CN112409388A - 一类开环葫芦脲柱芳烃双主体化合物及其制备方法和应用 - Google Patents
一类开环葫芦脲柱芳烃双主体化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一类开环葫芦脲柱芳烃双主体化合物及其制备方法,本发明开环葫芦脲柱芳烃双主体化合物以卤代烷烃修饰后的开环葫芦脲与羧酸修饰的柱芳烃上的羧基发生反应形成酯键而链接成双主体化合物;与单个开环葫芦脲及柱芳烃相比,本发明开环葫芦脲柱芳烃双主体化合物具有两种性质不同的空腔,其中一种是柱芳烃的空腔,另外一种是开环葫芦脲的空腔,并且这两种空腔的排列呈现线性结构,该类载体的空腔具有不同的性质,使得该化合物既有柱芳烃的性能又具有开环葫芦脲的性能,该化合物具有很好的分子识别能力,可以作为分子离子跨膜转运分子,并应用于生物医药研究,制药、食品、香精香料、烟草等行业。
Description
技术领域
本发明属于化学合成、新材料制备领域,具体涉及一类开环葫芦脲柱芳烃双主体化合物及其制备方法和应用。
背景技术
超分子化学是一门研究两种或以上的分子通过非共价键作用进行分子间识别、自组装从而形成复杂而有序的分子聚集体系的学科。其中,超分子主体分子与其他分子间的识别和自组装是超分子研究的主要内容。其中,大环化合物是主要的超分子主体。常见的超分子主体有冠醚、环糊精、葫芦脲、柱芳烃和杯芳烃等;这些主体分子大多具有疏水性空腔能够用于封装小分子物质,形成主客体体系,并用于制药、食品、香精香料、烟草、化工催化等行业。此外,对超分子的研究已经不限于低级结构的超分子主体以及简单的主客体包合作用,近年来基于超分子在人工合成的跨膜转运通道的深入研究已经广泛报道,这也为化学家构建人工合成的系统,在体外模拟通道蛋白的结构和功能,并研究物质的跨膜机制提供一个简单的模型。
柱芳烃是2008年由日本学者Ogoshi合成的一种新型的柱状[n]芳烃超分子,它是通过1,4-二甲氧基苯(DMB)邻位的环化合成的。由于柱芳烃具有的优点,包括合成过程相对简单,大小可调,苯单元两侧的基团易于化学修饰等,因而广泛应用于药物传递、细胞粘附和荧光探针等领域,特别是基于柱芳烃的管状结构的分子离子跨膜转运通道研究,已经有一些专利和文献报道了基于柱芳烃的跨膜通道的研究。
开环葫芦脲是近年来由美国马里兰大学Lyle Isaacs团队制备出的一类新型超分子主体,这类开环葫芦脲不仅保留了闭环葫芦脲分子的优点,包括相对刚性的骨架结构、对许多分子的高结合亲合力等;而且解决了葫芦脲分子长期以来未解决的低水溶性和难衍生化的技术瓶颈,使之成为新兴的超分子主体研究平台,特别是其空腔结构为构筑人工合成的分子离子跨膜转运通道提供了理论可行性。
但是,目前还没有相关研究报道过使用柱芳烃和开环葫芦脲双主体键接的化合物作为跨膜通道分子进行相关研究和应用,鉴于开环葫芦脲柱芳烃双主体化合物具有两种不同的空腔,使得该分子既有柱芳烃的性能又具有开环葫芦脲的性能,开环葫芦脲柱芳烃双主体组成了线性空腔,因而在分子离子跨膜转运领域具有很强的应用研究。因此开发新的开环葫芦脲柱芳烃双主体化合物具有重要的研究及其应用价值。此外,开环葫芦脲柱芳烃双主体作为超分子载体,因其空腔多在作为载体时必然具有载量大的优势;而在作为超分子催化剂,因其具有两种性质不同的空腔,在催化方面会有意想不到的效果。
发明内容
鉴于此,本发明提供了一种简便、快捷、能够广泛应用的开环葫芦脲柱芳烃双主体化合物,其结构式如下式Ⅰ、式Ⅱ所示:
其中R为(CH2)mSO3Na或R为(CH2)x-OPO3K2,其中m=1~5,x=1~4,y=1~3,k=1~3,n=1~5。
