Strong Antiproliferative Activity Observed in Hammett-Guided Electronic Modulation of GPx-Mimetic Pathways in Aryl...

Organoselenium chemistry has undergone remarkable development over the past five decades, evolving from its initial association with high toxicity into a field with pivotal contributions to materials science, organic synthesis, catalysis, and Medicinal Chemistry. Among the diverse biological activities displayed by organoselenium compounds, their redox behaviour is particularly compelling, as many of these molecules act as efficient mimetics of the antioxidant enzyme glutathione peroxidase (GPx). In this work, we investigated the GPx-like activity of a series of N,N'-diaryl selenoureas toward the depletion of H₂O₂ and cumene hydroperoxide (CumOOH) as model ROS. Their reactivity was correlated with the electronic nature of the aryl substituents using a Hammett-type analysis, revealing a strong dependence of the reaction rate on remote electronic perturbations within the aromatic ring. Combined UV and NMR studies provided mechanistic evidence supporting a catalytic cycle in which selenoureas, operating at sub-stoichiometric loadings (1 mol%) and using a thiol as a cofactor-like molecule, can be used to efficiently scavenge ROS with half-lives of only a few minutes (~10-60 min). Furthermore, these selenoureas exhibited potent antiproliferative activity across several human solid tumour cell lines. Overall, these results offer mechanistic insight into the ROS-eliminating pathways of selenoureas and highlight their potential as chemopreventive or anticancer agents.