Structure-guided design and synthesis of isoflavone analogs of GW4064 with potent lipid accumulation inhibitory activities

Rongmao Qiu; Guoshun Luo; Xuerong Cai; Linyi Liu; Mingqi Chen; Deying Chen; Qidong You; Hua Xiang

doi:10.1016/j.bmcl.2018.10.021

Structure-guided design and synthesis of isoflavone analogs of GW4064 with potent lipid accumulation inhibitory activities

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3726-3730. doi: 10.1016/j.bmcl.2018.10.021. Epub 2018 Oct 15.

Authors

Rongmao Qiu¹, Guoshun Luo¹, Xuerong Cai¹, Linyi Liu¹, Mingqi Chen², Deying Chen³, Qidong You¹, Hua Xiang⁴

Affiliations

¹ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
² Laboratory of Biology, School of Higher Vocational Education, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
³ Department of Analytical Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
⁴ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xianghua@cpu.edu.cn.

PMID: 30342957
DOI: 10.1016/j.bmcl.2018.10.021

Abstract

Our group has previously reported a series of isoflavone derivatives with antidyslipidemic activity. With this background, a series of isoflavone analogs of GW4064 were designed, synthesized and evaluated the lipid-lowering activity of analogs. As a result, most of compounds significantly reduced the lipid accumulation in 3T3-L1 adipocytes and four of them (10a, 11, 15c and 15d) showed stronger inhibitory than GW4064. The most potent compound 15d exhibited promising agonistic activity for FXR in a cell-based luciferase reporter assay. Meanwhile, 15d up-regulated FXR, SHP and BSEP gene expression and down-regulated the mRNA expression of lipogenesis gene SREBP-1c. Besides, an improved safety profile of 15d was also observed in a HepG2 cytotoxicity assay compared with GW4064. The obtained biological results were further confirmed by a molecular docking study showing that 15d fitted well in the binding pocket of FXR and interacted with some key residues simultaneously.

Keywords: Dyslipidemia; FXR agonist; GW4064; Isoflavone; Lipid accumulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / drug effects*
Adipocytes / metabolism
Animals
Drug Design
Hep G2 Cells
Humans
Isoflavones / chemical synthesis
Isoflavones / chemistry*
Isoflavones / pharmacology*
Isoxazoles / chemical synthesis
Isoxazoles / chemistry*
Isoxazoles / pharmacology*
Lipid Metabolism / drug effects*
Mice
Molecular Docking Simulation
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism
Up-Regulation / drug effects

Substances

Isoflavones
Isoxazoles
Receptors, Cytoplasmic and Nuclear
farnesoid X-activated receptor
GW 4064