Bioactivity-guided isolation of anti-adipogenic diarylpentanoids from Rhamnoneuron balansae

A bioactivity-guided phytochemical investigation of Rhamnoneuron balansae led to the isolation of eight undescribed diarylpentanoids, named rhamnbalaoxy A-H (1-5, 13-15), along with seven known compounds (6-12). A key structural feature of these isolates is their shared diphenylpentane (C6-C5-C6) skeleton, and the diversity stems primarily from variations in the oxygenation and cyclization patterns of the central C5 unit. Notably, compounds 1 and 2 represent rare diarylpentanoid derivatives that incorporate a 2-phenylethylchromane moiety. Their structures were elucidated through comprehensive spectroscopic analysis, including HRESIMS and 1D/2D NMR, with their absolute configurations confirmed by experimental and calculated electronic circular dichroism (ECD) data. Bioactivity evaluation revealed that all compounds except 6 and 7 inhibited lipid accumulation in 3T3-L1 preadipocytes, demonstrating anti-adipogenic effects. Compound 15 demonstrated the highest potency, with an EC₅₀ value of 2.17 μM, about 3.3-fold lower than that of the positive control berberine (EC₅₀ = 7.24 μM). Mechanistic studies show that compound 15 inhibits adipogenesis by downregulating PPARγ, activates lipolysis by upregulating HSL and ATGL, and induces thermogenesis and metabolic reprogramming via FGF21 and UCP1.