Insight into Mechanism of Action of Anticancer Benzazoles

Abstract

Background: Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription, and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome. This ultimately leads to the accumulation of DNA strand breaks and cell death.

Methods: Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell-free system. Their interactions with the enzyme were studied by carrying out molecular docking studies using and comparing two different docking programs.

Results: The results of the docking studies clarified binding modes of these compounds to the topoisomerase II enzyme.

Conclusion: This study also provides guidelines to design novel and more potent antitumor agents functioning as human topoisomerase II enzyme inhibitors.

Keywords: Anticancer; Benzazole; Enzyme inhibitors; Homology modeling; Molecular docking; Topoisomerase II.