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A Late-Stage Aryl C-H Olefination Strategy and Its Application Towards Global Proteome Profiling of ∆8-Tetrahydrocannabinol.

Ying-Jie Lim,Guanghui Tang,Zi Ye,Chong-Jing Zhang,Jie Wu,S. Yao

Published 2023 in Chemistry

ABSTRACT

Drugs and bioactive natural products exert their pharmacological effects by engaging numerous cellular targets in our body. Identification of these protein targets is essential for understanding the mechanism-of-action of these compounds, thus contributing to improved drug design in drug discovery programs. Termed "in situ drug profiling", a common strategy for studying these bioactive compounds centralized on the covalent capture of protein targets along with a reporter tag to facilitate downstream proteomic analyses. Though highly successful, such a strategy required innate electrophilic traps to facilitate covalent capture, and its dependence on classical alkylation/acylation strategies to install reporter tags has restricted its applications on non-covalent compounds. Late-stage C-H functionalization (LSF) may resolve this by substituting biologically inert C-H bonds with desired electrophilic groups. Herein, we demonstrated this concept by arming a diverse range of electron-rich aromatic drugs and natural products with α,β-unsaturated esters, via late-stage C-H olefination with a arylthio-based carboxylic acid ligand developed by Ibanez and co-workers. We also showed that covalent probes generated from this LSF approach could be applied for "in situ drug profiling" of ∆8-THC, as exemplified by the successful target engagement of α-4db, a ∆8-THC-based probe, to its native target hCB2R. In combination with probe 7, a photoaffinity-based derivative of ∆8-THC, we identified several novel putative targets that could account for some of the effects in THC consumption. We anticipate our C-H LSF strategy to be widely adopted for future studies of non-covalent drugs.

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