其中R为(CH2)mSO3Na或R为(CH2)x-OPO3K2,其中m=1~5,x=1~4,y=1~3,k=1~3,n=1~5。
本发明所述的开环葫芦脲柱芳烃双主体化合物同时具有开环葫芦脲和环糊精分子;该类化合物具有两种空腔,其中一种是环糊精的空腔另一种是开环葫芦脲的空腔,并且这两种空腔的排列呈现线性结构,该类化合物的空腔具有两种性质,使得该化合物既有柱芳烃的性能又具有开环葫芦脲的性能,可以作为超分子载体、超分子催化剂,同时该化合物具有很好的分子识别能力,可以很好的应用于制药、食品、香精香料、烟草、化工催化等行业。
上述开环葫芦脲柱芳烃双主体化合物的制备方法如下:
(1)将卤素修饰的开环葫芦脲与羧基修饰的柱芳烃在碱和有机溶剂的混合溶液中进行反应,反应的温度为30~60℃,反应时间为1~3h,其中卤素修饰的开环葫芦脲与羧酸修饰的柱芳烃的摩尔比为4~2:1,卤素修饰的开环葫芦脲与碱的摩尔比为1:3~5;
所述碱包括但不限于三乙胺、苯胺、碳酸氢钠、碳酸钠、碳酸钾或碳酸氢钾;有机溶剂包括但不限于二氯甲烷、四氢呋喃、吡啶、甲烷磺酸、三氟乙酸、醋酸酐、N,N-二甲基甲酰胺、二甲基亚砜;
所述卤素修饰的开环葫芦脲是参照申请号201910966226.X“一类不对称开环葫芦脲及其制备方法”中的方法制得;
所述羧基修饰的柱芳烃的制备是参照Xin P,Sun Y,Kong H,et al.Aunimolecular channel formed by dual helical peptide modified pillar[5]arene:correlating transmembrane transport properties with antimicrobial activityand haemolytic toxicity[J].Chemical Communications,2017,53(83):11492-11495.中的方法制得。
(2)反应完成后冷却至室温,在反应液中加入溶剂产生沉淀,过滤,固体用水溶解后,透析或膜分离,透析液或分离液干燥后制得开环葫芦脲柱芳烃双主体化合物;
所述使反应液析出沉淀的溶剂包括但不限于丙酮、甲醇、乙酸乙酯、石油醚、乙醚;所述的透析时间为48h~96h。
上述开环葫芦脲柱芳烃双主体化合物式Ⅰ制备工艺过程如下:
其中R为(CH2)mSO3Na或R为(CH2)x-OPO3K2,其中m=1~5,x=1~4,y=1~3,k=1~3,n=1~5。
上述开环葫芦脲柱芳烃双主体化合物式Ⅱ反应工艺过程如下:
其中R为(CH2)mSO3Na或R为(CH2)x-OPO3K2,其中m=1~5,x=1~4,y=1~3,k=1~3,n=1~5。
本发明另一目的是将上述开环葫芦脲柱芳烃双主体化合物作为跨膜转运通道分子,并通过人工囊泡荧光实验来验证合成的开环葫芦脲柱芳烃双主体化合物的脂质双层嵌入能力和跨膜转运离子的能力。
本发明的优点和效果如下:
本发明提供的开环葫芦脲柱芳烃双主体化合物合成方法简单,操作简便安全和高效,易于操控,合成得到的产品纯度高,品质优良;该类分子可作为分子离子跨膜转运通道,此外,由于开环葫芦脲柱芳烃双分子化合物具有两种性质的空腔,其也可以作为超分子载体、超分子催化剂,与匹配客体物质形成多分子体系并应用于制药、食品、香精香料、烟草等行业。
附图说明
图1是制备实施例1开环葫芦脲柱芳烃双主体化合物分子的核磁共振氢谱(1HNMR)图;
图2是制备实施例2开环葫芦脲柱芳烃双主体化合物分子的核磁共振氢谱(1HNMR)图;
图3是开环葫芦脲柱芳烃双主体化合物在荧光素Lucigenin存在下(λex=372nm,λem=503nm),相对荧光强度随时间的变化图;
