Synthesis and in vitro exploration of the 8-carbo substituted 5-methoxyflavones as anti-breast and anti-lung cancer agents targeting protein kinases (VEGFR-2 & EGFR)

  • Bioorg Chem. 2024 Dec:153:107875. doi: 10.1016/j.bioorg.2024.107875.
Jackson K Nkoana  1 ,  Garland K More  2 ,  Malose J Mphahlele  3 ,  Ahmed A Elhenawy  4
Affiliations
  • 1. Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa.
  • 2. College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa.
  • 3. Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa. Electronic address: [email protected].
  • 4. Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, 11884 Cairo, Egypt; Chemistry Department, Faculty of Science, Al-Baha University, Al-Baha 1988, Saudi Arabia.
PMID: 39396454 DOI: 10.1016/j.bioorg.2024.107875
Abstract

The 8-aryl-, 8-styryl- and 8-arylethynyl substituted 5-methoxyflavones were synthesized and characterized using a combination of spectroscopic techniques. Single crystal X-ray diffraction (XRD) study on a representative compound 3h shows an inverted dimer linked by fused ten and six-membered ring motifs involving intermolecular CO⋯HC and CH⋯OC hydrogen bonds. Compounds 3b, 3c, 3d, 4a and 4b exhibited strong activity against the human breast (MCF-7) Cancer cell line (IC50 = 13.68 ± 0.72, 16.91 ± 0.40, 13.63 ± 0.36, 14.66 ± 0.47 and 12.26 ± 0.45 μM, respectively) and lung (A549) Cancer cell line (IC50 = 15.38 ± 0.33, 10.00 ± 0.28, 12.38 ± 0.30, 12.84 ± 0.33 and 8.47 ± 0.30 μM, respectively) compared to quercetin (IC50 = 40.61 ± 1.07 and 58.17 ± 0.50 μM, respectively). Compounds 3b, 3c and 4b exhibited dual inhibitory effect against the vascular endothelial growth factor receptor-2 (VEGFR-2) and the epidermal growth factor receptor (EGFR) tyrosine kinase phosphorylation. Molecular docking revealed that strong alignment with the enzyme backbone is achieved mostly by hydrophobic (π-π, and π-H) contacts and by hydrogen bonding interaction with the residues in the active sites of VEGFR-2 and EGFR. The test compounds possess favorable drug-likeness properties, supporting their potential as promising therapeutic candidates.

Keywords
8-Carbo substituted 5-methoxyflavones, synthesis; Computations; Crystal structure; Cytotoxicity; Tyrosine kinase (VEGFR-2 & EGFR).
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