CN113968906A - 一种利用外壁季铵化葫芦脲赋予胶原持久抗菌功能的方法 - Google Patents
一种利用外壁季铵化葫芦脲赋予胶原持久抗菌功能的方法 Download PDFInfo
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Abstract
本发明公开了一种利用超分子化学赋予胶原持久抗菌功能的方法。该方法先制备外壁含多个短链季铵的葫芦[7]脲，再利用葫芦[7]脲对苯丙氨酸、酪氨酸残基的超分子包合作用，将季铵基团引入胶原表面，通过控制每个葫芦[7]脲外壁共价接枝的季铵基团数及共价连接臂长度，在不破坏天然胶原三股螺旋结构的前提下，赋予其长效抗菌功能。
Description
技术领域
本发明涉及一种利用外壁季铵化葫芦脲赋予胶原持久抗菌功能的方法，属于生物质材料领域。
背景技术
胶原蛋白因其良好的低免疫原性、可生物降解性、止血和修复功能，已成为生物医用材料产业最关键的原材料之一。然而，由于自身属富营养生物质材料，胶原蛋白极易受细菌侵蚀。研究表明，细菌新陈代谢会产生多种蛋白酶，进而破坏胶原化学、空间结构，使其凝血、促细胞粘附和增殖等生物活性降低。此外，胶原器件中累积的微生物代谢产物含多种有害物质，对使用者的健康也会造成威胁。因此，抗菌防腐是天然胶原作为生物医用材料高值利用的必要前提。
目前，赋予胶原蛋白材料抗菌防腐功能最常用方法有以下两种：（1）直接添加抗菌剂；（2）将抗菌剂共价接枝到胶原表面。直接添加抗菌剂能有效防止胶原长菌，但外添加抗菌剂与胶原间并无结合力，易发生迁移，造成胶原抗菌防腐功能下降。将抗菌剂共价接枝到胶原表面可解决长效抗菌问题，但大多数化学反应都过于剧烈，可能破坏决定胶原生物活性的三股螺旋结构，降低其实际应用价值。因此，赋予胶原长效抗菌功能和维持其三股螺旋结构完整间矛盾亟待解决。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足，而提供一种利用外壁季铵化葫芦脲赋予胶原持久抗菌功能的方法，其特征在于该方法的合成步骤和条件如下，以下所用原料的份数均为重量份数：
1、将1-5份葫芦[7]脲与3-15份过硫酸钾分散于30-80份蒸馏水中，在60-90℃氮气保护下反应6-8小时，反应结束后冷却过滤，将滤液真空干燥，再将所得固体溶于1-5份二甲亚砜，随后过滤，向滤液中加入50-100份丙酮，获得沉淀，最后将沉淀用丙酮洗涤、干燥至恒重后即得第一步合成产物；
2、将1-3份第一步合成产物溶于10-40份溶剂，再加入2-6份强碱，在室温下反应1小时，随后向上述溶液中加入1-3份卤代季铵盐，室温下搅拌12-14小时，反应结束后，收集沉淀真空干燥至恒重后即得目标产物；
3、将3-15份上述目标产物溶于40-50份水中，再将1-5份胶原浸没其中，搅拌30-60分钟，制成抗菌胶原；
步骤（2）中所述溶剂为二甲亚砜、N,N-二甲基甲酰胺中的一种或多种；
步骤（2）中所述强碱为氢化钠、氢氧化钠、碳酸钾中的一种或多种；
步骤（2）中所述卤代季铵盐为溴化溴胆碱、氯化氯胆碱中的一种或多种。
本发明所涉及的方法的原理是：
1、葫芦[7]脲是由七个苷脲单元通过亚甲基桥联而成的刚性大环化合物，具有一个疏水空腔和两个由羰基环绕而成的富电子洞口，可依靠疏水作用、离子-偶极相互作用，选择性包合芳香胺类化合物。胶原表面的苯丙氨酸、酪氨酸残基虽不是典型的芳香胺（α-氨基已参与形成酰胺键），但都具有苯环结构，无论是极性还是尺寸，都与葫芦[7]脲的疏水空腔正好匹配，仍能与葫芦[7]脲形成较为稳定的包合物。上述结合完全依赖超分子相互作用，胶原天然的化学与空间结构并未发生任何改变。
