Fmoc保护的二肽小分子水凝胶的研究
摘要
9-芴甲氧基(Fmoc)保护的二肽是多肽合成中常见一种中间产物,研究发现该类物质具有以下优点:(1)具有生物相容性;(2)容易被生物降解;(3)具有一定的药物作用;因此由该类分子形成的水凝胶在药物载体、药物缓释、组织工程和化学传感器等方面应用广泛。
本论文选用N-羟基琥珀酰亚胺作为羧基活化试剂,DCC作为缩合剂,在二甲氧基乙烷溶剂中将Fmoc-D-丙氨酸的羧基进行活化,然后以乙醇和丙酮的混合液(V_1:V_2=4:1)作溶剂,在碳酸氢钠提供的弱碱性条件下,直接用上述反应生成的活化酯分别与另外的五种氨基酸反应,合成出了Fmoc-D-丙氨酰基-D-丙氨酸、Fmoc-D-丙氨酰基-L-丝氨酸、Fmoc-D-丙氨酰基-L-苏氨酸、Fmoc-D-丙氨酰基-L-酪氨酸和Fmoc-D-丙氨酰基-L-赖氨酸五种Fmoc-D-丙氨酰基二肽。运用紫外可见(UV)、核磁共振(1H NMR)和傅里叶变换红外(FTIR)等测试手段对产物分子进行了结构签定,并根据反应物及其产物的性质特征推测了该类反应的反应机理。
研究了上述合成的五种结构相似侧链基团大小不同的Fmoc-D-丙氨酰基二肽形成凝胶的情况。运用流变测试手段检测了五种二肽形成凝胶的性能,采用TEM和SEM对形成的凝胶的形貌进行了表征,并用CD测试手段测试了分子间的微观排列情况。另外还研究了pH、酸根离子以及外界温度的变化对四种Fmoc-D-丙氨酰基二肽水凝胶的影响。
研究发现,尽管五种Fmoc-D-丙氨酰基二肽结构相似,但其侧链基团的大小不同,其形成凝胶的微观形貌及机械性能有很大的差别,随着侧链基团的增大,形成凝胶的形貌逐渐由丝状变成管状,机械性能也随侧链基团的增加而降低。根据测试数据对上述五种凝胶的形成机制进行了推测。另外研究还发现,用含有不同阴离子的酸调节Fmoc-D-丙氨酰基二肽溶液的pH值来制备水凝胶,在pH＜5的条件下四种Fmoc-D-丙氨酰基二肽都能形成水凝胶,并且同一种Fmoc-D-丙氨酰基二肽用含有不同阴离子的酸调节pH值形成的水凝胶的形貌相似,说明酸的阴离子对Fmoc-D-丙氨酰基二肽形成的水凝胶没有产生明显的影响。由于氯元素是人体中常见的元素,所以在用作药物载体、组织工程等方面的水凝胶的研究时可以选择盐酸作为酸化试剂来制备水凝胶。温度对四种Fmoc-D-丙氨酰基二肽形成的水凝胶的影响比较显著,酸化后形成的水凝胶随外界温度的变化而发设定那个相应的相变,即当温度达到一定的高度(溶胶-凝胶转变温度)时,凝胶变成溶胶,室温下冷却又恢复成凝胶状,说明四种Fmoc-D-丙氨酰基二肽水凝胶是温敏型可逆凝胶。
本论文研究的意义在于合成了五种Fmoc-D-丙氨酰基二肽,制备出了四种温敏型可逆水凝胶,发现了结构相似的分子,侧链基团的大小对分子性质产生很大影响的现象。
本论文的研究结果为生物药物寻找合适的载体提供了一定的参考,在某种程度上,丰富生物药物载体库。
9-Fluorenylmethoxycarbonyl(Fmoc)protected dipeptides are ones of common intermediates in the synthesis of peptides.It was found that 9-Fluorenylmethoxy carbonyl(Fmoc)protected dipeptides have some advantages such as biocompatibility, biodegradability and drug effects,so the hydrogels formed by these dipeptides can be used in drug delivery,drug release,tissue engineering,chemical sensor and so on.
