CN111000979A - 一种基于角蛋白的硫化氢供体及其合成方法和应用 - Google Patents
一种基于角蛋白的硫化氢供体及其合成方法和应用 Download PDFInfo
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Abstract
本发明公开了一种基于角蛋白的硫化氢供体及其合成方法和应用，该合成包括如下步骤：将角蛋白溶于缓冲液中，加入活化剂，进行反应得到溶液A；将小分子硫化氢供体溶于有机溶剂中，然后加入到溶液A中，继续反应得反应液B；将反应液B透析后，冷冻干燥得到基于角蛋白的硫化氢供体。本发明合成的基于角蛋白的硫化氢具有良好的水溶性，解决了难以在水环境中不溶解的问题；采用角蛋白大分子供体延长了硫化氢释放的时间，解决了小分子供体释放过快的问题。本发明合成方法简单易行、无毒且成本低，可以大规模生产应用，实现与其他材料或分子的偶联，有利于制备多功能的硫化氢释放复合材料。
Description
技术领域
本发明涉及硫化氢供体，具体涉及一种基于角蛋白的硫化氢供体及其合成方法和应用。
背景技术
硫化氢是继NO、CO后发现的生物体内第三类气体信号分子，在心血管系统、神经系统中发挥着重要的调节作用。其对多种疾病的发生和发展有着重要的意义，也具有极大的治疗性应用前景。NaHS和Na2S做作为硫化氢供体，被用于治疗心肌细胞的缺血性损伤。硫化氢也可调节血管的收缩与舒张，促进血管内皮生长因子的分泌，调节血管平滑肌细胞的增殖与凋亡，预防动脉粥样硬化的发生发展。目前常用的硫化氢供体主要有：硫化物盐NaHS和Na2S，该两种无机盐可在短时间内释放出大量的硫化氢；2.4－甲氧基苯基(吗晰代)二硫代磷酸酯吗啡盐(GYY4137)，GYY4137是一种水溶性极好的有机盐的硫化氢供体，可高效的释放硫化氢；茴三硫类化合物及其衍生物也是一种常用的硫化氢供体，且具有良好的稳定性；生物硫醇类的硫化氢供体，可在半胱氨酸的作用下，释放出硫化氢气体。
角蛋白，尤其是人发角蛋白，不引起免疫排斥反应，也不干扰正常的机体免疫应答，是一种优秀的无抗原、组织相容性材料。角蛋白中含有丰富的二硫键，具有pH、还原性和酶响应等优点，在可用作药物载体、组织工程支架材料、创伤敷料等方面具有较多探索和研究，但是目前关于采用角蛋白的硫化氢供体没有相关报道。
发明内容
发明目的：针对现有技术存在的问题，本发明提供一种基于角蛋白的硫化氢供体及其合成方法和应用。本发明合成的基于角蛋白的硫化氢供体延长了硫化氢释放的时间，解决了小分子供体溶解性差和硫化氢释放过快的问题；可有效应用在制备心血管支架、人造血管或治疗心肌细胞缺血性损伤的药物或材料中
技术方案：为了实现上述目的，本发明所述一种基于角蛋白的硫化氢供体的合成方法，包括如下步骤：
(1)将角蛋白溶于缓冲液中，加入活化剂，进行反应得到溶液A；
(2)将小分子硫化氢供体溶于有机溶剂中，然后加入到步骤(1)的溶液A中，继续反应得反应液B；
(3)将步骤(2)得到的反应液B透析后，冷冻干燥得到基于角蛋白的硫化氢供体。
其中，步骤(1)所述的角蛋白由人或动物的毛发中提取均可，人发角蛋白的提取按照文献：Extraction,characterization,and NO release potential of keratin fromhuman hair.Materials Letters,2016,175:188-190.
动物毛发角蛋白的提取方法按照文献：Keratin:dissolution,extraction andbiomedical application.Biomaterials Science,2017,5:1699-1735.两种角蛋白在本发明中的效果一致。
其中，步骤(1)所述活化剂为EDC·HCl和NHS。
其中，步骤(1)所述缓冲液为磷酸盐缓冲液或MES缓冲液，pH为5.0-7.0。
作为优选，步骤(1)所述反应为20-30℃反应0.5-1h。
其中，步骤(2)所述小分子硫化氢供体前体(苯甲酮硫胺)如下所示，合成方法参考文献：Cysteine-Activated Hydrogen Sulfide(H2S)Donors.J.Am.Chem.Soc.2011,133,15-17.
