Tigliane Diterpenoids as a New Type of Antiadipogenic Agents Inhibit GRα-Dexras1 Axis in Adipocytes.
J Med Chem
; 62(4): 2060-2075, 2019 02 28.
Article
in En
| MEDLINE
| ID: mdl-30707022
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phorbols
/
Receptors, Glucocorticoid
/
Ras Proteins
/
Anti-Obesity Agents
/
Adipogenesis
Limits:
Animals
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2019
Document type:
Article