CN111518025A - 联吡啶双酰胺基作为有机人工离子通道单体的应用 - Google Patents
联吡啶双酰胺基作为有机人工离子通道单体的应用 Download PDFInfo
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Abstract
本发明公开了一种含联吡啶基团的具有双酰胺基有机人工离子通道单体的应用,该化合物可以用于细胞膜上的跨膜离子传输性能及金属离子选择性。本发明解决现有人工离子通道单体的制备方法复杂,成本高,传输效果不高以及离子选择性差或其他手段的问题。本发明所提供的含联吡啶基团的具有双酰胺结构的有机人工离子通道单体,其锂离子跨膜传输的EC50值为0.57μM。
Description
技术领域
本发明属于化工领域,特别是涉及一种含联吡啶基团的具有双酰胺基的有机人工离子通道单体的应用。
背景技术
离子通道是由细胞膜上的通道蛋白组成,具有高效率的离子传输性能。为了更好地研究天然通道蛋白的输送机制,化学家们不断地进行探索,创造了多种类型的人工合成的离子转运体系,试图构建可以与大自然相媲美的跨膜离子传输系统。人工离子通道通常以寡聚冠醚类、大环类、大环寡聚芳烃、胆固醇类、聚合物类、多肽及多肽模拟体、金属有机框架结构及组装体类(通过共价键相互作用)为构建模块。
但是,目前现有人工离子通道单体的制备方法复杂,成本高,传输效果不高以及离子选择性差或其他手段的问题。因此,设计开发低成本、高性能且离子选择性好的人工离子通道单体具有十分重要的意义。
发明内容
本发明提供一种含联吡啶基团的具有双酰胺基的有机人工离子通道单体及其制备方法和在跨膜离子传输性能及其离子选择性的应用,旨在解决现有人工离子通道单体的制备方法复杂,成本高,传输效果不高以及离子选择性差或其他手段的问题。本发明所提供的含联吡啶基团的具有双酰胺结构的有机人工离子通道单体,其锂离子跨膜传输的EC50值为0.57μM。
本发明提供了一种具有式(I)结构的化合物作为人工离子通道单体的应用,
其中,R1表示C1-C6烷基或者-(C1-C6亚烷基)(C6-C10芳基),R2表示C1-C16的烷基,优选为C6-C16烷基。
优选地,在本发明的技术方案中,R1表示C1-C6烷基。
优选地,在本发明的技术方案中R1表示甲基,乙基,正丙基,正丁基,异丙基,1-甲基丙基,2-甲基丙基,苄基;
优选地,在本发明的技术方案中,R1表示1-甲基丙基;
优选地,在本发明的技术方案中,R2表示-C12H25;
优选地,在本发明的技术方案中,选自以下结构的化合物:
本发明取得了以下有益效果,本发明的发明人研究了属于本发明的化合物双酰胺基可以作为粉末型有机凝胶因子(中国专利申请号:CN201910886420.7),进一步的研究表明,本发明的化合物还可以作为人工离子通道单体,发现了属于本发明的化合物2Py-Ile-C10的跨膜离子传输性能相对较好,其中锂离子跨膜传输的EC50值为0.57μM。
定义:在本发明的定义中,其中所述的烷基表示直链或支链烷基,例如,C1-C6烷基可以为甲基、乙基、正丙基、异丙基,正丁基,1-甲基丙基,2-甲基丙基,正戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,1-乙基丙基,2-乙基丙基,正己基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基等,芳基优选为苯基、萘基。
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。为了更好的说明本发明,下面通过实施例做进一步的举例说明。
具体实施例
本发明的化合物利用与申请号为CN201910886420.7的中国专利申请采用了相同或相近的合成方法制备所得,具体地:
实施例1以目标分子N(OH)2-Val-C12的制备为例:
第一步:
250mL圆底烧瓶中加入F-Val-OH(3.39g,10mmol),BOP 4.86g(11mmol),1粒搅拌子,然后向其中加入溶剂CH2Cl2 80mL,DMF 20mL。然后加入正十二胺(2.38mL,10mmol)。然后加入DIEA 3.9mL(22mmol),室温搅拌,用TLC监测实验进程。反应结束后,除去溶剂,并将残余物溶解于100mL甲醇中,然后滴加到2L快速搅拌的水中,期间有大量固体析出,过滤,冰乙腈洗涤,得到的固体直接用于下一步。
1H NMR(400MHz,CDCl3)δ7.76(d,J=7.5Hz,2H),7.58(d,J=7.5Hz,2H),7.40(t,J=7.5Hz,2H),7.31(t,J=7.4Hz,2H),5.95(s,1H),5.51(d,J=8.9Hz,1H),4.39(dt,J=24.4,10.0Hz,2H),4.21(t,J=7.0Hz,1H),3.90(t,J=7.8Hz,1H),3.38-3.09(m,2H),2.18-2.02(m,1H),1.56-1.39(m,2H),1.34-1.17(m,18H),0.99-0.84(m,9H).13C NMR(100MHz,CDCl3)δ172.30,156.03,143.81,141.31,127.73,127.09,125.09,119.99,67.01,50.87,47.20,39.58,31.91,29.63,29.57,29.52,29.35,29.24,26.88,22.69,19.23,18.62,17.99,17.31,14.12.
