Prenylated flavonoids with significant anti-hepatoma activity from Daphne giraldii and effects on Fibroblast Growth Factor Receptor 1 (FGFR1)

  • Eur J Med Chem. 2023 Feb 5:247:115006. doi: 10.1016/j.ejmech.2022.115006.
Ying Liu  1 ,  Pinyi Gao  2 ,  Xiao Liang  3 ,  Yangyang Zhang  1 ,  Xiaoqi Yu  1 ,  Xiaobian Xue  1 ,  Lara Kockaya  4 ,  Pankaj Pandey  5 ,  Robert J Doerksen  4 ,  Xiaojuan Wang  6 ,  Guodong Yao  1 ,  Wanchun Chu  1 ,  Xin Chen  1 ,  Shaojiang Song  1 ,  Mark T Hamann  7 ,  Lingzhi Li  8
Affiliations
  • 1. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 2. College of Pharmaceutical and Biotechnology Engineering, Shenyang University of Chemical Technology, Shenyang, 110142, PR China.
  • 3. College of Pharmacy, Liaoning University, 66 Chongshan Road, Shenyang, 110036, Liaoning, PR China.
  • 4. Division of Medicinal Chemistry, Department of BioMolecular Sciences, University of Mississippi, Mississippi, 38677, USA.
  • 5. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Mississippi, 38677, USA.
  • 6. School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, PR China.
  • 7. College of Pharmacy & Medicine, Medical University of South Carolina, Charleston, SC, 29425-5700, USA. Electronic address: [email protected].
  • 8. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China. Electronic address: [email protected].
PMID: 36549116 DOI: 10.1016/j.ejmech.2022.115006
Abstract

We report here the orchestration of molecular ion networking (MoIN) and a set of computational and informatics assisted structural elucidation approaches in the discovery of 23 new prenyl-flavonoids and 13 known molecules from Daphne giraldii Nitsche (Thymelaeaceae), some of which possess significant bioactivity against hepatoma carcinoma. Daphnegiratriprenylone A (DPTP-A) represents the class of polyprenyl-flavonoids possessing a triprenyl substitution, and was identified with the guidance of mass spectrometry and nuclear magnetic resonance combined with computational approaches. This approach illustrates a paradigm shift in the application of computational tools for the direct assignment of new natural product structures and it was demonstrated to be reliable compared to conventional 2D-NMR techniques. Seventeen compounds exhibited potent and selective activity against Hep3B cells (IC50 ranging from 0.42 to 7.08 μM). Tyrosine kinase FGFR1 has emerged as a potential target of polyprenyl-flavonoids by a reverse pharmacophore mapping approach. We validated that the prenyl-flavonoids effectively inhibit FGFR1 using the Mobility Shift Assay, Western blot and molecular dynamics simulations, and the results suggest significant potency of the compounds towards FGFR1. These findings provide a new chemical class with strong links to traditional medicines, possessing reasonable safety for developing potential therapeutic agents for FGFR1-related diseases.

Keywords
Daphne giraldii; FGFR1 inhibitory activity; Hep3B; MoIN; Prenyl-flavonoids.