Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity

• Design and synthesis of novel hydantoin and thiohydantoin derivatives.
• Screened them against human and Leishmania DNA topoisomerase 1.
• Compound 15 inhibits human Top1 through stabilization of Top1 cleavage complexes.
• It induces cytotoxicity in human breast and cervical cancer cells.
• Molecular modeling with HTop1 rationalized the inhibitory mechanism of compound 15.

DNA topoisomerase I is a potential chemotherapeutic target. Here, we designed and synthesized a library comprising of hydantoin and thiohydantoin derivatives and tested them against human and Leishmania Top1. One of the thiohydantoin compounds with substituted thiophenyl as the central moiety (compound 15) exhibited potent inhibition of human Top1 (HTop1) through stabilization of Top1-DNA cleavage complexes and showed selective anticancer activity against human cervical carcinoma (HeLa) and breast carcinoma (MCF-7) cell lines. Molecular modeling studies with HTop1 rationalized the inhibitory mechanism of compound 15.

Compound 15, a potential human Top1 (HTop1) inhibitor was discovered through random screening. It exhibited inhibition through stabilization of HTop1-DNA cleavage complexes and induces cytotoxicity in human cervical and breast cancer cells.Figure optionsDownload as PowerPoint slide