The Selenium Paradox: From Evolutionary Redox Chemistry to Medicinal Chemistry.

Selenium has played a fundamental role in the evolution of aerobic life, thanks to its unique redox properties and its incorporation into antioxidant selenoproteins such as glutathione peroxidases (GPx). This evolutionary perspective has inspired decades of research aimed at developing small organoselenium compounds as GPx-like antioxidant drugs. However, despite extensive in vitro evidence and numerous publications, no organoselenium antioxidant has been commercialized, and even Ebselen, the most extensively studied selenium-based drug candidate, has repeatedly failed in multiple clinical trials. In this opinion article, we posit the hypothesis that a conceptual bias may underlie a significant proportion of the research conducted to date in this field. The antioxidant activity of GPx is contingent on a highly regulated enzymatic environment that is extremely difficult to reproduce with small synthetic molecules. Consequently, many compounds described as GPx mimetics may behave less like true antioxidants and more like redox-active electrophiles capable of disrupting complex thiol-dependent equilibria. It is recommended that future research should adopt a more holistic approach to the study of selenium pharmacology, moving beyond a reductionist interpretation of GPx-like activity. Instead, the focus should be on the complex network of cellular redox processes and selective redox targeting. It is only through a more profound mechanistic comprehension of selenium chemistry within biological systems that it will be feasible to ascertain whether organoselenium compounds can genuinely establish a presence within the domain of medicinal chemistry, extending beyond their persistent yet predominantly laboratory-restricted achievements. In a similar vein, undertaking a thorough examination of the mechanisms may facilitate a more profound comprehension of the fate of organoselenium compounds in their intricate interaction with biological targets. This, in turn, may enable the conception of novel molecules that function as effective and selective pro-oxidants against specific targets.