Unlocking Selenium Chemical Space via a Programmable Synthesis Platform Bearing Cannabinoid Receptor Recognition...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Controllable homologation is crucial for exploring new chemical space in biological studies.
• G-protein-coupled receptor (GPCR) pharmacology can be advanced using underexplored elements as biological probes.

Purpose of the Study:

• To develop an expeditious and sustainable platform for synthesizing chiral, pro-chiral, and achiral selenosulfonyl homologated compounds.
• To create novel seleno-cannabinoid agents (SelenoCanns) targeting the cannabinoid receptor-1 (CB1R).

Main Methods:

• Utilized a Bunte-reaction-inspired seleno-homologation strategy.
• Employed sodium selenosulfate (Na2SeSO3), a benign selenium source, under aqueous conditions.
• Developed a one-pot synthesis for scalable conversion of chloro-imidoylsulfonylureas.

Main Results:

• Successfully synthesized novel seleno-cannabinoid agents (SelenoCanns).
• Many synthesized compounds demonstrated nanomolar to sub-nanomolar binding affinity for the CB1 receptor.
• The method enables on-demand synthesis of diverse organoselenium molecules.

Conclusions:

• The developed platform provides access to previously inaccessible molecules for structure-function studies on CB1R.
• This work facilitates the synthesis of drug-like molecules, covalent-drug conjugates, click handles, and seleno-fluorescent probes.
• The findings open new avenues for exploring GPCR pharmacology using organoselenium compounds.