龙血素B碳桥结构修饰对其选择性调节离子通道蛋白功能的影响  

Effect of structural modification of loureirin B carbon bridge on its selective regulation of ion channel protein function

作　　者：尹世金[1] 张旭 赵倩茹 骆滨 王强[1] 戴康[1] YIN Shijin;ZHANG Xu;ZHAO Qianru;LUO Bin;WANG Qiang;DAI Kang(School of Pharmaceutical Sciences,South-Central Minzu University,Wuhan 430074,China)

机构地区：[1]中南民族大学药学院,武汉430074

出　　处：《中南民族大学学报（自然科学版）》2022年第5期527-535,共9页Journal of South-Central University for Nationalities：Natural Science Edition

基　　金：国家自然科学基金资助项目(81641186,32000685);湖北省自然科学基金资助项目(2016CFB405);科技部重点研发计划项目(2019YFC1712402)。

摘　　要：为了对龙血素B碳桥结构进行改造,得到对钾、钠离子通道蛋白功能调节选择性更强的衍生物,以2,4,6-三甲氧基-4′-苄氧基查尔酮和2,4,6-三甲氧基苄胺为原料合成了OB(碳桥具有α,β-不饱和双键的龙血素B衍生物)和AB(碳桥具有酰胺键的龙血素B衍生物),通过核磁共振与质谱技术对合成的化合物进行了结构表征,并在HEK-293T细胞和急性分离的小鼠背根神经节细胞(dorsal root ganglion,DRG)当中进行了全细胞膜片钳实验,观察改造的龙血素衍生物对钾通道和钠通道的作用.OB对Kv1.3通道的抑制活性与龙血素B相当,但对DRG细胞河豚毒素敏感型钠通道及Nav1.7通道的活性有所降低.AB对DRG钠通道和Nav1.7通道的作用相比龙血素B略有减弱,但几乎丧失了对Kv1.3通道的抑制活性.以上结果表明,对龙血素B的碳桥进行结构修饰,能够改善其相应产物的理化性质,提高部分产物对离子通道蛋白的选择性.In order to modify the structure of loureirin B and obtain derivatives with stronger selectivity for potassium and sodium channels,OB(loureirin B derivatives withα,β-unsaturated double bonds)and AB(loureirin B derivatives with amide bonds)were synthesized from 2,4,6-trimethoxy-4'-benzyloxychalcone and 2,4,6-trimethoxybenzylamine.The structures of the compounds were characterized by NMR and mass spectrometry,Whole cell patch clamp experiments were carried out in HEK-293T cells and isolated dorsal root ganglion(DRG)cells of mice to observe the effects of the modified product on potassium and sodium channels.The inhibitory activity of the synthesized OB on Kv1.3 channel was equivalent to that of loureirin B,but the inhibition on tetrodotoxin sensitive sodium channel in DRG cells and Nav1.7 channel decreased.AB has weaker inhibition on DRG sodium channel and Nav1.7 channel than that of loureirin B,but almost lost the inhibitory effect on Kv1.3 channel.The results showed that the structural modification of the carbon bridge of loureirin B could improve the physical and chemical properties of its corresponding products,and their selectivity to ion channels.

关 键 词：龙血素B 结构修饰 选择性 钾通道 钠通道 

分 类 号：Q257[生物学—细胞生物学] R285.5[医药卫生—中药学]