第二步:
100mL圆底烧瓶中加入2.02g Fmoc-Val-C12(4mmol),1粒搅拌子,然后向其中加入溶剂氯仿20mL,然后加入哌啶0.8mL,室温搅拌12小时。反应结束,用旋转蒸发仪旋干所有的溶剂,然后用硅胶柱提纯产物。先正己烷或者石油醚装硅胶柱,将样品溶解在最少量的CH3Cl中,上样。首先用1:2乙酸乙酯:正己烷的洗脱液过掉副产物点,这个副产物点UV254nm下可见,为脱下来的Fmoc和哌啶的副产物。当这个副产物点出来后,将洗脱液换成甲醇:CH2Cl2=5/100,冲出产物点。
1H NMR(400MHz,CDCl3)δ3.36-3.15(m,3H),2.38-2.24(m,1H),1.63(s,2H),1.55-1.46(m,2H),1.35-1.23(m,18H),0.99(d,J=7.0Hz,3H),0.91-0.86(m,3H),0.83(d,J=6.9Hz,3H).13C NMR(100MHz,CDCl3)δ172.10,66.96,39.38,31.89,29.53,29.51,29.46,29.30,29.21,26.80,22.61,19.19,18.60,17.69,17.30,14.12.
第三步:
25mL圆底烧瓶中加入80.1mg 2Py-OH(0.4mmol),NH2-Val-C12 113.8mg(0.4mmol),BOP 194.7mg(0.44mmol),1粒搅拌子,然后向其中加入溶剂CH2Cl2 3.2mL,DMF0.8mL。然后加入DIEA 0.156mL(0.44mmol),室温搅拌20小时。反应结束,用旋转蒸发仪旋干所有的溶剂,然后将反应物溶解在12mL CH2Cl2中,用16mL水洗两次,然后旋干CH2Cl2得到粗产物,向粗产物中加入4mL的冰乙腈,摇晃让固体状乙腈中分散,过滤得到纯的固体。
1H NMR(400MHz,CDCl3)δ8.71(d,J=4.9Hz,1H),8.63(d,J=5.3Hz,2H),8.34(d,J=7.9Hz,1H),7.76(td,J=7.8,1.4Hz,1H),7.64(d,J=3.8Hz,1H),7.31-7.24(m,1H),7.15(d,J=7.0Hz,1H),6.05(s,1H),4.37(t,J=8.1Hz,1H),3.36-3.07(m,2H),2.16(dq,J=13.5,6.7Hz,1H),1.50-1.39(m,2H),1.18(d,J=16.5Hz,18H),0.98(dd,J=6.7,3.4Hz,6H),0.80(t,J=6.8Hz,3H).13C NMR(100MHz,CDCl3)δ169.81,164.76,156.04,154.19,148.96,148.24,141.24,136.03,123.17,120.39,120.23,117.04,58.55,38.67,30.89,30.45,28.61,28.55,28.51,28.43,28.32,28.22,25.92,21.66,18.30,17.74,13.10.
实施例2-5通过类似方法可以得到相应的化合物,具体表征如下:
实施例2
1H NMR(400MHz,CDCl3)δ8.72(d,J=5.0Hz,1H),8.63(d,J=4.4Hz,2H),8.34(d,J=8.0Hz,1H),7.78(td,J=7.8,1.7Hz,1H),7.63(dd,J=5.0,1.6Hz,1H),7.36(d,J=7.6Hz,1H),7.32-7.20(m,6H),5.55(t,J=4.9Hz,1H),4.77-4.65(m,1H),3.27-2.97(m,4H),1.24-1.13(m,18H),1.11-1.09(m,2H),0.84-0.78(m,3H).13C NMR(100MHz,CDCl3)δ169.13,164.29,149.11,148.26,140.95,136.12,135.63,128.36,127.80,126.18,123.24,120.43,120.28,116.88,54.52,38.65,37.95,30.90,28.69,28.62,28.61,28.56,28.47,28.33,28.20,25.74,21.67,13.10.