In this paper,we chose N-hydroxysuccinimide as activator of carboxyl group and DCC as condensing agent,the N-hydroxysuccinimide ester of Fmoc-D-Alanine was synthesized in anhydrous dimethoxyethane solvent,then the ester was used as one of reactant provided carboxyl to react with another amino acids in ethanol and acetone mixture(V_1:V_2=4:1),at last,five Fmoc-D-Alanyl-dipeptides were synthesized. The structures of Fmoc-D-Alanyl-dipeptides are established by experimental technique UV,1H-NMR and FTIR,and the reaction mechanism was speculated according to the properties of the reactants and products.
The character in gelled solvent of the above resulted Fmoc-D-Alanyl-dipeptides was studied,and the properties of the five Fmoc-D-Alanyl-dipeptides in rheology, morphology and microscopic arrangement was tested by the experimental technique Rheometer,TEM,SEM and CD.In addition,the effects of pH,the acid radical ion and the temperature to the hydrogels was studied.
It was found that although the five Fmoc-D-Alanyl-dipeptides have the similar structure,the five gels formed by them are different in the mechanical property and morphology.Along with the size of side group increasing,the morphology of the gels changed from nanofiber to nanotube.According to the information from the above test,we speculated the mechanism of the hydrogels formation,.In addition,it was also found that the above four compounds can form hydrogels adjusted by different acids on the condition of pH＜5,the results of TEM show that the morphologies of hydrogels acidized by hydrochloride,nitric acid and sulfuric acid are not different.The result suggests that we can acidized the Fmoc-D-Alanyl-dipeptides solution by hydrochloride in the study of preparation hydrogel used in drug delivery,drug release and tissue engineering.The temperature of surroundings made great effect to the hydrogels,when the temperature arrived the T_g,the hydrogels can change into solution,but cooled to the room temperature,the hydrogels formed again. The results show that the hydrogels are thermosensitive reversible hydrogels.
The research significance in this paper consists in synthesis of five Fmoc-D-Alanyl-dipeptides, prepared four Fmoc-D-Alanyl-dipeptides thermosensitive reversible hydrogels,finding the phenomenon of the side groups effects to the whole molecule.
The results of our research provide some reference for drug delivery and enriched the database of drug delivery to a certain extent.
本论文选用N-羟基琥珀酰亚胺作为羧基活化试剂,DCC作为缩合剂,在二甲氧基乙烷溶剂中将Fmoc-D-丙氨酸的羧基进行活化,然后以乙醇和丙酮的混合液(V_1:V_2=4:1)作溶剂,在碳酸氢钠提供的弱碱性条件下,直接用上述反应生成的活化酯分别与另外的五种氨基酸反应,合成出了Fmoc-D-丙氨酰基-D-丙氨酸、Fmoc-D-丙氨酰基-L-丝氨酸、Fmoc-D-丙氨酰基-L-苏氨酸、Fmoc-D-丙氨酰基-L-酪氨酸和Fmoc-D-丙氨酰基-L-赖氨酸五种Fmoc-D-丙氨酰基二肽。运用紫外可见(UV)、核磁共振(1H NMR)和傅里叶变换红外(FTIR)等测试手段对产物分子进行了结构签定,并根据反应物及其产物的性质特征推测了该类反应的反应机理。
研究了上述合成的五种结构相似侧链基团大小不同的Fmoc-D-丙氨酰基二肽形成凝胶的情况。运用流变测试手段检测了五种二肽形成凝胶的性能,采用TEM和SEM对形成的凝胶的形貌进行了表征,并用CD测试手段测试了分子间的微观排列情况。另外还研究了pH、酸根离子以及外界温度的变化对四种Fmoc-D-丙氨酰基二肽水凝胶的影响。
研究发现,尽管五种Fmoc-D-丙氨酰基二肽结构相似,但其侧链基团的大小不同,其形成凝胶的微观形貌及机械性能有很大的差别,随着侧链基团的增大,形成凝胶的形貌逐渐由丝状变成管状,机械性能也随侧链基团的增加而降低。根据测试数据对上述五种凝胶的形成机制进行了推测。另外研究还发现,用含有不同阴离子的酸调节Fmoc-D-丙氨酰基二肽溶液的pH值来制备水凝胶,在pH＜5的条件下四种Fmoc-D-丙氨酰基二肽都能形成水凝胶,并且同一种Fmoc-D-丙氨酰基二肽用含有不同阴离子的酸调节pH值形成的水凝胶的形貌相似,说明酸的阴离子对Fmoc-D-丙氨酰基二肽形成的水凝胶没有产生明显的影响。由于氯元素是人体中常见的元素,所以在用作药物载体、组织工程等方面的水凝胶的研究时可以选择盐酸作为酸化试剂来制备水凝胶。温度对四种Fmoc-D-丙氨酰基二肽形成的水凝胶的影响比较显著,酸化后形成的水凝胶随外界温度的变化而发设定那个相应的相变,即当温度达到一定的高度(溶胶-凝胶转变温度)时,凝胶变成溶胶,室温下冷却又恢复成凝胶状,说明四种Fmoc-D-丙氨酰基二肽水凝胶是温敏型可逆凝胶。
