Discovery of Bis-Thiourea Derivatives as Human DNA Topoisomerase IIα Inhibitors with Potent Anticancer Effects

Abstract

DNA topoisomerase IIα (Topo IIα) is essential for maintaining genomic stability during DNA replication and mitosis and is highly expressed in cancer cells, making it a promising target for anticancer therapy. In this study, bis-thiourea derivatives were investigated for their Topo IIα inhibitory activity and anticancer potential using in silico and in vitro studies. Molecular modeling demonstrated that compound 8 exhibited favorable binding affinity and stability within the ATPase domain of Topo IIα. Biochemical assays revealed that compound 8 inhibited Topo IIα activity and showed potent cytotoxicity against several cancer cell lines, particularly A549 cells. Mechanistic studies showed that compound 8 inhibited A549 cell migration and invasion by upregulating E-cadherin while downregulating the mesenchymal markers N-cadherin and vimentin, as well as the EMT-associated transcription factor Slug. Furthermore, compound 8 induced G1-phase arrest by downregulating cyclins D1 and E2 while upregulating p21. These results suggest that compound 8 represents a promising lead for Topo IIα-targeted cancer therapy.