Investigating the Anticancer Activity of Novel 1,2,4-Oxadiazole-Linked 1,2,3-Triazole Moieties via EGFR/pI3K/mTOR Cascade Down-Regulation

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Malignant transformation, apoptosis prevention, drug resistance, and metastasis are all impacted by the EGFR/PI3K/Akt/mTOR pathway. Usually, mutations in lung and colon cancer alter the expression of this pathway. This led to the creation of a new hybrid of 3,5-diaryl-1,2,4-oxadiazole/1,2,3-triazoles. These hybrids were rationalized and synthesized using click reaction via the Copper catalyzed azide-alkyes cyclo-addition (CuAAC). The antiproliferative properties of the novel library were investigated against lung (A549), colon (Caco-2) cancer cell lines and human lung fibroblast (WI38). 5b, 5c, 8a, 8b, and 9c showed potent antiproliferative effects (IC50 9.18–12.8 µM) against lung (A549). While 8a and 9a showed substantial cytotoxic effects against the colon (Caco-2) cancer cell line, with IC50 of 13.0 and 12.0 µM, respectively. It is evident that, in comparison to normal cells, the selective cytotoxic of compound 5c (SI 9.4), 8a (SI 5.1), and 9c (SI 3.7) demonstrated a small selectivity for Caco-2 cells and a significantly higher selectivity for A549 lung cancer cells. Using a CqPCR assay, the powerful cytotoxic compounds 5c, 8a, and 9c were selected to investigate the mechanism of action of their anticancer activities. It is noteworthy that compounds 5c, 8a, and 9c were able to inhibit PI3K gene expression by 4.76–8.33 folds, downregulate mTOR by 4.26–4.81 folds, and downstream gene EGFR by 4.55–5.88 times. Additionally, they raised the amount of the p53 gene (a tumor suppressor gene), which bolstered their mode of action. Interestingly, docking experiments of 5c, 8a, and 9c demonstrated enhanced binding with the important amino acid residues in the EGFR active site (docking energy −7.13, −7.16, and −7.67 kcal/mol, respectively) in comparison to the reference drug gefitinib (−5.84 kcal/mol), which further corroborate their mode of action. The previously mentioned results indicated that the intriguing hits 5c, 8a, and 9c might be investigated as promising medications.

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