Review3,3′-Diselenodipropionic acid (DSePA): A redox active multifunctional molecule of biological relevance
Graphical abstract
Introduction
Selenium, which was long considered as a poison for animals until 1957, has now been recognized as an essential micro-nutrient after the pioneering research work by Schwarz and Foltz [[1], [2], [3]]. Fifteen years later, selenocysteine (SeCys), a selenium analog of cysteine was discovered as 21st amino acid required for the synthesis of functionally important selenoproteins. Subsequently, epidemiological studies in different countries suggested that selenium, as a micro-nutrient (non-toxic level), might play a vital role in preventing chronic diseases including cancer in humans by maintaining immune and antioxidant functions [[4], [5], [6], [7], [8], [9]].
In natural sources, selenium exists both in inorganic forms like selenite and selenate and organic forms like selenomethionine (SeM) and methylselenocystine (MSeCys) (Scheme 1) [1]. MSeCys is found in selenised yeast, allium species (e.g. onion, garlic, etc.), broccoli, sprouts, etc. whereas SeM is found in Brazilian nuts, cereal grains, legumes, etc. The dietary selenium (inorganic and/or organic) obtained through food is channeled into synthesis of selenoprotein by its reduction into hydrogen selenide (H2Se) and subsequent incorporation into tRNASeCys [[4], [5], [6], [7]]. Nearly 25 selenoproteins have been identified in humans [[10], [11], [12]]. Most of these selenoproteins have redox regulatory functions, due to the nucleophillic selenolate group present in their active sites [3]. Some of the important selenoproteins are glutathione peroxidase (GPx), thioredoxin reductase (TrxR), iodothyroninedeiodinase (DIO) and selenoprotein P (SelP) [[10], [11], [12]]. Of these, GPx and TrxR maintain redox homeostasis, DIO regulates thyroid hormone functioning and SelP is involved in transport and storage of selenium within the body. Notably, GPx catalyses reduction of hydroperoxides and hydrogen peroxide to less reactive alcohol and water, respectively by using glutathione (GSH) as a cofactor, whereas TrxR maintains disulfide bonds in reduced state within cells [1,7]. Of the eight isoforms (GPx 1–8) of GPx present in human, only GPx1–4 and GPx6 are selenoproteins [12]. On the other hand, all the three isoforms (TrxR 1–3) of TrxR contain SeCys at their active sites [12].
While research on selenium biology is taking great strides [8], its importance in human health has attracted considerable attention. Indeed, laboratory studies in past two decades have provided encouraging results on the potential of synthetic selenium compounds of different chemical forms for the prevention and treatment of a number of diseases (Scheme 2) [1,[4], [5], [6], [7], [8],13,14]. In general, organoselenium compounds have appeared to be better than inorganic selenium compounds in these studies due to lesser toxicity and GPx mimicking activity. Accordingly, synthesis of organoselenium compounds, their evaluation as antioxidants, especially as GPx mimics and understanding their catalytic mechanisms, have been the area of extensive research [3,[15], [16], [17], [18], [19], [20]]. These studies have revealed that redox activity and stability of selenium in an organic compound play a very important role in dictating its GPx-like activity, which in turn is controlled by the oxidation state of selenium and also on the extent of non-bonding interactions between selenium and nearby hetero atoms containing lone pair of electrons. Moreover, physiochemical properties including nucleophillicity, ability to undergo reduction by thiols and to take part in sulfur exchange reaction are some of the important parameters which influence the efficacy of selenium compounds for GPx-like activity [1,3,[15], [16], [17], [18], [19], [20]]. Among synthetic organoselenium, mostly aromatic derivatives have been examined for GPx-like activity and other biological activities (such as anti-microbial, anti-fungal, anti-inflammatory, anti-cancer, anti-viral, etc.) using in vitro and in vivo models [11,15,[21], [22], [23], [24]]. One such compound, Ebselen (2-phenyl-1,2-benzoselenazol-3-one), first synthesized in 1924, is widely considered as a magical compound with anti-inflammatory, antioxidant, cyto-protective activities and several therapeutic properties [22,[25], [26], [27], [28], [29]]. Its GPx-like activity was first reported in 1984 [25] and tested clinically for use in stroke by Daiich Pharmaceuticals in 1997 [26]. Recently it has also been shown as a potent inhibitor for SARS-CoV2 main protease (MPro) with an IC50 value of 0.67 μM [30]. Thus, the search for other oragnoslenium compounds for pharmacological application is inevitable (Scheme 2).
