Rationale design and synthesis of new quinazoline derivatives as DNA intercalators and topoisomerase II inhibitors

In pursuit of novel anticancer agents with enhanced potency and selectivity, a new series of quinazoline-based derivatives was rationally designed, synthesized, and biologically evaluated as potential DNA intercalators and topoisomerase II (Topo II) inhibitors. Building upon a previously identified lead compound (6), structural modifications were introduced to reinforce key pharmacophoric features essential for DNA intercalation and enzyme inhibition. Two distinct series of compounds were developed, incorporating either N-phenylacetamide (VII-series) or N-(4-cinnamoylphenyl)acetamide (VIII-series) side chains to target DNA grooves. In vitro cytotoxicity assays against HepG-2 and MCF-7 cancer cell lines revealed that several compounds, particularly VIIIe, exhibited potent anti-proliferative activity slightly less than that of the reference drug doxorubicin. It showed favorable selectivity indices over normal WI-38 fibroblasts. Further biological evaluation showed that compound VIIIe effectively inhibited Topo II (IC₅₀ = 11.71 nM) and demonstrated strong DNA-binding affinity (IC₅₀ = 14.50 μM), outperforming doxorubicin in both assays. Apoptosis-related protein analysis in MCF-7 cells revealed a significant increase in Bax expression and suppression of Bcl-2, indicating activation of mitochondrial-mediated apoptotic pathways. Molecular docking studies supported these findings, showing that VIIIe achieved a high binding affinity within the Topo II-DNA complex through multiple stabilizing interactions. Collectively, these results underscore the therapeutic potential of VIIIe and its analogs as promising lead candidates for the development of selective, DNA-targeted anticancer agents.