Hydrolysis-Based Small-Molecule Hydrogen Selenide (H₂Se) Donors for Intracellular H₂Se Delivery

Abstract

Hydrogen selenide (H 2 Se) is a central metabolite in the biological processing of selenium for incorporation into selenoproteins, which play crucial antioxidant roles in biological systems. Despite being integral to proper physiological function, this reactive selenium species (RSeS) has received limited attention. We recently reported an early example of a H 2 Se donor (TDN1042) that exhibited slow, sustained release through hydrolysis. Here we expand that technology based on the PSe motif to develop cyclic-PSe compounds with increased rates of hydrolysis and function through well-defined mechanisms as monitored by 31 P and 77 Se NMR spectroscopy. In addition, we report a colorimetric method based on the reaction of H 2 Se with NBD-Cl to generate NBD-SeH (λ max = 551 nm), which can be used to detect free H 2 Se. Furthermore, we use TOF-SIMS (time of flight secondary ion mass spectroscopy) to demonstrate that these H 2 Se donors are cell permeable and use this technique for spatial mapping of the intracellular Se content after H 2 Se delivery. Moreover, these H 2 Se donors reduce endogenous intracellular reactive oxygen species (ROS) levels. Taken together, this work expands the toolbox of H 2 Se donor technology and sets the stage for future work focused on the biological activity and beneficial applications of H 2 Se and related bioinorganic RSeS.

Targeted carbon monoxide delivery combined with chemodynamic, chemotherapeutic and photothermal therapies for enhanced antitumor efficacy

“…DCFH-DA itself is non-fluorescent but it reacts with ROS to produce the highly fluorescent 2′,7′-dichlorofluorescein (DCF). 41 When co-incubated with DCFH-DA and HDPMF, HeLa cells exhibited bright green fluorescence in the absence of light irradiation, and the fluorescence intensity was further strengthened when NIR light (808 nm, 1.0 W cm −2 ) was applied (Fig. 5A).…”

Cysteine-Activated Small-Molecule H2Se Donors Inspired by Synthetic H2S Donors

“…Nevertheless, the physiological characteristics of H 2 Se and the molecular mechanisms by which H 2 Se may be involved still remain largely unclear and/or unexplored. These different aspects of H 2 Se biology support the need for development of chemical tools that can recognize, visualize, or release H 2 Se in vitro and in related complex biological systems.…”

“…H 2 Se also binds exogenous heavy metals efficiently for detoxification in vivo . However, excessive H 2 Se may induce damage, cause adverse bioeffects, and even result in selenosis. , Se deficiency and high levels of H 2 Se donors have anti-cancer characteristics, ,11c whereas a certain concentration range of H 2 Se appears to exhibit pro-cancer effects. , The two faces of H 2 Se, essential and toxic, as well as its complex roles in human cancers, require the development of well-defined H 2 Se donors with controllable releasing properties …”

“…Organic Se compounds as potential H 2 Se donors are generally believed to be safer (lower toxicity) than inorganic Se salts. ,,, For example, organic diselenides and phthalic selenoanhydride have shown promising biological activities including radioprotection, free radical scavenging, and multidrug-resistance reversing activity, but their H 2 Se release was not observed directly in the experiments . Recently, Pluth and co-workers pioneered and developed well-characterized, hydrolysis-based donors TDN1042 and its derivatives with a PSe motif (Figure ), which can release H 2 Se directly and tunably with a well-defined mechanism . To further advance the development of H 2 Se donors, synthetic small molecules activated by endogenous species (e.g., biothiols or enzymes) under physiological conditions would provide the much-needed chemical tools for expanding the research related to H 2 Se chemical biology and even intelligent drug design.…”

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications

“…The further expansion of H 2 S therapy also depends on the development of H 2 S donors with improved biosafety and optimized activating mechanisms. In addition, since other RSSs (such as persulfide and H 2 S n [ 187 ]) and their selenium analogue such as H 2 Se [ 188 ] have also been proven to exert specific regulating effects in various physiological processes, precision medicine of these RSSs therapies is worthy of further exploration.…”