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Cardiovascular & Hematological Agents in Medicinal Chemistry

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ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

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Research Article

Anti-angiogenic Potential of Trans-chalcone in an In Vivo Chick Chorioallantoic Membrane Model: An ATP Antagonist to VEGFR with Predicted Blood-brain Barrier Permeability

Author(s): Anna Senrung, Tanya Tripathi, Nikita Aggarwal, Divya Janjua, Arun Chhokar, Joni Yadav, Apoorva Chaudhary, Kulbhushan Thakur, Tejveer Singh and Alok Chandra Bharti*

Volume 22, Issue 2, 2024

Published on: 03 November, 2023

Page: [187 - 211] Pages: 25

DOI: 10.2174/0118715257250417231019102501

Price: $65

Abstract

Background: Glioblastoma multiforme (GBM) is characterized by massive tumorinduced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumordriven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored.

Methods: We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using in silico tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane.

Results: Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of > 0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity < -6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski’s rule of five. Our in silico analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression.

Conclusion: The present study showed TC to possess anti-angiogenic potential via the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.

Keywords: Glioblastoma multiforme, tumor-induced-angiogenesis, VEGF, blood-brain barrier, anti-angiogenesis, brain parenchyma.

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