A series of α-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIα catalytic activity

He Huang, Qin Chen,Xin Ku, Linghua Meng, Liping Lin, Xiang Wang, Caihua Zhu, Yi Wang, Zhi Chen, Ming Li, Hualiang Jiang, Kaixian Chen, Jian Ding , Hong Liu

A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde
moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity
in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed
that TSC24 was not only an iron chelator but also a topoisomerase IIR catalytic inhibitor. Its inhibition
on topoisomerase IIR was due to direct interaction with the ATPase domain of topoisomerase IIR which
led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP
binding site, which was confirmed by the competitive inhibition assay. These results about the
mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design
of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development
of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity
of topoisomerase IIR.