biostudies-literaturePage ACSNIEHS NIH HHSMark Foundation For Cancer ResearchNational Institutes of Health3851-3856https://www.ebi.ac.uk/biostudies/studies/S-EPMC8966736biostudies-literatureUnknown13(13)Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule-protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an <i>i</i>Pr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silaneChemical sciencePhoto-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design.PMC8966736P42 ES004705R01GM136945P42ES004705R01CA240981Belcher BPToste FDNomura DKKeenan KNSchirle MScholz SOTallarico JAMcKenna JMBrittain SMPage ACSSpradlin JNfalsePhoto-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design.Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule-protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an <i>i</i>Pr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silane2022-01-01T00:00:00Z2022 Mar2025-04-04T10:44:35.526Z2025-04-04T10:44:35.526ZS-EPMC89667363543289010.1039/d2sc00426g