Tigliane Diterpenoids as a New Type of Antiadipogenic 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 antiadipogenic 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 μM, respectively) and reduced cytotoxicity (selectivity
index for 1 and 1a: 28 and 312, respectively).
The structure–activity relationship study revealed that the trans-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-Dexras1
axis in adipocyte, leading to the retardation of cell differentiation
at the early stage. These findings may provide a new type of lipid-lowering
agents for future antiobesity drug development.