CN109651336B - 一种基于药物分子的检测硫化氢荧光探针及其制备方法 - Google Patents

一种基于药物分子的检测硫化氢荧光探针及其制备方法 Download PDF

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CN109651336B
CN109651336B CN201910131574.5A CN201910131574A CN109651336B CN 109651336 B CN109651336 B CN 109651336B CN 201910131574 A CN201910131574 A CN 201910131574A CN 109651336 B CN109651336 B CN 109651336B
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hydrogen sulfide
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牟心茹
孙国新
刘晓磊
梁帅
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Abstract

本发明公开了一种基于药物分子检测硫化氢分子荧光探针的合成方法，具体为（2‑（2,6‑二氧代哌啶‑3‑基）‑1,3‑二氧代异吲哚‑4‑基）2,4‑二硝基苯磺酸酯的制备方法。本发明所涉及的探针以药物分子作为母核，荧光核是3‑羟基沙利度胺。该合成过程简单，反应条件温和，易纯化，选择性高，抗干扰能力强，可以灵敏快速的检测出样品中的硫化氢。该方法操作简单，在环境检测中具有重要的实际应用价值，在生物医学等领域具有潜在的应用价值。

Description

一种基于药物分子的检测硫化氢荧光探针及其制备方法
技术领域
本发明涉及一种新型的基于药物分子的检测硫化氢荧光探针的制备方法，属于化学分析检测技术领域。
背景技术
硫化氢(H2S)是一种无色、易燃、易溶于水的酸性气体, 有刺激性气味的信号分子。H2S不仅污染大气, 含H2S的水会发臭, 对混凝土和金属都也有侵蚀破坏作用。此外，研究发现H2S 在许多生理过程中扮演着重要角色。目前，已经报道了多种检测H2S的荧光探针。将叠氮基还原为氨基的荧光增强型的H2S 荧光探针被广泛接受和应用。这类探针是通过改变含有不同含叠氮基的荧光团来设计的。而这类探针在细胞、组织或水体中对H2S 进行实时传感, 且具有高灵敏度和可视化成像的仍是一大挑战。
沙利度胺，又名酞胺哌啶酮、反应停，为谷氨酸衍生物。近年来，研究发现沙利度胺及其衍生物具有免疫调节和抗肿瘤的作用，对许多疾病有很好的治疗效果。Sven S.Kampmann等人合成了一系列的多功能沙利度胺衍生物，并确定了其荧光特性，可用于进一步的生物学或物理学性质研究。硫化氢水平的异常与许多疾病密切相关，所以基于沙利度胺自身结构特点，可应用于检测硫化氢的荧光探针的合成。目前，未见以3-羟基沙利度胺作为荧光核的研究及作为检测H2S分子探针母核的相关报道。
发明内容
本发明公开了一种基于药物分子的检测硫化氢荧光探针的合成方法，采用3-羟基沙利度胺和2,4-二硝基苯磺酰氯为原料，以N,N- 二异丙基乙胺作为碱（缚酸剂），磺酸酯基作为识别硫化氢的基团。
本发明采取的技术方案为，一种检测硫化氢的荧光探针，该探针的合成路线如下所示：
Figure 135747DEST_PATH_IMAGE001
将3-羟基沙利度胺和 N,N- 二异丙基乙胺溶于二氯甲烷中，冷却至0℃，分批加入定量的2,4-二硝基苯磺酰氯，在室温氩气氛围下搅拌16 h，然后浓缩，通过层析柱法得到纯的产物。
本发明中探针的使用方法：将探针溶于乙腈和磷酸缓冲溶液中，室温下进行测试。加入硫氢化钠后，磺酸酯基断裂，进而引起荧光基团荧光变化，表现为荧光绿。反应过程如下所示：
Figure 937481DEST_PATH_IMAGE002
