Identification of novel sulfathiazole-triazolo-chalcone hybrids as VEGFR-2/EGFR dual inhibitors with antiangiogenic activity and apoptotic induction.

ABSTRACT

Certain sulfathiazole-triazolo chalcone hybrids were identified as anticancer agents with dual vascular endothelial growth factor receptor-2 (VEGFR-2)/epidermal growth factor receptor (EGFR) kinase inhibitory effect. All of the compounds were evaluated for their cytotoxic activity against the MCF-7 and HepG-2 tumor cell lines. Compounds 11g, 11h, and 11j exhibited the most potent antiproliferative activity against both cancer cell lines, with good safety toward WI-38 normal cells. Thus, they were further assessed for VEGFR-2 inhibitory activity. They have suppressed VEGFR-2 enzyme at IC50 of 0.316, 0.076, and 0.189 µM, respectively in comparison to sorafenib (IC50 = 0.035 µM). EGFR enzyme inhibition was further screened for the most potent inhibitors, 11h and 11j, where they displayed enhanced potency with IC50 of 0.085 and 0.108 µM, respectively, compared to erlotinib (IC50 = 0.037 µM). Compounds 11h and 11j were additionally investigated for inhibition of comparable kinases, PDGFR-ß and B-Raf, where results assessed adequate selectivity of both compounds toward the VEGFR-2 and EGFR kinases. Furthermore, the wound healing assay of compound 11h manifested a percent wound closure of 65.18% in MCF-7 cells compared to doxorubicin (58.51%) and untreated cells (97.77%), proving its antiangiogenic activity. The cell cycle assay of MCF-7 cells treated with 11h demonstrated cell cycle arrest at the S phase. Moreover, compound 11h induced apoptosis with a 44-fold increase compared to that induced in the control MCF-7 cells. Molecular docking results of compounds 11h and 11j established their efficacies, and in silico studies showed convenient safety profiles with drug-likeness properties.