Novel Light-Promoted Bioorthogonal Reaction via Molecular Recombination for the Synthesis of Polysubstituted Pyrrole and Its Application in In Vitro and In Vivo Studies

Abstract

Bioorthogonal chemistry has revolutionized organic, medicinal, and biochemical research by designing and developing selective and rapid reactions that do not interfere with biological processes. Despite significant advancements, the existing bioorthogonal reactions can normally introduce only one functional group to a biomolecule, limiting their versatility in biological systems. In this study, we report a novel light-promoting reaction, namely light-promoted bioorthogonal multifunctionalized molecular recombination (LBMR) reaction, that can facilitate the synthesis of polysubstituted pyrroles via molecular editing and recombination of isoxazole-3-carboxylate and isoxazole-3-carboxylic acid derivatives. The proposed LBMR reaction exhibited rapid kinetics, high efficiency, wide substrate scope, and the potential for in situ fluorescence imaging under normal physiological conditions without the need for a catalyst. The LBMR reaction allowed incorporating multiple functional groups and using well-soluble carboxylic salts as bioorthogonal substrates. The in vitro experiments performed in different types of cells and the in vivo studies performed on zebrafish demonstrated the potential applicability of the proposed LBMR for biological imaging. This work not only introduces a new photo-bioorthogonal reaction paradigm but also expands the scope of bioorthogonal chemistry, paving the way for future applications in biomedical research.