molecules Review Selenides and Diselenides: A Review of Their Anticancer and Chemopreventive Activity Mónica Álvarez-Pérez 1 ID , Wesam Ali 2,3, Małgorzata Anna Mar´c 3, Jadwiga Handzlik 3 and Enrique Domínguez-Álvarez 1,* 1 Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (IQOG, CSIC), Juan de la Cierva 3, 28006 Madrid, Spain; [email protected] 2 Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B2 1, D-66123 Saarbruecken, Germany; [email protected] 3 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland; [email protected] (M.A.M.); [email protected] (J.H.) * Correspondence: [email protected]; Tel.: +34-912587590 Received: 3 January 2018; Accepted: 9 March 2018; Published: 10 March 2018 Abstract: Selenium and selenocompounds have attracted the attention and the efforts of scientists worldwide due to their promising potential applications in cancer prevention and/or treatment. Different organic selenocompounds, with diverse functional groups that contain selenium, have been reported to exhibit anticancer and/or chemopreventive activity. Among them, selenocyanates, selenoureas, selenoesters, selenium-containing heterocycles, selenium nanoparticles, selenides and diselenides have been considered in the search for efficiency in prevention and treatment of cancer and other related diseases. In this review, we focus our attention on the potential applications of selenides and diselenides in cancer prevention and treatment that have been reported so far. The around 80 selenides and diselenides selected herein as representative compounds include promising antioxidant, prooxidant, redox-modulating, chemopreventive, anticancer, cytotoxic and radioprotective compounds, among other activities. The aim of this work is to highlight the possibilities that these novel organic selenocompounds can offer in an effort to contribute to inspire medicinal chemists in their search of new promising derivatives. Keywords: selenium; selenocompounds; selenides; diselenides; antioxidants; chemoprevention; anticancer compounds; cytotoxicity; cytostaticity 1. Introduction Various authors have extensively reviewed the different applications of selenium in human health [1–4]. Selenium is an essential element that forms part of the selenoaminoacids selenomethionine (1, Figure1a) and selenocysteine ( 2). The latest is an essential constituent of the selenoproteins [5–7] and its deficiency can cause serious disorders [1,2]. Selenoproteins have crucial functions for human health. The most known are the gluthathione peroxidases, the iodothyronine deiodinases, the thioredoxin reductases and the selenoprotein P. The different glutathione peroxidases (GPx) are involved in the elimination of free radicals; the iodothyronine deiodinases enable the activation and deactivation of thyroid hormones. Thioredoxin reductases regenerate the thioredoxin (an important antioxidant class of proteins), and the selenoprotein P is involved in the transport of selenium in plasma and in the antioxidant defense against free radicals in lipids [5–7]. Molecules 2018, 23, 628; doi:10.3390/molecules23030628 www.mdpi.com/journal/molecules Molecules 2018, 23, 628 2 of 19 Molecules 2018, 22, x 2 of 19 FigureFigure 1. 1.Naturally Naturally occurringoccurring selenides ( (aa)) and and diselenides diselenides (b ().b ). An intense research in the chemopreventive and/or anticancer activity of organic and inorganic An intense research in the chemopreventive and/or anticancer activity of organic and inorganic selenium-containing compounds has been developed, as has been reviewed by different authors [8– selenium-containing14]. The duality of compoundsselenium as hasan antioxidant been developed, and as as a has prooxidant been reviewed agent provides by different the authorsbasis for [ 8its–14 ]. Thepotential duality ofapplications selenium asin an both antioxidant cancer prevention and as a prooxidant and treatment. agent This provides dual thechemopreventive basis for its potential and applicationsanticancer in action both has cancer been prevention extensively and discussed treatment. or reported This dual by chemopreventive different authors and[15–18]. anticancer Regarding action hasthe been chemopreventive extensively discussed activity, or a reported mechanism by different usually authorsexerted [by15– different18]. Regarding selenocompounds the chemopreventive is the activity,glutathione a mechanism peroxidase-like usually exertedactivity by[19]. different Althou selenocompoundsgh inorganic selenocompounds is the glutathione may peroxidase-likebe superior activitychemopreventive [19]. Although agents inorganic than organic selenocompounds ones, current mayresearch be superioris focused