Tigliane Diterpenoids as A New Type of Anti-adipogenic Agents Inhibit GRα-Dexras1 Axis in Adipocytes.

The phytochemical study of Euphorbia prolifera led to the isolation of two tiglianes (1 and 2) and 23 mysrinanes (3-25). Most of these isolates showed significant anti-adipogenic activity in 3T3-L1 adipocyte without apparent cytotoxicity. Subsequent structural modification yielded 10 derivatives, among which 1a, the 5-O-acetyl derivative of 1, turned out to be the most active compound with improved triglyceride-lowering activity (EC50 for 1 and 1a: 0.61 and 0.32 uM, respectively) and reduced cytotoxicity (selectivity index for 1 and 1a: 28 and 312, respectively). The structure-activity relationship (SAR) study revealed that the tans-fused 5/7/6 ring system in an angular shape was important to the activity. A mechanistic study indicated that 1 and 1a could inhibit the glucocorticoid receptor α (GRα)-Dexras1 axis in adipocyte, leading to the retardance of cell differentiation at the early stage. These findings may provide a new type of lipid-lowering agents for future anti-obesity drug development.