Biologically relevant natural organoselenium compounds are primarily seleno amino acids (Scheme 1). Of these, SeCys is highly unstable, and is difficult to isolate in high purity. It is readily oxidized to a diselenide, DL-selenocystine (CysSeSeCys) or meso-3, 3′-diselenodialanine. Chemically, SeM and MSeCys belong to selenoether (C-Se-C linkage) family whereas CysSeSeCys is a diselenide (-Se-Se- linkage). Interestingly, CysSeSeCys has been identified to be highly redox active selenium compound in cells [31]. It is effective against melanoma, human lung and cervical cancers, inducing apoptotic cell death through p53 and caspase dependent pathways in cellular and mice models [31]. It is also clinically tested for treatment of acute and chronic myeloid leukemia [32]. Thus, organoselenium compounds, based on C-Se-C and SeSe linkages, containing alkyl groups substituted at the terminal carbon, [{X(CH2)n}2Se] and [{X(CH2)nSe}2] (X = OH, NH2 or COOH; n = 1–3) (Supplementary table S1), have also been considered for synthesis and evaluation as pharmacologically active agents. Both selenoethers and diselenides derived from hydroxy and amine bearing alkyl groups are liquids, often contaminated with mono- and di-selenides and their purification becomes a tedious process. Although they can be distilled under reduced pressure, yields are considerably reduced due to decomposition on distillation [[33], [34], [35]]. The compounds with carboxylic acid bearing alkyl groups are colorless to pale yellow crystalline solids and are conveniently purified by re-crystallization to the highest degree. Both mono- and di-selenides are reported for in vitro antioxidant activity through GPx-like catalytic mechanism. The diselenides show better activity than the corresponding monoselenides probably due to presence of two selenium nuclei and labile nature of SeSe bond. Initial screening of these compounds indicates that among all the functional groups, carboxylic acid derivatives exhibit excellent scavenging activity of reactive oxygen species (ROS), 3,3′-diselenodipropionic acid (DSePA) (1) being the most active [36].
This review provides an updated and concise, yet a comprehensive report on the application and redox modulatory activities of DSePA in different areas of biological sciences.
Section snippets
Synthesis and physicochemical properties of DSePA
The synthesis of DSePA was first reported by Backer and Dam [37,38] and Fredga [39] in 1929 by using 3-bromopropionic acid and dipotassium diselenide (K2Se2). Potassium salt of a halo-acid, e.g. BrCH2CH2COOK, can also be used in the reaction with K2Se2 [38,40]. Subsequently, several workers prepared DSePA with minor modifications using either 3-chloropropionic acid [[41], [42], [43]] or 3-bromopropionic acid [[44], [45], [46]] in aqueous Na2Se2 obtained by reduction of selenium by NaBH4. DSePA
Glutathione peroxidase (GPx) -like catalytic reactions
GPx-like catalytic activity is commonly used to assess antioxidant behavior of selenium compounds [1,[15], [16], [17], [18], [19], [20], [21], [22]]. As discussed earlier, GPx is an oxido-reductase enzyme and its catalytic activity is associated with both oxidation and reduction steps (Scheme 4).