本论文研究的意义在于合成了五种Fmoc-D-丙氨酰基二肽,制备出了四种温敏型可逆水凝胶,发现了结构相似的分子,侧链基团的大小对分子性质产生很大影响的现象。
本论文的研究结果为生物药物寻找合适的载体提供了一定的参考,在某种程度上,丰富生物药物载体库。
9-Fluorenylmethoxycarbonyl(Fmoc)protected dipeptides are ones of common intermediates in the synthesis of peptides.It was found that 9-Fluorenylmethoxy carbonyl(Fmoc)protected dipeptides have some advantages such as biocompatibility, biodegradability and drug effects,so the hydrogels formed by these dipeptides can be used in drug delivery,drug release,tissue engineering,chemical sensor and so on.
In this paper,we chose N-hydroxysuccinimide as activator of carboxyl group and DCC as condensing agent,the N-hydroxysuccinimide ester of Fmoc-D-Alanine was synthesized in anhydrous dimethoxyethane solvent,then the ester was used as one of reactant provided carboxyl to react with another amino acids in ethanol and acetone mixture(V_1:V_2=4:1),at last,five Fmoc-D-Alanyl-dipeptides were synthesized. The structures of Fmoc-D-Alanyl-dipeptides are established by experimental technique UV,1H-NMR and FTIR,and the reaction mechanism was speculated according to the properties of the reactants and products.
The character in gelled solvent of the above resulted Fmoc-D-Alanyl-dipeptides was studied,and the properties of the five Fmoc-D-Alanyl-dipeptides in rheology, morphology and microscopic arrangement was tested by the experimental technique Rheometer,TEM,SEM and CD.In addition,the effects of pH,the acid radical ion and the temperature to the hydrogels was studied.
It was found that although the five Fmoc-D-Alanyl-dipeptides have the similar structure,the five gels formed by them are different in the mechanical property and morphology.Along with the size of side group increasing,the morphology of the gels changed from nanofiber to nanotube.According to the information from the above test,we speculated the mechanism of the hydrogels formation,.In addition,it was also found that the above four compounds can form hydrogels adjusted by different acids on the condition of pH＜5,the results of TEM show that the morphologies of hydrogels acidized by hydrochloride,nitric acid and sulfuric acid are not different.The result suggests that we can acidized the Fmoc-D-Alanyl-dipeptides solution by hydrochloride in the study of preparation hydrogel used in drug delivery,drug release and tissue engineering.The temperature of surroundings made great effect to the hydrogels,when the temperature arrived the T_g,the hydrogels can change into solution,but cooled to the room temperature,the hydrogels formed again. The results show that the hydrogels are thermosensitive reversible hydrogels.
The research significance in this paper consists in synthesis of five Fmoc-D-Alanyl-dipeptides, prepared four Fmoc-D-Alanyl-dipeptides thermosensitive reversible hydrogels,finding the phenomenon of the side groups effects to the whole molecule.
The results of our research provide some reference for drug delivery and enriched the database of drug delivery to a certain extent.
引文
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