A Late‐Stage Aryl C−H Olefination Strategy and Its Application Towards Global Proteome Profiling of Δ8‐Tetrahydrocannabinol

• Published in: Chemistry : a European journal 2023-05, Vol.29 (29), p.e202300531-n/a
• Main Authors: Lim, Ying‐Jie, Tang, Guanghui, Ye, Zi, Zhang, Chong‐Jing, Wu, Jie, Yao, Shao Q.
• Format: Article
• Language: English
• Subjects: activity-based protein profiling; affinity-based protein profiling; Bioactive compounds; Biological activity; Carboxylic acids; Chemistry; Covalence; Drug development; Drugs; Esters; late-stage functionalization; Natural products; Proteins; Proteomes; Proteomics; Tetrahydrocannabinol; THC
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202300531

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 reliance on innate electrophilic traps to facilitate covalent capture restricted its applications to covalent acting 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 an 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 Δ8‐THC, as exemplified by the successful target engagement of α‐4 db, a Δ8‐THC‐based probe, to its native target hCB2R. In combination with AfBP 7, a photoaffinity‐based derivative of Δ8‐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. A strategy that empowers activity‐based proteome profiling of Δ8‐THC, a psychoactive natural product from Cannabis sativa, through a late‐stage arene olefination method is described. This olefination method is capable of converting non‐covalent acting compounds, such as Δ8‐THC, into activity‐based probes after silyl deprotection. Its ability to interrogate protein interaction landscape of Δ8‐THC is then compared with AfBPP.