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Abstract
The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode. Among them 3b and 3d are more active than the parent compound OA. A molecular simulation study was performed to attempt to explain the structure-activity relationship (SAR) and the antagonistic action. To the best of our knowledge, this is the first report on semi-synthetic pentacyclic triterpenoids with FXR-modulatory activities.
Highlights
Farnesoid X receptor (FXR), initially discovered as a bile acid homeostasis regulating transcriptional factor [1,2], is well known for its involvement in diverse metabolic processes, including the control of cholesterol, lipid and glucose metabolism [3]
Some of them are very potent FXR-interacting agents with sub-μM or even nM level IC50 values, such as 6-ECDCA/INT-747, the first FXR agonist approved by the U.S FDA in 2016 for the treatment of primary biliary cholangitis, GW4064, feraxamine, Molecules 2017, 22, 690; doi:10.3390/molecules22050690
oleanolic acid acid (OA) functioned as a gene selective modulator of FXR in HepG2 including several nuclear receptors, and the effects on suppressed in the presence (SHP) or CYP7A1 cannot unambiguously be cells
Summary
Shao-Rong Wang 1,2,† , Tingting Xu 3,4,† , Kai Deng 1 , Chi-Wai Wong 5 , Jinsong Liu 4 and. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia. State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese.
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