Light-driven activation: Developing photoremovable protecting groups for synthesis and biomedical applications

Abstract

This dissertation encompasses an interdisciplinary exploration of Photo-removable protecting groups (PPGs), which includes identifying novel PPGs, performance optimization of existing PPGs and demonstration of their applications. The research delves into the design and optimization of PPGs for biomedical fields, emphasizing the importance of tailored structural features for optimal function within biological environments. Especially, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based PPGs were refined to improve the efficiency of photorelease in the NIR (Near Infra-Red) region addressing a critical shortcoming of previously reported NIR absorbing BODIPY-based PPGs. This was achieved via structure rigidification and trapping the intermediate cation, resulting in a maximum of ~50-fold improvement in quantum yield of release (Φr) than the previous BODIPY-based similar PPGs. Complementing these efforts, structure-photoreactivity studies aimed at enhancing the deprotection efficiency of BODIPY-based PPGs provide profound insights into the correlation between substituted functional groups and Φr. Both Electron-donating groups (EDG) and electron-withdrawing groups (EWG) were used to assess the effect on Φr when substituted at the boron and 2-core positions. While EDGs improved the Φr, EWGs had the opposite effect. Additionally, the substitution at the meso methyl position by aryl groups unexpectedly lowered the Φr indicating the presence of competing photophysical/photochemical pathways. Furthermore, in this dissertation strategic design initiatives targeting a pyridinium-based zwitterionic PPG for biological applications are discussed. This zwitterionic PPG showed excellent water solubility and a great release efficiency at biological pH compared to similar-sized PPGs, showcasing its potential applications in light-triggered biomolecule activity modulation. Finally, the dissertation highlights a proof of principle study demonstrating the applicability of BODIPY-based PPGs in glycan synthesis, broadening their utility beyond the most studied biological applications. This study showed a synthesis of trisaccharide with an impressive 70% yield with just one purification. Collectively, these findings underscore the interdisciplinary nature of the research, demonstrating PPGs’ potential to be used in biology and synthetic chemistry.