title: Synthesis and Biological Evaluation of Novel Bouchardatine Derivatives as Potential Adipogenesis/Lipogenesis Inhibitors for Antiobesity Treatment.
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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Rao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Hong-Gen
authors.initials: HG
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University , Melbourne, Victoria 3083, Australia.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism*; D052999:Quinazolinones
chemical_list: D055372:AMP-Activated Protein Kinases; D019440:Anti-Obesity Agents; D002784:Cholesterol; D026121:Indole Alkaloids; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; D014280:Triglycerides; C028632:rutecarpine; D052999:Quinazolinones; C491654:Stk11 protein, mouse