本发明的有益效果在于：(1) 合成简单，易纯化；（2）对硫化氢有较高的选择性和抗干扰能力；（3）该探针用已知的药物分子做为母核，选择性强，灵敏度高，在生物医学等领域具有潜在的应用价值。
附图说明
图1为本发明合成探针的核磁滴定图，以及探针与不同NaHS浓度的核磁滴定图。
图2为本发明合成的探针在不同NaHS浓度下的荧光光谱图。
图3为本发明合成探针对不同物质的荧光光谱图。
具体实施方式
实施例1 （2,6-二氧代哌啶-3-基）-1,3-二氧代异吲哚-4-基）2,4-二硝基苯磺酸酯的制备
将3-羟基沙利度胺(137 mg, 0.5 mmol)和 N,N- 二异丙基乙胺(130 mg, 1.0mmol)溶于二氯甲烷(10 mL)中,冷却至0℃，分批加入2,4-二硝基苯磺酰氯(160 mg, 0.6mmol)，在室温氩气氛围下搅拌16 h，然后浓缩，通过层析柱分析方法得到纯的探针产物(产量：148 mg, 产率:58.8%)。
1H NMR (400 MHz, DMSO-d6), δ：11.13(s, 1H), 8.95(d, J = 2.8 Hz, 1H),8.44 (dd, J = 9.2, 2.8 Hz, 1H), 8.07-7.97 (m, 1H), 7.91 (d, J = 7.3 Hz, 1H),7.76 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 5.09 (dd, J = 12.9, 5.3Hz, 1H), 2.94-2.75 (m, 1H), 2.63-2.52 (m, 1H), 2.47-2.31 (m, 1H), 2.05-1.92(m, 2H)。
13C NMR (100 MHz, DMSO- d6) δ：173.10, 170.02, 166.63, 164.71, 154.27,149.80, 142.72, 139.86, 138.32, 134.30, 130.07, 127.94, 122.43, 121.74,121.31, 120.23, 49.44, 31.28, 22.26。
实施例2
合成的硫化氢荧光探针随NaHS加入当量的增加荧光谱图的变化
取实施例1中制备的硫化氢荧光探针溶于乙腈中，用PBS缓冲溶液稀释，加入不同当量（0-30eq）的NaHS标准溶液，测其荧光性质。荧光谱图如图2。由图可以看出，荧光强度随着NaHS加入当量的增加而增强。
实施例3
合成的硫化氢荧光探针对不同离子的选择性
为了验证该探针是否具有专一的选择性和较强的抗干扰能力, 我们选择了各种阴离子(Cl-, AcO-, H2PO4 -, HCO3 -, CO3 2-, H2PO4 -, SO4 2-, Br-, I-, NO2-, NO3-, HS-, F-)并进行荧光测试。发现其荧光强度几乎没有什么变化, 而加入NaHS之后探针的荧光显著增强。因此, 本发明的探针可以作为一种检测H2S 的有较高选择性的荧光探针。

Claims (4)

1.一种基于药物分子的检测硫化氢荧光探针，其特征在于具有如下结构。
Figure 82785DEST_PATH_IMAGE001
2.权利要求1的基于药物分子的检测硫化氢荧光探针
Figure 349818DEST_PATH_IMAGE002
的制备方法，
其合成步骤为以3-羟基沙利度胺为原料，N,N-二异丙基乙胺为碱，以二氯甲烷为溶剂，分批加入2,4-二硝基苯磺酰氯；反应完成后，用甲醇淬灭，真空浓缩，得到粗产物，通过柱层析方式获得提纯得到一种对硫化氢有较高的选择性和抗干扰能力目标产物。
3.如权利要求2所述一种基于药物分子的检测硫化氢荧光探针的制备方法，其特征在于：反应温度为0-25℃，反应时间为16h，反应在氩气氛围下进行。
4.如权利要求1所述一种基于药物分子的检测硫化氢荧光探针，其特征在于，所述探针是采用药物分子沙利度胺作为母核，3-羟基沙利度胺为荧光核。
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