2、季铵阳离子能破坏带负电荷的细菌外膜，致使细菌死亡。本发明通过分子设计，将烷基三甲基季铵接枝于葫芦[7]脲外壁，制得外壁季铵化葫芦[7]脲。实验发现，当外壁季铵化葫芦[7]脲与胶原的比例符合权利要求1步骤（3）所述时，胶原表面大约30%的苯丙氨酸、酪氨酸残基可被超分子包合。此时，如1个葫芦[7]脲外壁接枝烷基三甲基季铵数≥6，由于胶原表面局部阳电荷充足，能杀灭周围环境中的细菌（见实施例1、实施例2）；如 1个葫芦[7]脲外壁接枝烷基三甲基季铵数＜6，胶原表面阳电荷聚集效应不明显，抗菌防腐功能难以正常体现（见对比例1）。
3、由于葫芦[7]脲可以超分子包合特定链长的季铵阳离子，导致外壁季铵化葫芦[7]脲可能相互包合，影响其与胶原表面苯丙氨酸、酪氨酸残基结合能力。实验发现，当三甲基季铵盐与葫芦[7]脲外壁间连接臂长度＜3个碳时，外壁季铵化葫芦[7]脲自身间超分子包合作用可以得到完全抑制（见实施例1、实施例2）；而当上述连接臂长度≥3个碳时，所制得的外壁季铵化葫芦[7]脲无法与胶原表面疏水残基结合（见对比例2）。
本发明与现有技术相比，具有以下积极效果：
1、胶原具有苯丙氨酸、酪氨酸等含有苯环的氨基酸残基。本发明利用葫芦[7]脲与上述疏水残基间超分子结合，将外壁季铵化葫芦[7]脲引入胶原表面，通过阳电荷聚集效应，破坏细菌带负电荷的外膜，使胶原获得长效抗菌功能。
2、本发明通过超分子作用将抗菌基团固定于胶原表面，并未破坏胶原三股螺旋结构，最大程度保留了胶原的生物活性。
附图说明
图1 为本发明涉及的外壁季铵化葫芦[7]脲合成步骤示意图。
图2 为本发明工作机制示意图。
具体实施方式
下面通过实施例对本发明进行具体的描述，只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限定，该领域的技术工程师可根据上述发明的内容对本发明作出一些非本质的改进和调整。
实施例1
1、将1份葫芦[7]脲与3份过硫酸钾分散于30份蒸馏水中，在60℃氮气保护下反应6小时，反应结束后冷却过滤，将滤液真空干燥，再将所得固体溶于1份二甲亚砜，随后过滤，向滤液中加入50份丙酮，获得沉淀，最后将沉淀用丙酮洗涤、干燥至恒重后即得第一步合成产物；
2、将1份第一步合成产物溶于10份二甲亚砜，再加入2份氢化钠，在室温下反应1小时，随后向上述溶液中加入1份氯代氯胆碱，室温下搅拌12小时，反应结束后，收集沉淀真空干燥至恒重后即得目标产物；
3、将3份上述目标产物溶于40份水中，再将1份胶原浸没其中，搅拌60分钟，制成抗菌胶原；
质谱检测结果显示，实施例1中每个葫芦[7]脲外壁平均接枝有7个季铵基团；等温滴定量热实验结果显示，上述外壁季铵化葫芦[7]脲与胶原的结合常数为3.0×104 M-1；采用GB4789.2-94 标准中规定的菌落总数测定方法，对实施例1中制备的抗菌胶原的抗菌效果进行测定，其对大肠杆菌的抑菌率≥95%，上述抗菌胶原反复清洗3次后，对大肠杆菌的抑菌率≥93%；通过红外光谱、圆二色谱测定结合外壁季铵化葫芦[7]脲后胶原的结构，发现胶原的三股螺旋结构未受破坏。
实施例2
1、将2份葫芦[7]脲与3份过硫酸钾分散于60份蒸馏水中，在80℃氮气保护下反应8小时，反应结束后冷却过滤，将滤液真空干燥，再将所得固体溶于2份二甲亚砜，随后过滤，向滤液中加入75份丙酮，获得沉淀，最后将沉淀用丙酮洗涤、干燥至恒重后即得第一步合成产物；
2、将1份第一步合成产物溶于10份二甲亚砜，再加入2份氢化钠，在室温下反应1小时，随后向上述溶液中加入1份溴代溴胆碱，室温下搅拌12小时，反应结束后，收集沉淀真空干燥至恒重后即得目标产物；
3、将3份上述目标产物溶于40份水中，再将1份胶原浸没其中，搅拌60分钟，制成抗菌胶原；