Similarly, GPx-like activity of a diselenide (R-Se-Se-R') can be initiated by its reduction through GSH to form a selenol. The latter is oxidized by hydroperoxide to form seleninc acid which is
Toxicological studies on DSePA
Although selenium is an essential micronutrient, it has a very narrow window for its deficiency-suboptimal-optimal-therapeutic-toxic-lethal levels [67]. Acute over exposure of selenium causes gastrointestinal, respiratory and cardiovascular problems [67], whereas chronic exposure may result in mental problems, garlic-smelling breath, hair loss, fragile nails, excessive tooth decay, increase in blood pressure [68] and risk of type-2 diabetes [69], and ingestion of large quantity of selenium
Pharmacokinetics and bioequivalence studies on DSePA
Another important parameter that determines the safety of a compound is its pharmacokinetic and bio-distribution profile. The pharmacokinetic and bio-distribution studies of DSePA have been performed in mice model through both IP and oral routes [85,86]. DSePA administration shows a concentration–time profile in plasma and tissues, characterized by an early (15 to 30 min) peak concentration followed by a rapid clearance within an hour [85]. The circulation half-life of DSePA is ~4.27 h and its
Antioxidant activity of DSePA
The antioxidant activity of DSePA has been evaluated in cellular models against a variety of oxidants. In most of these studies, DSePA has been compared with other organo‑selenium and/or ‑sulfur compounds for ROS scavenging and inhibition of lipid peroxidation, DNA damage and cell death. For example, it is shown to protect red blood cells (RBCs) from 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) induced oxidative hemolysis with IC50 value (20 ± 2 μM) comparable to ebselen [57]. Similarly,
DSePA and its conjugates as redox responsive drug delivery systems
The objective of cancer therapy is to achieve maximum tumor kill and to reduce drug associated side effects. Ideal drug delivery system should offer minimum release of the drug into normal cells and maximum release of the drug into tumor cells [120]. Cancer cells are characterized by an increased level of ROS and reducing equivalents (GSH/GSSG) and acidic micro-environment (4.5–6.5) due to accelerated glycolysis. Nano-materials have been developed which can dissociate to release the drug at a
Biocidal activity of DSePA
Several organoselenium compounds exhibit biocidal activities. DSePA has also been evaluated for biocidal activities. The first report on the biocidal activity of DSePA can be traced back to 1951. A US patent by MacPeek et al. described fungicidal activity of DSePA and its usage in making the fungal resistant coating material for electronic equipment [130]. More specifically the invention demonstrated a method for preparation of DSePA and its evaluation as a fungicidal agent using a
Conclusions and future directions
Form the foregoing account; it is evident that DSePA is an interesting organoselenium compound exhibiting different biological and chemical activities (Fig. 6). DSePA acts as an antioxidant in cellular systems by two major pathways, (i) neutralizing ROS, and (ii) inducing GPx like activity or its endogenous expression. During the reaction with oxidizing free radicals, it generates different types of intermediates and some of them like selenenic acid can participate in GPx like activity.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We are grateful to the Department of Atomic Energy for funding this research activity. The authors thank all the collaborators, colleagues and students whose names appeared as co-authors in the publications. Permission from publishers to reproduce figures is gratefully acknowledged. KIP thanks DAE for Raja Ramanna
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2022, European Polymer JournalCitation Excerpt :Despite having paramount performance and superior properties, diselenide-based self-recovery methods have rarely been reported, especially systems based on free radical polymerization. The main reason for this is the free radical scavenging activity of Se-Se moieties [84,85]. For example, Liu,and et al. reported a diselenide-containing shape memory material obtained by synthesizing of a polymeric network.
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2021, Free Radical Biology and MedicineCitation Excerpt :Apart from aryl diselenides, our group has also been working on the pharmacological evaluation of aliphatic diselenides. In this context, we have identified a compound called 3,3′-diselenodipopionic acid (DSePA) showing multiple pharmacological activities like GPx-like catalytic activity, ROS scavenging and lung radioprotection against thoracic and whole-body irradiation [15–19]. The median lethal dose (LD50), pharmacokinetics and bio-distribution of this compound are also well established [20,21].