的化合物5溶于CH3OH/PBS(V/V＝7:3)的混合溶剂中，配置成1×10-5M，分别加入10eq的Hg2+、K+、Na+、Ca2+、Fe2+、Cr3+、Zn2+、Mg2+、Ni2+、Co2+、Cu2+、ClO-、Cl-、Br-、I-、NO3 -、H2PO4 -、HS-、HSO3 -、S2O3 2-、SO4 2-、S2-、SO3 2-、CO3 2-、H2O2、Cys等被测物质。结果显示(图2)，加入Hg2+后，365nm紫外灯下荧光探针显示橙红色荧光；加入ClO-后，365nm紫外灯下荧光探针显示绿色荧光；加入其他干扰物质，则不会导致荧光探针的荧光发生变化。由此说明，化合物5是一种检测Hg2+/ClO-的新型双通道荧光探针。
Claims (6)
1.一种双通道小檗碱基荧光探针，其特征在于，结构式为：
2.权利要求1所述的双通道小檗碱基荧光探针的制备方法，其特征在于，包括以下步骤：
1)盐酸小檗碱经脱甲氧基化、酸异构化得到的酚类化合物3，在乌洛托品/三氟乙酸作用下发生Duff醛基化反应得到化合物4；
2)化合物4与氨基硫脲缩合得到缩氨基硫脲类席夫碱化合物5；
具体反应式为：
3.根据权利要求2所述的双通道小檗碱基荧光探针的制备方法，其特征在于，步骤1)中，在乌洛托品/三氟乙酸作用下，化合物3发生Duff醛基化反应得到化合物4；具体的制备方法包括：
(1)在50mL的圆底烧瓶中加入1.0g化合物3，10～20mLTFA，0.5～1.0gHMTA，回流反应6～10h后冷却，滴加5～15mL3.0MHCl,继续回流反应1～3h；
(2)将反应液迅速倒入20～40mL冰水中，用60～100mL的乙酸乙酯萃取3次，合并有机相，采用蒸馏水和饱和食盐水洗涤，蒸去溶剂后得到粗产物，经柱层析纯化，得红色固体化合物4。
4.根据权利要求2所述的双通道小檗碱基荧光探针的制备方法，其特征在于，步骤2)中，化合物4与氨基硫脲缩合得到缩氨基硫脲类席夫碱化合物5的具体制备方法包括：
(1)在25mL的圆底烧瓶中加入0.1g化合物4，10～20mL乙醇，0.2～0.4g氨基硫脲，滴加1～5滴三乙胺，室温搅拌8h；
(2)反应液经蒸馏脱除乙醇后，蒸馏剩余物用甲醇重结晶，得红色固体颗粒状物质，即为化合物5。
5.根据权利要求1所述的双通道小檗碱基荧光探针在检测Hg2+和/或ClO-中的应用。
6.根据权利要求5所述的应用，其特征在于，所述的双通道小檗碱基荧光探针能专一性识别Hg2+和ClO-，在365nm紫外光照射下，在Hg2+存在下探针发出橙红色荧光；在ClO-存在下探针则发出绿色荧光。
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