实施例3
1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.61(s,2H),8.30(d,J=7.9Hz,1H),7.79-7.69(m,1H),7.62(d,J=4.1Hz,1H),7.34(s,1H),7.26(dd,J=6.9,5.1Hz,1H),6.41(s,1H),4.47(t,J=8.3Hz,1H),3.27(dd,J=13.2,6.4Hz,1H),3.16-3.05(m,1H),2.03-1.88(m,1H),1.66-1.52(m,1H),1.49-1.36(m,2H),1.29-1.09(m,19H),0.94(d,J=6.7Hz,3H),0.87(t,J=7.4Hz,3H),0.80(t,J=6.8Hz,3H).13C NMR(100MHz,CDCl3)δ169.68,164.48,155.91,154.13,148.86,148.16,141.20,136.00,123.15,120.37,120.16,116.91,57.53,38.58,36.41,30.82,28.61,28.54,28.48,28.44,28.35,28.25,28.15,25.84,24.21,21.59,14.34,13.03,10.14.
实施例4
1H NMR(400MHz,CDCl3)δ8.68(d,J=5.0Hz,1H),8.61(d,J=4.9Hz,2H),8.32(d,J=8.0Hz,1H),7.75(td,J=7.8,1.7Hz,1H),7.62(dd,J=5.0,1.6Hz,1H),7.30-7.24(m,1H),7.18(s,1H),6.35(t,J=5.4Hz,1H),4.70-4.60(m,1H),3.28-3.05(m,2H),1.78-1.60(m,3H),1.48-1.37(m,2H),1.15(s,18H),0.92(d,J=5.8Hz,6H),0.83-0.77(m,3H).13C NMR(100MHz,CDCl3)δ170.53,164.62,156.05,154.18,149.03,148.22,140.99,136.03,123.19,120.44,120.24,116.77,51.43,40.44,38.69,30.89,28.62,28.61,28.55,28.51,28.41,28.32,28.23,25.86,23.91,21.83,21.66,21.37,13.10.
实施例5
1H NMR(400MHz,CDCl3)δ8.72(dd,J=4.9,0.7Hz,1H),8.63(q,J=2.3Hz,2H),8.35(dd,J=8.0,1.1Hz,1H),7.77(td,J=7.7,1.8Hz,1H),7.65(dd,J=5.0,1.7Hz,1H),7.28(ddd,J=7.5,4.8,1.2Hz,1H),7.17(d,J=7.3Hz,1H),6.14(t,J=5.7Hz,1H),4.64(p,J=7.0Hz,1H),3.27-3.16(m,2H),1.51-1.39(m,5H),1.25-1.15(m,18H),0.80(t,J=6.8Hz,3H).13C NMR(100MHz,CDCl3)δ170.71,164.36,156.09,154.17,149.06,148.23,140.98,136.06,123.22,120.40,120.24,116.79,48.49,38.76,30.89,28.61,28.60,28.55,28.51,28.44,28.32,28.24,25.86,21.66,17.67,13.10.
实施例6目标分子的跨膜离子传输性能及其离子选择性的测定:
利用HPTS荧光标记实验检测离子通道的跨膜离子传输性能及其离子选择性。
囊泡制备:取蛋黄卵磷脂和适量甲醇在圆底烧瓶中混合。混合溶液的溶剂在室温下减压除去后再在室温、高真空下过夜干燥。然后将干燥所得的卵磷脂与包含pH敏感染料的8-羟基芘-1,3,6-三磺酸三钠盐(HPTS)的4-羟乙基哌嗪乙磺酸(10mM HEPES)的缓冲溶液在室温下进行水合45分钟后以得到奶状悬浮液。最后对混合液进行9次周期性的冻融处理:在液氮中冷冻1分钟,接着室温下在水浴中加热2分钟。囊泡悬浮物可以通过挤压机两端带有过滤支撑膜的聚碳酸盐膜挤出以获得尺寸比较均一的包裹HPTS的囊泡悬浮物。
荧光实验:将包裹着HPTS的囊泡悬浮物(100mM NaCl,pH=7.0)加入到HEPES缓冲溶液中(MCl,其中M+=Li+,Na+,K+,Rb+,Cs+)。在轻柔的搅拌过程中,将目标分子的DMSO溶液注入悬浮液。加入目标分子后,立即在510nm处监测HPTS的释放,用荧光分光光度计每1.7秒同时记录460和403nm处的激发,获得染料荧光在300秒内的变化曲线用以判断金属离子的选择性。
目标分子2Py-Ile-C12的跨膜离子传输性能相对较好,锂离子跨膜传输的EC50值为0.57μM,钠离子跨膜传输的EC50值为1.05μM,钾离子跨膜传输的EC50值为0.86μM,铷离子跨膜传输的EC50值为0.94μM,铯离子跨膜传输的EC50值为1.15μM。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换或改进等,均应包含在本发明的保护范围之内。
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