Evolution of Thiosemicarbazones: From First‐ to Second‐Generation Metal Chelators and Their Reactive Oxygen Species‐Mediated Effects in Melanoma

Worldwide, melanoma remains a significant public health concern, with an estimated 325,000 new cases and 57,000 deaths recorded in 2020. If current trends persist, these figures are projected to rise to 510,000 new cases and 96,000 deaths annually by 2040, a 50% and 68% increase, respectively. Despite advances in targeted therapies and immunotherapy, there remains an urgent need for novel, selective treatments-particularly potential low cost oral treatments in low and middle income countries. Thiosemicarbazone (TSC) derivatives, particularly those incorporating ONS (ONS, first generation) and NNS (NNS, second generation) donor motifs, have emerged as promising candidates for melanoma therapy. This review traces the evolution of TSCs from early-stage compounds to more advanced analogs, emphasizing how structural refinements have enhanced their anticancer potency and selectivity. Classical thiosemicarbazones such as Triapine and Dp44mT display multifaceted mechanisms of action, including potent metal ion chelation, inhibition of ribonucleotide reductase (RR), and the induction of oxidative stress through reactive oxygen species (ROS) generation. The redox activity of their metal complexes facilitates ROS accumulation, which contributes to apoptosis in melanoma cells, that often exhibit elevated basal oxidative stress. Preclinical studies demonstrate strong cytotoxicity and some tumor selectivity for these agents, though clinical translation remains limited. The ongoing development of thiosemicarbazone-based therapeutics continues to offer promise for more effective and selective melanoma treatment strategies.