质谱检测结果显示，实施例2中每个葫芦[7]脲外壁平均接枝有9个季铵基团；等温滴定量热实验结果显示，上述外壁季铵化葫芦[7]脲与胶原的结合常数为2.3×104 M-1；采用GB4789.2-94 标准中规定的菌落总数测定方法，对实施例2中制备的抗菌胶原的抗菌效果进行测定，其对大肠杆菌的抑菌率≥99%，上述抗菌胶原反复清洗3次后，对大肠杆菌的抑菌率≥97%；通过红外光谱、圆二色谱测定结合外壁季铵化葫芦[7]脲后胶原的结构，发现胶原的三股螺旋结构未受破坏。
对比例1
1、将2份葫芦[7]脲与3份过硫酸铵和3份亚硫酸氢钠（两者结合的氧化能力远低于过硫酸钾）分散于60份蒸馏水中，在80℃氮气保护下反应8小时，反应结束后冷却过滤，将滤液真空干燥，再将所得固体溶于2份二甲亚砜，随后过滤，向滤液中加入75份丙酮，获得沉淀，最后将沉淀用丙酮洗涤、干燥至恒重后即得第一步合成产物；
2、将1份第一步合成产物溶于10份二甲亚砜，再加入2份氢氧化钠，在室温下反应1小时，随后向上述溶液中加入1份溴代溴胆碱，室温下搅拌12小时，反应结束后，收集沉淀真空干燥至恒重后即得目标产物；
3、将3份上述目标产物溶于40份水中，再将1份胶原浸没其中，搅拌60分钟，制成抗菌胶原；
质谱检测结果显示，对比例1中每个葫芦[7]脲分子外壁平均接枝2个季铵基团；等温滴定量实验结果显示，上述外壁季铵化葫芦[7]脲与胶原的结合常数为4.3×104 M-1；采用GB4789.2-94 标准中规定的菌落总数测定方法，对对比例1中制备的抗菌胶原溶液的抗菌效果进行测定，其对大肠杆菌的抑菌率＜40%。
对比例2
1、将2份葫芦[7]脲与3份过硫酸钾分散于60份蒸馏水中，在80℃氮气保护下反应8小时，反应结束后冷却过滤，将滤液真空干燥，再将所得固体溶于2份二甲亚砜，随后过滤，向滤液中加入75份丙酮，获得沉淀，最后将沉淀用丙酮洗涤、干燥至恒重后即得第一步合成产物；
2、将1份第一步合成产物溶于10份二甲亚砜，再加入2份氢化钠，在室温下反应1小时，随后向上述溶液中加入2份6-溴己基三甲基溴化铵，室温下搅拌12小时，反应结束后，收集沉淀真空干燥至恒重后即得目标产物；
3、将3份上述目标产物溶于40份水中，再将1份胶原浸没其中，搅拌60分钟，制成抗菌胶原；
质谱检测结果显示，对比例2中每个葫芦[7]脲分子外壁平均接枝7个季铵基团；等温滴定量热实验结果显示，上述外壁季铵化葫芦[7]脲与胶原间无相互作用，所制得的胶原无抗菌功能。
Claims (1)
1.一种利用外壁季铵化葫芦脲赋予胶原持久抗菌功能的方法，其特征在于该方法的合成步骤和条件如下，以下所用原料的份数均为重量份数：
（1）将1-5份葫芦[7]脲与3-15份过硫酸钾分散于30-80份蒸馏水中，在60-90℃氮气保护下反应6-8小时，反应结束后冷却过滤，将滤液真空干燥，再将所得固体溶于1-5份二甲亚砜，随后过滤，向滤液中加入50-100份丙酮，获得沉淀，最后将沉淀用丙酮洗涤、干燥至恒重后即得第一步合成产物；
（2）将1-3份第一步合成产物溶于10-40份溶剂，再加入2-6份强碱，在室温下反应1 小时，随后向上述溶液中加入1-3份卤代季铵盐，室温下搅拌12-14小时，反应结束后，收集沉淀真空干燥至恒重后即得目标产物；
（3）将3-15份上述目标产物溶于40-50份水中，再将1-5份胶原浸没其中，搅拌30-60分钟，制成抗菌胶原；
步骤（2）中所述溶剂为二甲亚砜、N,N-二甲基甲酰胺中的一种或多种；
步骤（2）中所述强碱为氢化钠、氢氧化钠、碳酸钾中的一种或多种；
步骤（2）中所述卤代季铵盐为溴化溴胆碱、氯化氯胆碱中的一种或多种。
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