图4为开环葫芦脲柱芳烃双主体化合物在脂质双层中形成离子通道的示意图。
具体实施方式
下面通过实施例进一步对本发明中所述方法进行描述,但本发明保护范围不受实施例限制,本实施例中使用的试剂如无特殊说明均为常规市售试剂或按常规方法配制的试剂,使用的方法如无特殊说明均为常规方法;
实施例1:本实施例开环葫芦脲柱芳烃双主体化合物及制备如下:
其中R为(CH2)mSO3Na,其中m=3,y=1,k=1,n=1;
制备时,取双羧酸柱芳烃(25.14mg,0.03mmol)与卤素修饰的开环葫芦脲(164.64mg,0.12mmol)溶于20mL的N,N-二甲基甲酰胺溶液中,再向反应液中加入三乙胺(36.43mg,0.36mmol),在60℃下反应12h;反应结束冷却至室温后,将反应液倒入甲醇中产生沉淀,抽滤,固体用水溶解后,在透析袋(MW=2000)中透析48h,透析结束后,将透析袋内的透析液旋干,在30℃真空下干燥,得到开环葫芦脲柱芳烃双主体化合物,白色固体71.17mg,产率:71.25%;
核磁共振氢谱和碳谱确定开环葫芦脲柱芳烃双主体化合物的结构,开环葫芦脲环糊精双主体化合物的1HNMR如图1显示,在DMSO条件下在5.25~5.75ppm,4.3~4.2ppm及2.3~1.5ppm处出现开环葫芦脲的特征峰;而柱芳烃在该处没有出峰,在3.5~3.75ppm,7.2~6.5ppm处出现柱芳烃上的特征峰;特别是6.5~7.2ppm处既出现的开环葫芦脲苯环上的H,又出现了柱芳烃苯环上的氢;通过计算氢谱的积分总数,正好符合柱芳烃和开环葫芦脲的摩尔比为1:2的理论结果,可初步说明开环葫芦脲与环糊精发生了反应,生成了柱芳烃:开环葫芦脲摩尔比为1:2的键接物。
实施例2:本实施例开环葫芦脲柱芳烃双主体化合物及制备如下:
其中R为(CH2)mSO3Na,其中m=3,y=1,k=1,n=2;
制备时,取双羧酸柱芳烃(25.14mg,0.03mmol)与卤素修饰的开环葫芦脲(84.00mg,0.06mmol)溶于20mL的四氢呋喃溶液中,再向反应液中加入碳酸钠(19.08mg,0.18mmol),在70℃下反应18h,反应结束冷却至室温后,将反应液倒入丙酮中中产生沉淀,抽滤,固体用水溶解后,在透析袋(MW=2000)中透析72h,透析结束后,将透析袋内的透析液旋干,在45℃真空下干燥,得到开环葫芦脲柱芳烃双主体化合物分子2(核磁氢谱见图二),白色固体68.41mg,产率:66.08%。
实施例3:本实施例开环葫芦脲柱芳烃双主体化合物及制备如下:
其中R为-(CH2)x-OPO3K2,其中x=2,y=1,k=1,n=1;
制备时,取双羧酸柱芳烃(25.14mg,0.03mmol)与开环葫芦脲(133.57mg,0.09mmol)溶于20mL的二甲基亚砜溶液中,再向反应液中加入碳酸钾(62.19mg,0.45mmol),在100℃下反应36h;反应结束冷却至室温后,将反应液倒入乙醚中产生沉淀,抽滤,固体水溶解后在透析袋(MW=2000)中透析48h,透析结束后,将透析袋内的透析液旋干,在60℃真空下干燥,得到开环葫芦脲柱芳烃双主体化合物,白色固体76.86mg,产率:70.26%。
实施例4:本实施例开环葫芦脲柱芳烃双主体化合物及制备如下:
其中R为-(CH2)x-OPO3K2,其中x=4,y=1,k=1,n=2;
制备时,取双羧酸柱芳烃(25.14mg,0.03mmol)与开环葫芦脲(188.18mg,0.12mmol)溶于20mL的吡啶溶液中,再向反应液中加入碳酸氢钠(40.32mg,0.48mmol),在90℃下反应24h,反应结束冷却至室温后,将反应液倒入中石油醚产生沉淀,抽滤,固体水溶解后在透析袋(MW=2000)中透析96h,透析结束后,将透析袋内的透析液旋干,在60℃真空下干燥,得到开环葫芦脲柱芳烃双主体化合物,白色固体82.92mg,产率:73.54%。
