Bavachinin analogues as agonists of pan-peroxisome proliferator-activated receptors

  • Jingyu Yi
  • Guoxin Du
  • Yuanyuan Zhao
  • Liuqiang Zhang
  • Bo Li
  • Weiliang Zhu
  • Cheng Huang
  • Yiming Li
  • Fujiang Guo
Original Research
  • 17 Downloads

Abstract

Peroxisome proliferator-activated receptors (PPARs) agonists contribute to the regulation of glucose, lipid, and cholesterol metabolism and have emerged as key targets to treat metabolic syndrome. In our previous study, the natural compound bavachinin was found to have pan-PPAR agonist activity. In this study, five isoflavones, three isoflavanones, and five scaffold-hopping analogues of bavachinin were designed, synthesised, and evaluated through reporter gene assays for pan-PPAR agonist activity. The analogue 2-(4-hydroxyphenyl)-6-isopentenyl-7-methoxy-2,3-dihydroquinolin-4(1H)-one (21) was identified as a pan-PPAR agonist, exhibiting substantially higher PPAR α/β agonist activity and equal PPAR-γ agonist activity than does bavachinin.

Keywords

Bavachinin Metabolic syndrome PPARs Reporter gene assays 

Notes

Acknowledgements

This work was supported by the Excellent Academic Leaders Program of Shanghai (16XD1403500), the Shanghai Science and Technology Committee funding (16401902000) and the program of Shanghai E-Research Institute of Bioactive Constituents in Traditional Chinese Medicine.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2197_MOESM1_ESM.pdf (879 kb)
Supporting Information

