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

• Published in: Chemistry : a European journal 2023-05, Vol.29 (29), p.e202300531
• Main Authors: Lim, Ying-Jie, Tang, Guanghui, Ye, Zi, Zhang, Chong-Jing, Wu, Jie, Yao, Shao Q
• Format: Article
• Language: English
• Subjects: Biological Products - chemistry; Dronabinol; Drug Discovery; Humans; Proteome - metabolism; Proteomics
• 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 Δ -THC, as exemplified by the successful target engagement of α-4 db, a Δ -THC-based probe, to its native target hCB R. In combination with AfBP 7, a photoaffinity-based derivative of Δ -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.