SMART-guided discovery of anti-adipogenic guaiane sesquiterpenoids from the roots of Edgeworthia gardneri.

Employing a dual strategy combining Small Molecule Accurate Recognition Technology and bioactivity-guided approaches, the roots of Edgeworthia gardneri were investigated for the first time, leading to the isolation of seventeen previously unreported guaiane-type sesquiterpenoids, edgewolides A-Q (1-17), together with one known analogue (18). Notably, compounds 2 and 3 incorporate an unusual endoperoxide bridge, forging a 7,8-dioxabicyclo[4.2.1]nonane and a 6,7-dioxabicyclo[3.2.2]nonane scaffold, respectively. Their structures were elucidated through comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and quantum chemical calculations. Anti-adipogenic screening revealed that eight members attenuated lipid accumulation in differentiated 3T3-L1 adipocytes, with 2 exhibiting the highest potency. Structure-activity relationships pinpoint an α-substituted acrolein moiety appears to be critical for activity. Preliminary mechanistic studies indicated that 2 promotes lipolysis via HSL activation and boosts thermogenesis by up-regulating UCP1 and PGC-1α.