References

  1. Beltrán-Sánchez H, Harhay MO, Harhay MM, Mcelligott S (2013) Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999–2010. J Am Coll Cardiol 62:697–703CrossRefPubMedPubMedCentralGoogle Scholar
  2. Biegasiewicz KF, Gordon JS, Rodriguez DA, Priefer R (2014) Development of a general approach to the synthesis of a library of isoflavonoid derivatives. Tetrahedron Lett 55:5210–5212CrossRefGoogle Scholar
  3. Cairns WJ (2004) Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes. J Invest Dermatol 122:971–983CrossRefPubMedGoogle Scholar
  4. Del Bas JMD, Laos S, Caimari A, Crescenti A, Arola L (2012) Detection of bioavailable peroxisome proliferator-activated receptor gamma modulators by a cell-based luciferase reporter system. Anal Biochem 427:187–189CrossRefPubMedGoogle Scholar
  5. Du GX, Feng L, Yang Z, Shi J, Huang C, Guo F, Li B, Zhu W, Li Y (2015) Separation and peroxisome proliferator-activated receptor-γ agonist activity evaluation of synthetic racemic bavachinin enantiomers. Bioorg Med Chem Lett 25:2579–2583CrossRefPubMedGoogle Scholar
  6. Du GX, Zhao YY, Feng L, Yang Z, Shi J, Huang C, Li B, Guo F, Zhu W, Li Y (2017) Design, synthesis, and structure–activity relationships of bavachinin analogues as peroxisome proliferator-activated receptor γ agonists. ChemMedChem 12:183–193CrossRefPubMedGoogle Scholar
  7. Farmer JL, Hunter HN, Organ MG (2012) Regioselective cross-coupling of allylboronic acid pinacol ester derivatives with aryl halides via Pd-PEPPSI-IPent. J Am Chem Soc 134:17470–174703CrossRefPubMedGoogle Scholar
  8. Feng L, Luo H, Xu ZJ, Yang Z, Du G, Zhang Y, Yu L, Hu K, Zhu W, Tong Q, Chen K, Guo F, Huang C, Li Y (2016) Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice. Diabetologia 59:1276–1286CrossRefPubMedGoogle Scholar
  9. Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodríguez De Fonseca F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425:90–93CrossRefPubMedGoogle Scholar
  10. Gim HJ, Li H, Jung SR, Park YJ, Ryu JH, Chung KH, Jeon R (2014) Design and synthesis of azaisoflavone analogs as phytoestrogen mimetics. Eur J Med Chem 85:107–118CrossRefPubMedGoogle Scholar
  11. Gisch N, Balzarini J, Meier C (2007) Enzymatically activated cycloSal-d4T-monophosphates: the third generation of cycloSal-pronucleotides. J Med Chem 50:1658–1667CrossRefPubMedGoogle Scholar
  12. Grundy SM (2016) Metabolic syndrome update. Trends Cardiovasc Med 26:364–373CrossRefPubMedGoogle Scholar
  13. Jin Z, Lin H, Srinivasan S, Nwachukwu JC, Bruno N, Griffin PR, Nettles KW, Kamenecka TM (2017) Synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor. Bioorg Med Chem 27:347–353CrossRefGoogle Scholar
  14. Liu Z, Zhang H, Ye N, Zhang J, Wu Q, Sun P, Li L, Zhen X, Zhang A (2010) Synthesis of dihydrofuroaporphine derivatives: identification of a potent and selective serotonin 5-HT 1A receptor agonist. J Med Chem 53:1319–1328CrossRefPubMedGoogle Scholar
  15. Ma S, Huang Y, Zhao Y, Du G, Feng L, Huang C, Li Y, Guo F (2016) Prenylflavone derivatives from the seeds of Psoralea corylifolia exhibited PPAR-γ agonist activity. Phytochem Lett 16:213–218CrossRefGoogle Scholar
  16. Malan-Müller S, Kilian S, Van LL, Bardien S, Asmal L, Warnich L, Emsley RA, Hemmings SM, Seedat S (2016) A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia. Schizophr Res 170:1–17CrossRefPubMedGoogle Scholar
  17. Matin A, Doddareddy MR, Gavande N, Nammi S, Groundwater PW, Roubin RH, Hibbs DE (2013) The discovery of novel isoflavone pan peroxisome proliferator-activated receptor agonists. Bioorg Med Chem 21:766–778CrossRefPubMedGoogle Scholar
  18. Mutai P, Pavadai E, Wiid I, Ngwane A, Baker B, Chibale K (2015) Synthesis, antimycobacterial evaluation and pharmacophore modeling of analogues of the natural product formononetin. Bioorg Med Chem Lett 25:2510–2513CrossRefPubMedGoogle Scholar
  19. Pourcet B, Fruchart JC, Staels B, Glineur C (2006) Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type-2 diabetes and atherosclerosis. Expert Opin Emerg Drugs 11:379–401CrossRefPubMedGoogle Scholar
  20. Wang GL, Chen XL, Deng YY, Li Z, Xu X (2015) Synthesis and nematicidal activities of 1,2,3-Benzotriazin-4-one derivatives against Meloidogyne incognita. J Agric Food Chem 63:6883–6889CrossRefPubMedGoogle Scholar
  21. Wang XB, Xu DL (2017) A radical cascade enabling collective syntheses of natural products. Chem 2:803–816CrossRefGoogle Scholar
  22. Wehle S, Espargarό A, Sabaté R, Decker M (2016) Investigation into the stability and reactivity of the pentacyclic alkaloid dehydroevodiamine and the benz-analog there of. Tetrahedron 72:2535–2543CrossRefGoogle Scholar
  23. Weidner C, de Groot JC, Prasad A, Freiwald A, Quedenau C, Kliem M, Witzke A, Kodelja V, Han CT, Giegold S, Baumann M, Klebl B, Siems K, Müller-Kuhrt L, Schürmann A, Schüler R, Pfeiffer AF, Schroeder FC, Büssow K, Sauer S (2012) Amorfrutins are potent antidiabetic dietary natural products. Proc Natl Acad Sci 109:7257–7262CrossRefPubMedPubMedCentralGoogle Scholar
  24. Xie F, Du G, Ma S, Li Y, Wang R, Guo F (2016) Structural elucidation of in vitro metabolites of bavachinin in rat liver microsomes by LC-ESI-MSn and chemical synthesis. Xenobiotica 46:296–306CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jingyu Yi
    • 1
    • 2
  • Guoxin Du
    • 1
  • Yuanyuan Zhao
    • 1
  • Liuqiang Zhang
    • 1
  • Bo Li
    • 3
  • Weiliang Zhu
    • 3
  • Cheng Huang
    • 1
  • Yiming Li
    • 1
  • Fujiang Guo
    • 1
  1. 1.School of PharmacyShanghai University of Traditional Chinese MedicineShanghaiChina
  2. 2.Pharmacy DepartmentZhejiang HospitalHangzhouChina
  3. 3.Key Laboratory of Receptor Research & Drug Discovery and Design Center, Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina

Personalised recommendations