Development of silicon-fluorescein-based photolabile protecting groups with enhanced uncaging quantum yield

Abstract

Photolabile protecting groups (PPGs) that respond to visible light are valuable tools for spatiotemporal control of biological events. However, achieving high uncaging efficiency at biocompatible wavelengths remains a significant challenge. In this study, we report a new class of PPGs triggered by photoinduced electron transfer (PeT) and activated by orange light (ca. 600 nm), designed to overcome this limitation. Using a structure-based approach assisted by quantum-chemical calculations, we focused on minimizing the activation energy (ΔE_a) of the bond cleavage step following PeT. By rationally tuning the picolinium cation and antenna moieties, we achieved significantly improved reaction quantum yields, surpassing conventional PeT-based systems operating in this window. These results were consistent with the predicted energetics of the post-PeT intermediates, validating our design strategy. The practical utility of the system was demonstrated through the design and synthesis of a photoactivatable prodrug of a vasodilator. Upon orange light irradiation, the compound induced vasodilation in a sustained and controllable manner. This work not only provides a new strategy for designing high-efficiency PPGs operating at biologically compatible wavelengths, but also highlights the importance of combining quantum-chemical predictions with molecular design. Furthermore, the generality of the approach suggests its applicability to other single-electron-driven reactions. We believe these findings open a new avenue for the rational development of visible-light-responsive molecular tools in chemical biology and photopharmacology.