Design, synthesis and biological evaluation of sulfur-containing epicaryolane derivatives as FXR agonists

A biomimetic carbocation-trapping reaction of (-)-β-caryophyllene with heteroaryl thiols, aryl thiols, and aryl sulfinates has been developed, enabling the efficient construction of a series of epicaryolane-based thioether and sulfone derivatives with fully determined absolute configurations. The reaction proceeds rapidly under mild and operationally straightforward conditions. The synthesized derivatives were evaluated for farnesoid X receptor (FXR) agonist activity and hepatoprotective effects, with the 2-benzoyl-substituted thioether exhibiting the strongest FXR activation (EC₅₀ = 2.2 μM). Subsequent oxidation afforded the corresponding epicaryolane sulfones, thereby enhancing hydrophilicity while retaining bioactivity. These sulfones could be further converted into epicaryolane sulfonyl fluoride covalent warheads and diversified through multiple functionalization reactions, demonstrating their potential as versatile pharmacologically active scaffolds. This study highlights a concise and efficient strategy for the synthesis and diversification of sulfur-containing epicaryolane derivatives with promising therapeutic potential.