实施例5:本实施例开环葫芦脲柱芳烃双主体化合物及制备如下:
其中R为(CH2)mSO3Na,其中m=3,y=2,k=3,n=3;
制备时,取双羧酸柱芳烃(25.14mg,0.03mmol)与开环葫芦脲(276.96mg,0.12mmol)溶于20mL的二甲基亚砜溶液中,再向反应液中加入三乙胺(60.72mg,0.60mmol),在90℃下反应24h,反应结束冷却至室温后,将反应液倒入中乙酸乙酯产生沉淀,抽滤,固体水溶解后在透析袋(MW=2000)中透析72h,透析结束后,将透析袋内的透析液旋干,在60℃真空下干燥,得到开环葫芦脲柱芳烃双主体化合物,淡黄色固体86.00mg,产率:62.63%。
实施例6:跨膜转运能力测试
首先,制备包含有荧光素Lucigenin(LG)的蛋黄卵磷脂囊泡(LG是对氯离子敏感的荧光剂,一旦与氯离子结合,LG的荧光将被被淬灭)。在囊泡体系中,囊泡外的K+浓度高于囊泡内,在加入开环葫芦脲柱芳烃分子后,若分子能够嵌入脂质双层中形成离子通道(如图4所示),K+会经过通道分子内流入囊泡内,造成囊泡内外的阴阳离子失衡,促使Cl-内流,进而与囊泡内的荧光素LG结合,促使荧光强度降低;通过监测体系中相对荧光强度随时间的变化程度确定人工离子通道是否形成,其中,体系中相对荧光强度计算依照其中Ir为相对荧光强度,It为荧光强度随着时间变化的值,I0为初始荧光强度,I∞为荧光不再随时间变化时的荧光强度值。
如图3所示,向人工囊泡体系加入不同烷基链长度的开环葫芦脲柱芳烃双主体分子后,相对荧光强度随时间的变化图;从图中我们可以看出当向体系中加入等量的纯水时,相对荧光强度变化很低,表明KCl自身跨膜输送的能力非常弱。当加入相同当量的实施例1和实施例2的环葫芦脲柱芳烃双主体化合物(浓度为脂质体囊泡浓度的0.1%)后,相对荧光强度变化显著增加,结果都表明这两种开葫芦脲柱芳烃分子都能插入人工制备的囊泡的脂质双层上,并跨膜转运离子;这证实了实施例1和实施例2化合物可以嵌入囊泡的脂质双层并形成离子跨膜转运通道,并且实施例2化合物对于K+的传输效率明显高于实施例1化合物,这可能是实施例2化合物的长度更加合适,使其更能稳定插入脂质双层,从而具有更好的离子跨膜转运能力。
Claims (6)
2.权利要求1所述的开环葫芦脲柱芳烃双主体化合物的制备方法,其特征在于:将卤素修饰的开环葫芦脲与羧酸修饰的柱芳烃在碱和有机溶剂的混合溶液中进行反应,反应的温度为60~100℃,反应时间为12~36h,反应完成后冷却至室温,在反应液中加入溶剂产生沉淀,过滤,固体水溶解后透析或膜分离,透析液或分离液干燥得到开环葫芦脲柱芳烃双主体化合物。
3.根据权利要求2所述的制备方法,其特征在于:卤素修饰的开环葫芦脲与羧酸修饰的柱芳烃的摩尔比为4~2:1,卤素修饰的开环葫芦脲与碱的摩尔比为1:3~5。
4.根据权利要求2所述的制备方法,其特征在于:碱选自三乙胺、苯胺、碳酸氢钠、碳酸钠、碳酸钾、碳酸氢钾;有机溶剂选自二氯甲烷、四氢呋喃、吡啶、甲烷磺酸、三氟乙酸、醋酸酐、N,N-二甲基甲酰胺、二甲基亚砜。
5.根据权利要求2所述的制备方法,其特征在于:使反应液析出沉淀的溶剂为丙酮、甲醇、乙酸乙酯、石油醚或乙醚。
6.权利要求1所述的开环葫芦脲柱芳烃双主体化合物在作为跨膜转运通道分子中的应用。
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