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  1. Home
  3. Design, Synthesis, And Evaluation Of Antitumor Activity In Pseudolaric Acid B Azole Derivatives: Novel And Potent Angiogenesis Inhibitor Via Regulation Of The Pi3k/akt And Mapk Mediated Hif-1/vegf Signaling Pathway.
  1. Home
  3. Design, Synthesis, And Evaluation Of Antitumor Activity In Pseudolaric Acid B Azole Derivatives: Novel And Potent Angiogenesis Inhibitor Via Regulation Of The Pi3k/akt And Mapk Mediated Hif-1/vegf Signaling Pathway.

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Design, synthesis, and evaluation of antitumor activity in Pseudolaric acid B Azole derivatives: Novel and potent

Hao Deng1, Qian Xu1, Xiao-Ting Li1

  • 1Key Laboratory of Natural Medicines of the Changbai Mountain, Affifiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China.

European Journal of Medicinal Chemistry
|September 3, 2024

View abstract on PubMed

Summary
This summary is machine-generated.
Keywords:
AntitumorAzolesHIF-1αPseudolaric acid BVEGF

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A new compound, M2, derived from Pseudolaric acid B (PAB), effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α). This promising agent shows low toxicity and curbs tumor growth in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tumor growth and metastasis are dependent on angiogenesis, a process regulated by vascular endothelial growth factor (VEGF).
  • Pseudolaric acid B (PAB) is a known inhibitor of tumor cell proliferation, migration, and angiogenesis.
  • Enhancing PAB's efficacy against angiogenesis is crucial for developing novel cancer therapeutics.

Purpose of the Study:

  • To synthesize and evaluate novel PAB derivatives for their ability to inhibit VEGF secretion in SiHa cells under hypoxic conditions.
  • To identify potent PAB derivatives with enhanced anti-angiogenic and anti-tumor properties.
  • To elucidate the mechanism of action of the most effective derivative.

Main Methods:

  • Synthesis of 37 PAB derivatives and assessment of their VEGF inhibitory activity in SiHa cells.
  • Evaluation of compound M2's effects on human umbilical vein endothelial cell (HUVEC) migration and angiogenesis, and SiHa cell invasion.
  • Mechanistic studies involving hypoxia-inducible factor 1α (HIF-1α) accumulation, nuclear translocation, protein synthesis, and signaling pathway modulation (PI3K/AKT/mTOR, MAPK).
  • In vivo studies to assess compound M2's efficacy and toxicity in tumor models.

    • Main Results:

    • Most synthesized PAB derivatives significantly inhibited VEGF secretion without cytotoxicity; compound M2 showed the highest potency (IC50 = 0.68 μM).
    • Compound M2 suppressed HUVEC migration, angiogenesis, and SiHa cell invasion, and reduced HIF-1α accumulation and nuclear translocation.
    • Compound M2 decreased HIF-1α levels by reducing its synthesis and modulated PI3K/AKT/mTOR and MAPK pathways.
    • In vivo studies confirmed compound M2's low toxicity and significant tumor growth inhibition, with reduced HIF-1α and VEGF expression in tumor tissues.

    Conclusions:

    • Compound M2 is a potent inhibitor of tumor angiogenesis, acting by downregulating HIF-1α and VEGF expression.
    • M2's mechanism involves reduced HIF-1α synthesis and modulation of key signaling pathways.
    • Compound M2 demonstrates significant anti-tumor efficacy with low toxicity, highlighting its potential as a therapeutic agent for targeting tumor angiogenesis.