小分子供体前体
其中，步骤(2)所述有机溶剂为甲醇或四氢呋喃。
作为优选，步骤(2)所述反应温度为20-30℃，反应时间为2-12h。
进一步地，步骤(1)和(2)中的反应温度均控制在20-25℃；步骤(1)中的反应时间为0.5h，步骤(2)中的反应时间为6-12h。
进一步地，步骤(3)透析采用透析袋透析48-60h，截留分子量为3500Da。
本发明所述的基于角蛋白的硫化氢供体的合成方法所合成的基于角蛋白的硫化氢供体。
本发明所述的基于角蛋白的硫化氢供体的合成方法所合成的基于角蛋白的硫化氢供体在制备心血管支架、人造血管或治疗心肌细胞缺血性损伤的药物或材料中的应用。
有益效果：与现有技术相比，本发明具有如下优点：
(1)本发明合成制备的基于角蛋白的硫化氢供体具有良好的水溶性，解决了难以在水环境中不溶解的问题，与GYY4137相比，本发明通过将小分供体与角蛋白偶联，制备的大分子供体稳定性好，生物毒性低；
(2)本发明合成制备的基于角蛋白的硫化氢供体延长了硫化氢释放的时间，解决了小分子供体释放过快的问题。
(3)本发明所采用的方法操作简便，反应条件温和，易于实现，对角蛋白的结构不造成破坏。
(4)本发明制备的基于角蛋白的硫化氢供体结具有氨基羧基等活性基团，易于实现与其他材料或分子的偶联，有利于制备多功能的硫化氢释放复合材料，如制备心血管支架、人造血管或治疗心肌细胞缺血性损伤的药物或材料。
附图说明
图1是本发明实施例1合成的角蛋白硫化氢供体硫化氢释放曲线示意图；
图2是本发明实施例1合成的角蛋白硫化氢供体硫化氢释放曲线示意图；
图3是对比例中小分子硫化氢供体的释放曲线示意图。
具体实施方式
以下结合附图和实施例对本发明作进一步说明。
本发明中的原料如无特殊说明均市售可得，其中还原型角蛋白或羧甲基化角蛋白按现有技术中方法合成。
实施例1
(1)将0.5g角蛋白溶于50ml磷酸盐缓冲液(pH 6.8)中，加入0.036g EDC·HCl和0.09g NHS，25℃反应1h得到溶液A。
(2)将14mg硫化氢供体前体苯甲酮硫胺溶于50ml四氢呋喃中，然后加入到步骤(1)的溶液A中，25℃反应4h得到反应液B。
(3)步骤(2)的反应液B置于MWCO＝3500Da的透析袋中，每隔12h换水一次，透析48h，将透析袋内溶液冷冻干燥得到基于角蛋白的硫化氢供体；
(4)将0.1g角蛋白硫化氢供体溶于10ml含4mM半胱氨酸的PBS缓冲液中(pH 7.4)，采用亚甲基蓝显色法检测H2S在溶液中的含量。
本实施例合成制备的硫化氢供体释放曲线如图1所示，释放时间可达到2h。
本发明基于角蛋白的硫化氢供体H2S释放浓度峰值大约在70min，而图3对比例：小分子供体(N-(苯甲酰硫)苯甲酰胺)
小分子供体
(对照文献：Cysteine-Activated Hydrogen Sulfide(H2S)Donors.J.Am.Chem.Soc.2011,133,15–17.)在相同的条件下小分子H2S的释放在15min达到峰值，结果表明本发明基于角蛋白硫化氢供体具有更好的H2S缓释作用
实施例2
(1)将0.5g角蛋白溶于50ml磷酸盐缓冲液(pH＝6.0)中，加入0.036g EDC·HCl和0.09g NHS，25℃反应0.5h得到溶液A。
(2)将14mg苯甲酮硫胺溶于50ml甲醇中，然后加入到步骤(1)的溶液A中，25℃反应6h得到反应液B。
(3)步骤(2)的反应液B置于MWCO＝3500Da的透析袋中，每隔12h换水一次，透析48h，将透析袋内溶液冷冻干燥得到基于角蛋白的硫化氢供体；
(4)将0.1g角蛋白硫化氢供体溶于10ml含4mM半胱氨酸的PBS缓冲液中(pH 7.4)，采用亚甲基蓝显色法检测H2S在溶液中的含量。
本实施例合成制备的硫化氢供体释放曲线如图2所示，释放时间可达到2h。
实施例3
(1)将0.5g角蛋白溶于50ml的MES冲液(pH＝6.0)中，加入0.036g EDC·HCl和0.09g NHS，25℃反应1h得到溶液A。
(2)将14mg苯甲酮硫胺溶于50ml四氢呋喃中，然后加入到步骤(1)的溶液A中，25℃反应12h得到反应液B。
