Synthesis and Biological Evaluation of Novel Bouchardatine Derivatives as Potential Adipogenesis/Lipogenesis Inhibitors for Antiobesity Treatment
- J Med Chem. 2015 Dec 10;58(23):9395-413. doi: 10.1021/acs.jmedchem.5b01566.
- 1. School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
- 2. Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University , Melbourne, Victoria 3083, Australia.
Our recent study has shown that the natural product bouchardatine (1) can reduce the triglyceride (TG) content in 3T3-L1 adipocytes (EC50 ≈ 25 μM). Here, we synthesized two series of compounds by introducing amine side chains at the 5 or 8 position of 1 and evaluated the lipid-lowering activity of derivatives. It was found that some of the compounds had significant lipid-lowering effects, and the most active compound 3d showed better activity (EC50 = 0.017 μM) than 2 (EC50 = 0.086 μM), a compound reported by us. Further, the mechanism studies revealed that 3d blocked TG accumulation via activation of the LKB1-AMPK signaling pathway, efficiently down-regulating the expression of key regulators of adipogenesis/lipogenesis. Cell uptake assay and confocal imaging of 3d in cells indicated that compound 3d had favorable cell permeability. Our results suggest that 3d may be a promising agent for the treatment of Obesity and related metabolic disorders.