A red-emission fluorescent probe for monitoring polarity changes during ER stress induced by DTT

The endoplasmic reticulum (ER) is the most extensive organelle within eukaryotic cells and functions as a critical hub for cellular biosynthesis. It plays a pivotal role in protein biosynthesis and lipid metabolism, and changes in its polarity are closely associated with various diseases, including non-alcoholic fatty liver disease, atherosclerosis and type 2 diabetes. Herein, we designed and synthesised a series of ER-targeting compounds ER-A, ER-B and ER-C, incorporating methyl sulfonamide as the ER-targeting moiety by copper-catalysed azide–alkyne cycloaddition reactions (CuAAC). These compounds are capable of detecting environmental polarity changes within a defined range. Notably, the colocalisation coefficient of compound ER-A and ER-Tracker Green were found to be 0.9, indicating precise localisation to the ER site of cells. Additionally, compound ER-A demonstrated the ability to detect polarity changes induced by endoplasmic reticulum stress (ERS) in HepG2 cells upon treatment with 1,4-dithiothreitol (DTT). In conclusion, the compounds developed in this study offer an effective method for monitoring ER polarity changes and provide a novel approach for investigating diseases associated with abnormal ER polarity.