Synthesis, Molecular Dynamics Simulation, and In-vitro Antitumor Activity of Quinazoline-2,4,6-triamine Derivatives as Novel EGFR Tyrosine Kinase Inhibitors

Abstract

Background: Developing a potent and safe scaffold is challenging in anti-cancer drug discovery. Objectives: The study focused on developing novel series of compounds based on the inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) as one of the most promising compounds in cancer therapy. Methods: In this study, a novel series of quinazoline-2,4,6-triamine derivatives were designed and synthesized through intramolecular C-H activation reaction of para-nitro aniline, trichloroacetonitrile, and isocyanides employing a one-pot reaction. Results: The in-vitro antitumor activities of the compounds which showed acceptable inhibitory effects were investigated against breast (MCF-7), lung (A-549), and colon (HT-29) cancer cell lines by employing MTT assay. All compounds had the most negligible cytotoxicity toward normal fibroblast human cell lines. Based on structural and thermodynamics analysis results, it was found that Met 769 is a key residue in interaction with all inhibitors through the formation of hydrogen bonds with high occupancies with the amine group on the quinazoline ring of inhibitors. Also, there was a good consistency between calculated ΔG binding and experimental IC50 values of compounds 10d, 10e, and erlotinib. Conclusions: Compound 10e had an extensive range of antitumor activity on three diverse cell lines comparable with erlotinib and doxorubicin reference drugs. Also, compound 10d showed selective cytotoxicity against cancerous lung cells (A-549). On the other side, computational studies confirmed that Met 769 is a crucial residue in interaction with all inhibitors.

Antifungal and Antiproliferative Activity of Pistagremic Acid and Flavonoids Extracted from the Galls of Pistacia chinensis subsp. integerrima

“…The 3D structures of the considered targets were obtained from the Protein Data Bank (PDB, http://www.rcsb.org/, access 11 September 2023). The models of Uox from A. flavus (PDB ID: 1R51) and EGFRk (PDB ID: 1 M17) were used in the simulations, in agreement with previous studies [25,41] …”

“…The models of Uox from A. flavus (PDB ID: 1R51) and EGFRk (PDB ID: 1 M17) were used in the simulations, in agreement with previous studies. [25,41] The preparation step was done through the Protein Preparation Wizard tool. The assignment of disulfide bonds, adding missing side chains using Prime, removing waters, adjusting charges, and minimizing the convergence of heavy atoms to RMSD under the OPLS4 force field was done.…”