chemopreventive on the latter group agents due to than organictheir ones,lowercurrent toxicityresearch risk [20]. is Am focusedong the on inorganic the latter selenocompounds, group due to their selenite lower toxicity can be highlighted risk [20]. Among by theits inorganic chemopreventive selenocompounds, [21] and anticancer selenite can action be highlighted [22]. by its chemopreventive [21] and anticancer action [22On]. the other hand, the mechanisms of action of the organic selenocompounds are very diverse [23].On Some the other of the hand, most the frequent mechanisms are the of reduction action of of the oxidative organic stress selenocompounds through the elimination are very diverse of free [23 ]. Someradicals of the [24,25], most i.e., frequent the induction are the of reduction mutations of[26], oxidative the cytotoxic stress activity through [27] theand elimination the triggering of of free radicalsapoptotic [24, 25events], i.e., [28,29]. the induction Nevertheless, of mutations certain selenocompounds [26], the cytotoxic can activity act through [27] and other the triggeringless usual of mechanisms, such as the inhibition of angiogenesis [30], the inhibition of the efflux pumps in cancer apoptotic events [28,29]. Nevertheless, certain selenocompounds can act through other less usual multidrug resistant cell lines [31] and the enhancement of the activity of chemotherapeutic drugs [32]. mechanisms, such as the inhibition of angiogenesis [30], the inhibition of the efflux pumps in cancer The chemical structure of anticancer and chemopreventive organic selenocompounds also shows a multidrug resistant cell lines [31] and the enhancement of the activity of chemotherapeutic drugs [32]. great variety, including selenocyanates [33], selenoureas [34], selenoesters [35], heterocycles with The chemical structure of anticancer and chemopreventive organic selenocompounds also shows endocyclic selenium [36], selenium nanoparticles [37], selenides and diselenides. a greatHerein, variety, includingwe review selenocyanates an anticancer [and33], a selenoureas chemopreventive [34], selenoesters activity of [35both], heterocyclesselenides and with endocyclicdiselenides, selenium with a [36 special], selenium attention nanoparticles to mechanis [37ms], selenidesof their biological and diselenides. action. The question of diselenidesHerein, we symmetry, review an as anticancer a feature favorable and a chemopreventive for anticancer activity activity [38], of both is also selenides under consideration. and diselenides, with a special attention to mechanisms of their biological action. The question of diselenides symmetry, as a2. feature Selenides favorable and Diselenides for anticancer with activityTherapeutic [38], Perspective is also under consideration. 2. Selenides2.1. Naturally and Occurring Diselenides Selenides with and Therapeutic Diselenides Perspective 2.1. NaturallyDiselenides Occurring have Selenidesreceived andsignificant Diselenides attention, not only because this moiety is usually found among the metabolites of the dietary compounds but also particularly because they have been postulatedDiselenides as one have of receivedthe most important significant species attention, in redox-cycling. not only because In line this with moiety this, selenocystine, is usually found a amongnaturally the metabolitesoccurring diselenide of the ( dietary3, Figure compounds 1b), exhibits butstrong also antioxidant particularly properties because [39] they and has have been been postulatedconsidered as onein several of the moststudies important related to species chem inoprevention. redox-cycling. Thus, In it line was with effective this, selenocystine,against 4- a naturally(methylnitrosamino)-1-(3-pyridyl)-1-butanoneoccurring diselenide (3, Figure1b), exhibits(NNK) induced strong antioxidantlung tumors properties in a specific [ 39 ]mouse and has beenmodel considered sensitive into severalchemical studies carcinogenesis related to(the chemoprevention. A/J mouse model) Thus,when administered it was effective in a againstpre- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanoneinitiation period to tumor development, or, altern (NNK)atively, when induced supplementation lung tumors was in a restricted specific mouseto a modelpost-initiation sensitive period to chemical [40]. carcinogenesis (the A/J mouse model) when administered in a pre-initiationIn a different period study, to tumor 3 was development, found to trigger or, alternatively, apoptosis in whenhuman supplementation breast adenocarcinoma was restricted MCF-7 to cells through kinase regulation [41]. Induction of apoptosis was also attributed to 3 in HepG2 human a post-initiation