(3)步骤(2)的反应液B置于MWCO＝3500Da的透析袋中，每隔12h换水一次，透析48h，将透析袋内溶液冷冻干燥得到基于角蛋白的硫化氢供体。
实施例4
实施例4与实施例1制备方法相同，不同之处在于：步骤(1)中的缓冲液为pH 5.0的MES缓冲液；反应温度为30℃，反应时间0.5h；步骤(2)中有机溶剂为甲醇；反应为温度为30℃，反应时间为2h；步骤(3)中透析采用透析袋透析60h。
实施例5
实施例5与实施例1制备方法相同，不同之处在于：步骤(1)中缓冲液为pH 7.0的磷酸盐缓冲液；反应为温度20℃，反应时间为1h；步骤(2)中有机溶剂为甲醇；反应为温度20℃，反应时间为12h；步骤(3)中透析采用透析袋透析60h。
实施例6
分别在25±2℃和37±2℃的温度下，分别称取约0.5g供体(小分子供体N-(苯甲酰硫)苯甲酰胺、实施例1制备的角蛋白的硫化氢供体)置于100ml容量瓶，先加0.8ml水。按药典试验方法，每隔5分钟强力振摇30秒钟，观察30分钟内的溶解情况。如果未完全溶解，则接着往里加约8ml水，继续同法试验30分钟内观察溶解情况。如还未完全溶解，再往后加约20ml水(当加到90ml水时，如还未完全溶解，则减少样品重复上述步骤，待供体完全溶解，就是该供体在水中的溶解度。
表1小分子供体和角蛋白硫化氢供体在水中溶解度对比
从表1的对比结果可知，角蛋白硫化氢供体在水中具有良好的溶解性。小分子供体可直接与生物分子和细胞器作用，影响细胞的正常功能，而可溶的大分子硫化氢供体，更有利于在生物体内的应用，其他实施例制备的角蛋白的硫化氢供体也具有较高的溶解度。
综上，本发明制备的基于角蛋白的硫化氢供体具有良好的水溶性，同时延长了硫化氢释放的时间，解决了小分子供体释放过快的问题；易于实现与其他材料或分子的偶联，有利于制备多功能的硫化氢释放复合材料，如制备心血管支架、伤口敷料、人造血管或治疗心肌细胞缺血性损伤的药物或材料。
Claims (10)
1.一种基于角蛋白的硫化氢供体的合成方法，其特征在于，包括如下步骤：
(1)将角蛋白溶于缓冲液中，加入活化剂，进行反应得到溶液A；
(2)将小分子硫化氢供体前体溶于有机溶剂中，然后加入到步骤(1)的溶液A中，继续反应得反应液B；
(3)将步骤(2)得到的反应液B透析后，冷冻干燥得到基于角蛋白的硫化氢供体。
2.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(1)所述角蛋白为人或动物的毛发中提取的角蛋白。
3.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(1)所述活化剂为EDC·HCl和NHS。
4.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(1)所述缓冲液为磷酸盐缓冲液或MES缓冲液，pH为5.0-7.0。
5.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(1)所述反应优选为20-30℃反应0.5-1h。
6.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(2)所述小分子硫化氢供体前体为苯甲酮硫胺，其化学分子式如下：
7.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(2)所述有机溶剂为甲醇或四氢呋喃。
8.根据权利要求1所述的基于角蛋白的硫化氢供体的合成方法，其特征在于，步骤(2)所述反应温度为20-30℃，反应时间为2-12h。
9.一种权利要求1所述的基于角蛋白的硫化氢供体的合成方法所合成的基于角蛋白的硫化氢供体。
10.一种权利要求1所述的基于角蛋白的硫化氢供体的合成方法所合成的基于角蛋白的硫化氢供体在制备心血管支架、伤口敷料、人造血管或治疗心肌细胞缺血性损伤的药物或材料中的应用。
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