Presentation Information
[P04-516]Visible light-mediated photocatalytic coupling between diaryltetrazoles and carboxylic acids for biomolecule labelling
○Yuya Komatani1, Sogo Ueno2, Sumika Yamada3, Rei Nonaka2, Sota Hirugami4, Hidetaka Kosako4,5, Shinsuke Inuki1,3,5 (1. Graduate School of Biomedical Sciences, Tokushima University (Japan), 2. Faculty of Pharmaceutical Sciences, Tokushima University (Japan), 3. Graduate School of Pharmaceutical Sciences, Kyoto University (Japan), 4. Institute of Advanced Medical Sciences, Tokushima University (Japan), 5. Institute of Photonics and Human Health Frontier, Tokushima University (Japan))
Keywords:
proximity labelling,photocatalyst,visible light,diaryltetrazole,nitrile imine
Detecting and tracking biomolecular interactions are essential for a deep understanding of biological phenomena, leading to the development of numerous biological and chemical techniques. Proximity labelling has emerged as a powerful and versatile approach for mapping such interactions in complex biological environments. In this strategy, a catalyst is localized to a target molecule or cell, and reactive intermediates are generated from labelling reagents in a catalyst-dependent manner. By controlling the lifetime and diffusion distance of these intermediates, biomolecules or cells in close proximity to the target can be selectively labelled. Among these approaches, visible light-mediated photocatalytic systems have attracted considerable attention because they enable not only spatial control but also temporal regulation through light irradiation, offering precise control over labelling processes in living systems.
In our laboratory, we have developed a photocatalytic strategy that targets carboxylic acid functionalities, which are widely distributed across biomolecules, including proteins. Previously, we reported a photocatalyst-dependent modification of carboxylic acids using diaryltetrazoles as labelling reagents. Upon activation, these reagents generate highly reactive nitrile imine intermediates, which can be coupled with carboxylic acids to form hydrazide linkages. This reaction was successfully applied to the labelling of proteins and cell surfaces in aqueous environments. However, despite its broad applicability, the initial system exhibited limitations in labelling efficiency, highlighting the need for further optimization.
In this study, we focused on the structural optimization of diaryltetrazole-based labelling reagents to enhance their reactivity under visible light photocatalytic conditions. By systematically modifying the substituents on the tetrazole scaffold, we identified key structural features that promote efficient generation of nitrile imine intermediates via photocatalyst-mediated energy transfer. In particular, the introduction of electron-donating group to aryl group of diaryltetrazole significantly improved the reactivity toward carboxylic acids, enabling efficient coupling under physiologically relevant conditions.
To further expand the applicability of this system toward biomolecular interaction analysis, we designed and synthesized biotin-conjugated diaryltetrazole derivatives. The optimized labelling reagents were successfully applied to the modification of proteins. The labelling process proceeded in a photocatalyst- and light-dependent manner.
Overall, this work establishes an improved photocatalytic platform for carboxylic acid-directed biomolecular labelling and provides a foundation for future development of proximity labelling technologies. Ongoing studies are directed toward applying this strategy to the comprehensive analysis of biomolecular interactions in living systems.
In our laboratory, we have developed a photocatalytic strategy that targets carboxylic acid functionalities, which are widely distributed across biomolecules, including proteins. Previously, we reported a photocatalyst-dependent modification of carboxylic acids using diaryltetrazoles as labelling reagents. Upon activation, these reagents generate highly reactive nitrile imine intermediates, which can be coupled with carboxylic acids to form hydrazide linkages. This reaction was successfully applied to the labelling of proteins and cell surfaces in aqueous environments. However, despite its broad applicability, the initial system exhibited limitations in labelling efficiency, highlighting the need for further optimization.
In this study, we focused on the structural optimization of diaryltetrazole-based labelling reagents to enhance their reactivity under visible light photocatalytic conditions. By systematically modifying the substituents on the tetrazole scaffold, we identified key structural features that promote efficient generation of nitrile imine intermediates via photocatalyst-mediated energy transfer. In particular, the introduction of electron-donating group to aryl group of diaryltetrazole significantly improved the reactivity toward carboxylic acids, enabling efficient coupling under physiologically relevant conditions.
To further expand the applicability of this system toward biomolecular interaction analysis, we designed and synthesized biotin-conjugated diaryltetrazole derivatives. The optimized labelling reagents were successfully applied to the modification of proteins. The labelling process proceeded in a photocatalyst- and light-dependent manner.
Overall, this work establishes an improved photocatalytic platform for carboxylic acid-directed biomolecular labelling and provides a foundation for future development of proximity labelling technologies. Ongoing studies are directed toward applying this strategy to the comprehensive analysis of biomolecular interactions in living systems.
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