State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering , Nanjing Tech University , Nanjing 210009 , China.
State Key Laboratory of Pharmaceutical Biotechnology , Nanjing University , Nanjing 210032 , China.
J Am Chem Soc. 2020 Feb 26;142(8):3806-3813. doi: 10.1021/jacs.9b11357. Epub 2020 Feb 14.
Photolabile groups offer promising tools to study biological processes with high spatial and temporal control. In the investigation, we designed and prepared several new glycine amide derivatives of Sanger's reagent and demonstrated that they serve as a new class of photocages for Zn and an acetylcholinesterase (AChE) inhibitor. We showed that the mechanism for photocleavage of these substances involves initial light-driven cyclization between the 2,4-dinitrophenyl and glycine methylene groups to form acyl benzimidazole -oxides, which undergo secondary photoinduced decarboxylation in association with rupture of an amide bond. The cleavage reactions proceed with modest to high quantum yields. We demonstrated that these derivatives can be used in targeted intracellular delivery of Zn, fluorescent imaging by light-triggered Zn release, and regulation of biological processes including the enzymatic activity of carbonic anhydrase (CA), negative regulation of -methyl-d-aspartate receptors (NMDARs), and pulse rate of cardiomyocytes. The successful proof-of-concept examples described above open a new avenue for using Sanger's reagent-based glycine amides as photocages for the exploration of complex cellular functions and signaling pathways.
光解基团提供了有前途的工具，可以实现具有高时空控制的生物过程研究。在研究中，我们设计并制备了几种桑格试剂的甘氨酸酰胺衍生物，证明它们是 Zn 的一类新光笼，并作为乙酰胆碱酯酶 (AChE) 抑制剂。我们表明，这些物质的光解机制涉及 2,4-二硝基苯基和甘氨酸亚甲基之间最初的光驱动环化，形成酰基苯并咪唑 -氧化物，其在与酰胺键断裂相关的次级光诱导脱羧作用下进行。裂解反应以中等至高的量子产率进行。我们证明这些衍生物可用于 Zn 的靶向细胞内递药、通过光触发 Zn 释放进行荧光成像，以及调节包括碳酸酐酶 (CA) 的酶活性、负调节 -甲基-d-天冬氨酸受体 (NMDARs) 和心肌细胞的搏动率在内的生物过程。上述成功的概念验证示例为使用基于桑格试剂的甘氨酸酰胺作为光笼来探索复杂的细胞功能和信号通路开辟了新途径。
