Design, synthesis, and cytotoxic screening of novel azole derivatives on hepatocellular carcinoma (HepG2 Cells)

  • Bioorg Chem. 2020 Aug;101:103995. doi: 10.1016/j.bioorg.2020.103995.
Mohammed K Abdelhameid  1 ,  Islam Zaki  2 ,  Manal R Mohammed  3 ,  Khaled O Mohamed  4
Affiliations
  • 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: [email protected].
  • 2. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
  • 3. Department of Radiation Biology, National Center for Radiation Research and Technology, Cairo, Egypt.
  • 4. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
PMID: 32569897 DOI: 10.1016/j.bioorg.2020.103995
Abstract

Novel azole derivatives 3-30 were designed, synthesized, and screened for their antitumor activity on HepG2 cell line. The cytotoxicity screening demonstrated that imidazolone 8 and triazoles 25 and 29 exhibited more potent cytotoxic activities by 1.21-, 4.75-, and 1.8-fold compared to Sorafenib (SOR). Furthermore, vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme inhibition assay declared that compounds 25 and 29 had inhibitory activity at the nanomolar concentration. Moreover, the tested compounds exhibited good β-tubulin (TUB) polymerization inhibition percentages. In addition, DNA flow cytometry analysis over HepG2 cells indicated that triazoles 25 and 29 demonstrated arrest at G1 and G2/M phase of the cell cycle and induced apoptotic activity by increasing sub-G1 phase. Finally, mechanistic studies of the proapoptotic activities of compounds 8, 10, 11, 25, and 29 indicated that they induced upregulation of P53, Fas/Fas-ligand, and Bax/Bcl-2 ratio expression that resulted in increasing the active Caspase 3/7 percentages and trigger Apoptosis.

Keywords
Anti-cancer; Apoptosis; Imidazolones; Oxazolones; Protein kinase; Triazoles; Tubulin.
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