Novel quinazolin-4-one based derivatives bearing 1,2,3-triazole and glycoside moieties as potential cytotoxic agents through dual EGFR and VEGFR-2 inhibitory activity

Abstract

Abstract The toxicity that was caused by the developed medications for anticancer treatment is, unfortunately, an earnest problem stemming from the various involved targets, and accordingly, intense research for overcoming such a phenomenon remains indispensable. In the current inquiry, an innovative category of substituted quinazoline-based glycosides incorporating a core of 1,2,3-triazole and attached to distinct acetylated likewise deprotected sugar segments are created and produced synthetically. The resulted 1,2,3-triazolyl-glycosides products were investigated for their ability to cause cytotoxicity to several human cancer cell lines. The quinazoline based glycosyl-1,2,3-triazoles 10–13 with free hydroxy sugar moiety revealed excellent potency against (IC50 range = 5.70–8.10 µM, IC50 Doxorubicin = 5.6 ± 0.30 µM, IC50 Erlotinib = 4.3 ± 0.1 µM). against MCF-7 cancer cell line. In addition, the derived glycosides incorporating quinazolinone and triazole core 6–13 with acetylated and deprotected sugar parts showed excellent and superior potency against HCT-116 (IC50 range = 2.90–6.40 µM). The potent products were revealed as safe cytotoxic agents as indicated by their studied safety profiles. Additional research of promising candidates inhibitory analysis performed against EGFR and VEGFR-2. The hydroxylated glycosides incorporating triazole and quinazoline system 11 and 13 with N-methyl substitution of quinazolinone, gave excellent potency against EGFR (IC50 = 0.35 ± 0.11 and 0.31 ± 0.06 µM, correspondingly) since glycoside 13 revealed comparable IC50 (3.20 ± 0.15 µM) to sorafenib against VEGFR-2. For more understanding of its action mode, it was analyzed how the 1,2,3-triazolyl glycoside 13 made an effect on the apoptosis induction and the arrest of the cell cycle. It was revealed that it had the ability to stop HCT-116 cells in their cell cycle’s G1 stage. Moreover, the influence of quinazolinone-1,2,3-triazole-glycoside 13 upon p53, Bax, and Bcl-2 levels in HCT-116 units was also studied for future approaches toward its behavior. Additionally, the latter derivative may trigger apoptosis, as indicated by a significant increase in apoptotic cells. Furthermore, molecular docking was simulated to make an obvious validation and comprehension acquirement of the binding’s characteristics also attractions among the most forceful compounds side by side with their aimed enzymes.

Keywords

• Quinazolin-4-one
• 1,2,3-Triazole
• Glycosides
• Cytotoxicity
• EGFR
• VEGFR-2