Thiosemicarbazone (TSC) derivatives have raised considerable interests in chemistry and biology due to their anticancer activities. However, the reported compounds were limited by their poor water solubility and toxicity profile. Therefore, there is increasing interest in structural modification of TSC derivatives with the aim of improving the pharmaceutical profile of existing candidates or discovering novel derivatives.

The teams led by Prof.LIU Hong and Prof. MENG Linghua  designed and synthesized a serial of novel thiosemicarbazone derivatives that bear condensed heterocyclic carboxaldehyde moieties. Five compounds were found which show promising anti-proliferative activity. Among them, compound TSC24 exhibited broad anti-proliferative activity in a panel of human tumor cells with IC50 values ranging from 0.002 to 0.83 μM. The interesting thing is that compound TSC24 was found to be more potent against multidrug resistant cells than against their corresponding parental cells. The anticancer activity of compound TSC24 was further solidified by its suppression of tumor growth in mice. The molecular and cellular mechanistic studies revealed that TSC24 exerts its anti-tumoractivities through inhibition of Topo IIα catalytic activity in addition to iron chelating. The results will provide insights into the discovery and development of new TSC derivatives and Topo II inhibitors.

This project was funded by the National Natural Science Foundation of China and the Science and Technology Commission of Shanghai Municipality. The results were published on Journal of Medicinal Chemistry (2010, 53: 3048-3064).

TSC24 binds to the ATPase domain of Topo IIR.(Image by  SIMM)

(Source: Professor LIU Hong's research group)