Thiosemicarbazones from the Old to New: Iron Chelators That Are More Than Just Ribonucleotide Reductase Inhibitors

Iron chelators have potential therapeutic use for the treatment of cancer. Studies with a range of chelators indicate that Fe chelation alone is not enough to generate compounds with pronounced antitumor efficacy. Structure-activity relationships demonstrated that chelators containing hard electron donors such as oxygen typically lead to ligands that bind Fe with high affinity that do not have pronounced antitumor efficacy. Such compounds aremore suitable for the treatment of iron-overload disease, e.g., β-thalassemia major. In contrast, ligands with soft donors such as sulfur and nitrogen lead to compounds that can redox cycle and induce a "double punch", namely, marked chelation and redox activity. Such compounds include the thiosemicarbazone chelators such as 3-AP and the ApT, BpT, and DpT series. Detailed investigations of the thiosemicarbazone group of ligands have demonstrated that they are highly effective chelators that, besides RR, also target a range of other molecules including NDRG1 and top2α, all of which contribute to their anticancer effects.