A novel series of quinazoline-1,2,3-triazole hybrid compounds ( 8–22 ) were synthesized and evaluated as multi-target directed ligands (MTDLs) against EGFR, VEGFR-2, and COX-2 enzymes for anticancer activity. The synthesized compounds demonstrated significant anticancer activity against four human cancer cell lines (HeLa, HepG2, HCT-116, and MCF-7), with compound 17 emerging as the most potent derivative. Compound 17 exhibited exceptional anticancer activity with IC₅₀ values of 4.93, 2.34, 6.07, and 3.35 μM against HeLa, HepG2, HCT-116, and MCF-7 cell lines, respectively, surpassing doxorubicin (DOX) against HepG2 cells (IC50 = 4.50 μΜ). Importantly, compound 17 demonstrated superior selectivity toward cancer cells over normal human lung fibroblasts (WI-38) with a selectivity index of 11.78, compared to DOX (SI = 1.61). Multi-target enzyme inhibition assays revealed that compound 17 exhibited potent EGFR inhibition (IC₅₀ = 0.0085 μM), comparable to erlotinib (IC₅₀ = 0.0078 μM), strong VEGFR-2 inhibition (IC₅₀ = 0.068 μM), approaching sorafenib's activity (IC₅₀ = 0.056 μM), and significant COX-2 inhibition (IC₅₀ = 0.158 μM), comparable to Celecoxib (IC₅₀ = 0.044 μM). Compound 13 also demonstrated multi-target activity with IC₅₀ values of 0.0323, 0.220, and 0.103 μM against EGFR, VEGFR-2, and COX-2, respectively. Mechanistic studies revealed that compound 17 induces G1-phase cell cycle arrest in MCF-7 cells. The compound triggered a 5.11-fold increase in the Bax/Bcl-2 ratio, 2.90-fold upregulation of caspase-8, and elevated caspase-9 protein levels from 139.48 to 392.53 ng/mL, confirming the intrinsic apoptotic pathway activation. Molecular docking and dynamics simulations provided structural insights into the multi-target binding modes. These findings establish quinazoline-1,2,3-triazole hybrids as promising multi-target anticancer agents, with compound 17 demonstrating exceptional therapeutic potential through the simultaneous inhibition of tumor proliferation, angiogenesis, and inflammation pathways while maintaining favorable selectivity profiles.
Exploiting COX-2 engagement for amplifying anticancer potential of Quinazoline-triazole conjugates with superior EGFR/VEGFR-2 inhibition
Brogi S.;
2025-01-01
Abstract
A novel series of quinazoline-1,2,3-triazole hybrid compounds ( 8–22 ) were synthesized and evaluated as multi-target directed ligands (MTDLs) against EGFR, VEGFR-2, and COX-2 enzymes for anticancer activity. The synthesized compounds demonstrated significant anticancer activity against four human cancer cell lines (HeLa, HepG2, HCT-116, and MCF-7), with compound 17 emerging as the most potent derivative. Compound 17 exhibited exceptional anticancer activity with IC₅₀ values of 4.93, 2.34, 6.07, and 3.35 μM against HeLa, HepG2, HCT-116, and MCF-7 cell lines, respectively, surpassing doxorubicin (DOX) against HepG2 cells (IC50 = 4.50 μΜ). Importantly, compound 17 demonstrated superior selectivity toward cancer cells over normal human lung fibroblasts (WI-38) with a selectivity index of 11.78, compared to DOX (SI = 1.61). Multi-target enzyme inhibition assays revealed that compound 17 exhibited potent EGFR inhibition (IC₅₀ = 0.0085 μM), comparable to erlotinib (IC₅₀ = 0.0078 μM), strong VEGFR-2 inhibition (IC₅₀ = 0.068 μM), approaching sorafenib's activity (IC₅₀ = 0.056 μM), and significant COX-2 inhibition (IC₅₀ = 0.158 μM), comparable to Celecoxib (IC₅₀ = 0.044 μM). Compound 13 also demonstrated multi-target activity with IC₅₀ values of 0.0323, 0.220, and 0.103 μM against EGFR, VEGFR-2, and COX-2, respectively. Mechanistic studies revealed that compound 17 induces G1-phase cell cycle arrest in MCF-7 cells. The compound triggered a 5.11-fold increase in the Bax/Bcl-2 ratio, 2.90-fold upregulation of caspase-8, and elevated caspase-9 protein levels from 139.48 to 392.53 ng/mL, confirming the intrinsic apoptotic pathway activation. Molecular docking and dynamics simulations provided structural insights into the multi-target binding modes. These findings establish quinazoline-1,2,3-triazole hybrids as promising multi-target anticancer agents, with compound 17 demonstrating exceptional therapeutic potential through the simultaneous inhibition of tumor proliferation, angiogenesis, and inflammation pathways while maintaining favorable selectivity profiles.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
