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  3. Exploring a novel thiazole derivatives hybrid with fluorinated-indenoquinoxaline as dual inhibitors targeting VEGFR2/AKT and apoptosis inducers against hepatocellular carcinoma with docking simulation

Exploring a novel thiazole derivatives hybrid with fluorinated-indenoquinoxaline as dual inhibitors targeting VEGFR2/AKT and apoptosis inducers against hepatocellular carcinoma with docking simulation

  • Bioorg Chem. 2025 Jan:154:108023. doi: 10.1016/j.bioorg.2024.108023.
Moustafa S Abusaif 1,  Ahmed Ragab 2,  Eman A Fayed 3,  Yousry A Ammar 4,  Ayah M H Gowifel 5,  Soha Osama Hassanin 6,  Ghada E Ahmed 7,  Nirvana A Gohar 8
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address: mostafahozaifa317@azhar.edu.eg.
  • 2 Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt; Chemistry Department, Faculty of Science, Galala University, Galala City, 43511, Suez, Egypt. Electronic address: Ahmed_ragab@azhar.edu.eg.
  • 3 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City 11754, Cairo, Egypt. Electronic address: alfayed_e@azhar.edu.eg.
  • 4 Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt.
  • 5 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
  • 6 Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11585, Egypt.
  • 7 Canal Higher Institute for Engineering and Technology- Suez, Egypt.
  • 8 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: nirvana.goher@pharm.mti.edu.eg.
PMID: 39644617 DOI: 10.1016/j.bioorg.2024.108023
Abstract

Hepatocellular carcinoma (HCC) ranks as the third most prevalent reason for cancer-related death on a global scale. Tyrosine kinase inhibitors (TKIs) continue to be the primary treatment option for advanced hepatocellular carcinoma. A series of fluoro-11H-indeno[1,2-b]quinoxaline derivatives as an HCC drug targeting the VEGFR2/KDR/Flk-1/Akt axis was designed and synthesized. The novel compounds were investigated against HepG-2 and HuH-7 liver tumor cell lines. Compound 5 was the most active derivative against HepG-2 and HuH-7 cell lines with IC50 = 0.75 ± 0.04 and 3.43 ± 0.16 μM, respectively, in contrast to Sorafenib which shows IC50 values of 5.23 ± 0.31 and 4.58 ± 0.21 μM, respectively. IC50 values on normal liver cells (THLE-2) show that all tests are more selective than Sorafenib, prompting further research. The most promising cytotoxic compound has virtually equal VEGFR2/KDR/Flk-1 inhibition efficacy to Sorafenib. The total VEGFR2/KDR/Flk-1 and p-VEGFR2 inhibitory effects were subsequently evaluated, showing 38.32 % and 77.64 % attenuation, respectively. Compound 5 also reduced total and phosphorylated Akt concentrations in HepG-2 cells by 55.29 % and 78.01 %, respectively. Furthermore, Compound 5 upregulated Bax and Caspase-3 and downregulated Bcl-2 to promote Apoptosis. Hybrid 5 stops HepG-2's cell cycle at the S phase 48.02 % higher than untreated. Docking experiments assessed Akt and VEGFR2/KDR/Flk-1 binding patterns.

Keywords

Anticancer and apoptosis; Docking studies; Fluorinated-indeno[1,2-b]quinoxaline; HCC; Thiazole; VEGFR2 and AKT.

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