XWL-5-11

DNA intercalators and topoisomerases are regarded as prominent targets for cancer treatment. Herein, a novel series of quinazoline hybrids 5-14 were designed and synthesized as potent DNA intercalators and topoisomerase II inhibitors for cancer treatment. Their antiproliferative activity was evaluated in vitro across the NCI-60 human tumor cell lines panel. Compounds 7 and 10 were the most potent and broad-spectrum compounds and were further tested at 5 dose concentrations which showed that compound 7 exhibited robust antiproliferative activity, with submicromolar GI₅₀ values against several cell lines. Moreover, DNA intercalation of the most prominent compounds 7 and 10 was assessed using the DNA/methyl green assay using doxorubicin as a positive control. It was revealed that compound 7 showed well-established DNA binding affinities with an IC₅₀ value of 17.19 μM in comparison to the reference drug doxorubicin (11.29 μM). Moreover, topoisomerase IIα inhibitory assay of compounds 7 and 10, was conducted using etoposide as a positive control. It was revealed that compound 7 could display an outstanding inhibitory potential against topoisomerase IIα with an IC₅₀ value of 40.51 μM, surpassing etoposide (IC₅₀ = 66.03 μM). Compounds 7 and 10 induced apoptosis in lung H460 cancer cells with an overall total apoptosis of 39.79 % and 47.17 %, respectively. Moreover, compound 7 significantly increased BAX expression levels to 5.48-fold and reduced Bcl-2 to 0.32-fold, resulting in a striking elevation of the BAX/Bcl-2 ratio to 17.12. Additionally, in silico molecular docking, pharmacokinetic properties, and toxicity features were conducted for all synthesized compounds. It was shown that feasible binding interactions at the target site and eligible pharmacokinetic/toxicity profiles were attained for the investigated compounds. Accordingly, the synthesized compounds can be regarded as promising lead compounds with future optimization for cancer treatment.