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Accepted Pacifichem Abstract. 

In recent years, selenium has garnered significant interest in biomedical research, particularly through its integration into bioisosteres, and chemical sensors. Despite these promising developments, selenium remains significantly underutilized as a redox-responsive trigger for drug delivery and prodrug activation. In contrast, sulfur—selenium’s lighter chalcogen counterpart—has been extensively utilized in these contexts, primarily through disulfide-based motifs that exploit sulfur’s well-characterized redox properties and metabolic behavior. Notably, disulfides function exclusively through reductive activation, and no broadly established oxidative triggering mechanism exists using sulfur. While selenium and sulfur share similar oxidation states and fundamental reactivity, selenium exhibits distinct chemical behavior arising primarily from its larger atomic size and higher polarizability. These distinctions give rise to unique reactivity profiles that can be strategically leveraged in the design of next-generation prodrugs, enabling unprecedented levels of reactivity and selectivity not achievable with traditional approaches. Here, we report the development of selenium-based prodrugs that harness this unique reactivity to enable dual responsiveness to both reducing and oxidizing conditions. This work highlights how selenium’s divergent chemical behavior can unlock entirely new and more versatile avenues for controlled drug release and targeted delivery—offering a breakthrough strategy to overcome longstanding limitations of traditional sulfur-based systems. 

Hydrogen sulfide (H2S), once regarded solely as a highly toxic gas, is now recognized as a crucial signaling molecule in plants, bacteria, and mammals. In humans, H2S signaling plays a role in numerous physiological and pathological processes, including vasodilation, neuromodulation, and cytoprotection. To exploit its biological functions and therapeutic potential, a wide range of H2S-releasing compounds, known as H2S donors, have been developed. These donors are designed to release H2S under physiological conditions in a controlled manner. Among them, self-reporting H2S donors are seen as a particularly innovative class, combining therapeutic delivery with real-time fluorescence-based detection. This dual functionality enables spatiotemporal monitoring of H2S release in biological environments, eliminating the need for additional sensors or probes that could disrupt cellular homeostasis. This review summarizes recent advancements in self-reporting H2S donor systems, organizing them based on their activation triggers, such as specific bioanalytes, enzymes, or external stimuli like light. The discussion covers their design strategies, performance in biological applications, and therapeutic potential. Key challenges are also highlighted, including the need for precise control of H2S release kinetics, accurate signal quantification, and improved biocompatibility. With continued refinement, self-reporting H2S donors offer great promise for creating multifunctional platforms that seamlessly integrate diagnostic imaging with therapeutic H2S delivery. 

Hydrogen selenide (H2Se) is an emerging biomolecule of interest with similar properties to that of other gaseous signaling molecules (i.e., gasotransmitters that include nitric oxide, carbon monoxide, and hydrogen sulfide). H2Se is enzymatically generated in humans where it serves as a key metabolic intermediate in the production of selenoproteins and other selenium-containing biomolecules. However, beyond its participation in biosynthetic pathways, its involvement in cellular signaling or other biological mechanisms remains unclear. To uncover its true biological significance, H2Se-specific chemical tools capable of functioning under physiological conditions are required but lacking in comparison to those that exist for other gasotransmitters. Recently, researchers have begun to fill this unmet need by developing new H2Se-releasing compounds, along with pioneering methods for selenide detection and quantification. In combination, the chemical tools highlighted in this review have the potential to spark groundbreaking explorations into the chemical biology of H2Se, which may lead to its branding as the fourth official gasotransmitter. 

Hydrogen sulfide (H2S) is an endogenous signaling molecule that greatly influences several important (patho)physiological processes related to cardiovascular health and disease, including vasodilation, angiogenesis, inflammation, and cellular redox homeostasis. Consequently, H2S supplementation is an emerging area of interest, especially for the treatment of cardiovascular-related diseases. To fully unlock the medicinal properties of hydrogen sulfide, however, the development and refinement of H2S releasing compounds (or donors) are required to augment its bioavailability and to better mimic its natural enzymatic production. Categorizing donors by the biological stimulus that triggers their H2S release, this review highlights the fundamental chemistry and releasing mechanisms of a range of H2S donors that have exhibited promising protective effects in models of myocardial ischemia-reperfusion (MI/R) injury and cancer chemotherapy-induced cardiotoxicity, specifically. Thus, in addition to serving as important investigative tools that further advance our knowledge and understanding of H2S chemical biology, the compounds highlighted in this review have the potential to serve as vital therapeutic agents for the treatment (or prevention) of various cardiomyopathies. 

Similar to hydrogen sulfide (H 2 S), its chalcogen congener, Hydrogen selenide (H 2 Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H 2 S, detailed investigations into the chemical biology of H 2 Se are limited and little is known about its innate physiological functions, cellular targets, and therapeutic potential. The obscurity surrounding these fundamental questions is largely due to a lack of small molecule donors that can effectively increase the bioavailability of H 2 Se through their continuous liberation of the transient biomolecule under physiologically relevant conditions. Driven by this unmet demand for H 2 Se-releasing moieties, we report that γ-keto selenides provide a useful platform for H 2 Se donation via an α-deprotonation/β-elimination pathway that is highly dependent on both pH and alpha proton acidity. These attributes afforded a small library of donors with highly variable rates of release (higher alpha proton acidity = faster selenide liberation), which is accelerated under neutral to slightly basic conditions—a feature that is unique and complimentary to previously reported H 2 Se donors. We also demonstrate the impressive anticancer activity of γ-keto selenides in both HeLa and HCT116 cells in culture, which is likely to stimulate additional interest and research into the biological activity and anticancer effects of H 2 Se. Collectively, these results indicate that γ-keto selenides provide a highly versatile and effective framework for H 2 Se donation.