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A Phenotype-Driven Discovery of Pro-Revascularization Chalcone Derivatives Using Zebrafish and CAM Models.

Yau-Hung Chen1, Biswajit Mohanty2, Tao-Sheng Li3

  • 1Department of Chemistry, Tamkang University, New Taipei City, Taiwan, tku.edu.tw.

Journal of Toxicology
|July 14, 2026
PubMed
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Novel chalcone derivative 1c significantly enhances blood vessel formation, offering a promising proangiogenic agent for treating vascular diseases. Computational analysis supports its superior activity and potential as a therapeutic lead.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • Angiogenesis is vital for tissue repair and treating ischemic diseases, but effective small-molecule proangiogenic agents are scarce.
  • Chalcone derivatives are recognized for their diverse biological activities, making them candidates for therapeutic development.

Purpose of the Study:

  • To synthesize and evaluate the proangiogenic potential of novel chalcone derivatives.
  • To elucidate the structure-activity relationship (SAR) of these compounds using computational chemistry.

Main Methods:

  • Synthesis and in vivo testing of six chalcone derivatives (1a-1f) in zebrafish models (Tg(fli1:egfp)).
  • Assessment of vascular network formation using the chick embryo chorioallantoic membrane (CAM) assay.
Keywords:
SARchalconechickpro-angiogenicreal-time PCRzebrafish

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  • Computational chemistry analyses including Density Functional Theory (DFT), Molecular Electrostatic Potential (MESP), and Frontier Molecular Orbital (FMO) theory.
  • Main Results:

    • Compound 1c demonstrated the highest proangiogenic activity, significantly increasing vessel branching and outgrowth in zebrafish.
    • Compound 1c promoted caudal vein plexus remodeling and increased intercapillary spaces in transgenic zebrafish.
    • Gene expression analysis revealed 1c upregulates cadherin 5 and neuropilin 1a while downregulating fms-related receptor tyrosine kinase 1.
    • Computational analyses correlated compound 1c's high electrophilicity and electron transfer capability with its potent biological activity.

    Conclusions:

    • Chalcone derivative 1c exhibits potent proangiogenic activity, validated through in vivo and in vitro assays.
    • The study provides a strong correlation between computational chemical properties and biological efficacy.
    • Compound 1c represents a promising lead for developing novel small-molecule therapeutics for vascular dysfunction diseases.