基于柱芳烃羧酸铵盐主客体识别的氮芥防护策略

Nitrogen Mustard Protection Strategy Based on Host-Guest Recognition by Carboxylatopillararene

双官能化的烷基化试剂氮芥(Nitrogen Mustard,NM)作为一种类似于硫芥的高毒物质,最初被设计用作军事目的,严重威胁人类安全。包括硫芥、NM在内的此类物质中毒至今仍没有特效的药物。本文选取柱[5]芳烃羧酸铵盐(Carboxylatopillar[5]arene,CP5A)和柱[6]芳烃羧酸铵盐(Carboxylatopillar[6]arene,CP6A)作为主体,基于直接主客体包结作用发展了一种针对NM的超分子防护策略。核磁氢谱结果证明CP5A和CP6A能够有效络合NM形成主客体复合物,其键合常数分别为(3.92±0.70)×10^(3)L·mol^(-1)和(1.19±0.28)×10^(4)L·mol^(-1)。体外细胞毒性实验和体内病理学分析初步表明该大环化合物具有良好的生物相容性。药效学实验则证实了在小鼠模型上,经大环化合物处理后可显著缓解NM引起的皮肤损伤。CP6A组的皮肤防护效果优于CP5A组,可能是由于CP6A与NM之间存在更强的主客体作用力。

The bifunctional alkylation agent nitrogen mustard(NM),a kind of highly toxic substance similar to sulfur mustard which were initially developed for military use,remains a threat to public health.Including sulfur mustard,NM and other such substances poisoning there are still no specific drugs.Herein,a supramolecular countermeasure to NM was developed via direct host-guest encapsulation by the popular macrocycle carboxylatopillar[5]arene(CP5A)and carboxylatopillar[6]arene(CP6A)as hosts.1H NMR results showed that NM could bind to both CP5A and CP6A to form host-guest complex with association constants of(3.92±0.70)×10^(3)L·mol^(-1) and(1.19±0.28)×10^(4)L·mol^(-1),respectively.In vitro cytotoxicity and in vivo histopathological analyses primarily revealed that such macrocycles possessed excellent biocompatibility.For pharmacodynamics studies,co-dosed with macrocycles could alleviate skin damage induced by NM on mice models.Notably,the protective outcomes from NM/CP6A group was superior than that from NM/CP5A group,presumably as a consequence of stronger complexation potency between CP6A and NM.