Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3-L1 Cells
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AMP-Activated Protein Kinases / metabolism
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Adipogenesis / drug effects*
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Animals
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Anti-Obesity Agents / chemical synthesis
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Anti-Obesity Agents / chemistry*
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / pharmacology*
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Cell Cycle Checkpoints / drug effects
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Cholesterol / metabolism
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Hep G2 Cells
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Humans
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Indole Alkaloids / chemical synthesis
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Indole Alkaloids / chemistry*
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Indole Alkaloids / pharmacokinetics
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Indole Alkaloids / pharmacology*
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Lipogenesis / drug effects*
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Mice
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Protein Serine-Threonine Kinases / metabolism
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Quinazolines / chemical synthesis
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Quinazolines / chemistry*
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Quinazolines / pharmacokinetics
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Quinazolines / pharmacology*
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Signal Transduction / drug effects
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Triglycerides / metabolism*
Substances
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Anti-Obesity Agents
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Indole Alkaloids
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Quinazolines
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Triglycerides
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rutecarpine
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Cholesterol
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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AMP-Activated Protein Kinases