Tuning SBDs as Endoplasmic Reticulum Self-Targeting Fluorophores and Its Application for Zn²⁺ Tracking in ER Stress

The emerging endoplasmic recticulum (ER) crosstalk system demands a more reliable approach for ER-targeting fluorophores to explore ER-associated biochemical species and events. Providing the aromatic sulfonamides' affinity to ATP-sensitive potassium channel protein localized mainly on ER membrane, the sulfonamide fluorophore 4-amino-7-sulfamoylbenzoxadiazole (SBD) was modified to construct ER self-targeting fluorophores without any additional targeting group by alternating the N-substituent structure and numbers of its 4-amino and 7-sulfamoyl groups. The results revealed that a ClogP value over 3.0 endowed those SBDs the ER self-targetability effectively. This provides a strategy to devise an ER-targeting probe by simply modifying the 4-amino group of SBDs as a sensing moiety to make the probe CLogP over 3.0 despite the CLogP value of parent SBDs, and two ER-targeting Zn²⁺ probes ER-SBD-Zn1 and ER-SBD-Zn2 were obtained following this idea. Moreover, ER Zn²⁺ tracking with ER-SBD-Zn1 disclosed for the first time tunicamycin concentration-dependent ER Zn²⁺ fluctuation behavior during ER stress induction.