Seleno- and Telluro-Functionalization of Quinones: Molecules with Relevant Biological Application

Quinones and organochalcogens are classes of compounds with great biological applicability, such as antioxidant, anticancer, anti-Alzheimer, and antidepressant activities, among others. Thus, the combination of these two classes of compounds is important to obtain new hits with biological activities that are additive or synergistic. Several methodologies for the preparation of this class of hybrid compound have been widely described. Many of the prepared hybrid molecules have shown increased biological activities and, in some cases, to act as two distinct pharmacophores. In this review, methods for the preparation of selenium-quinones, tellurium-quinones and their biological applications are highlighted.


Introduction
Quinones are pigments found in different living organisms and in a wide variety of plant families, such as Ranunculaceae, 1 Aphodelaceae, 2 Fabaceae, 3 Ebenaceae 4 and Rhamnaceae. 5 They are also present in bacteria, fungi, higher plants and some animals. Compounds with this core could be used as chemical intermediates, polymerization inhibitors, oxidizing agents, photographic chemicals, tanning agents, and chemical reagents. 6 The pharmacological properties of these compounds have been studied in depth, and they are considered privileged structures in medicinal chemistry. Quinones have been assessed for their biological activity against cancer and for their antiallergic, 7 antifungal, 8 antiviral, 9 antibacterial 10 and anti-inflammatory properties. 11 In addition, the quinone class also plays an important role in the prevention of chronic diseases such as Parkinson's and cardiovascular diseases, with a mechanism of action involving the fight against cell damage caused by reactive oxygen species (ROS). 12 Recent studies continue to show important applications of quinones, such as the use of mitochondrial ubiquinone as a potential treatment or adjuvant therapy in the context of coronavirus disease 2019 . 13 It is worth mentioning the importance that various quinones represent in the vitamin K family, being responsible for the function in several biological processes, and vitamin K3 being of vital importance in blood clotting. 14 Currently, there are already several commercialized drugs in which quinones form part of their molecular structures, as is the case of doxorubicin (1), a drug with the widest scope of anticancer activity in humans. Another promising quinone is β-lapachone (2), which is in phase II clinical trials under code ARQ501 for the treatment of pancreatic cancer ( Figure 1). [15][16][17] Tellurium-and selenium-containing organic compounds were for a long time considered dangerous to the environment and human health, and for this reason the interest in organochalcogen compounds has been growing only in recent decades. The importance of molecules containing chalcogens is highlighted in different fields, including materials science, organic synthesis, medicine and biology. [18][19][20][21][22] In this review, several organochalcogens will be highlighted: more specifically, tellurium-and seleniumcontaining quinones, since they themselves have undergone more recent and unique chemical and biological studies in relation to their counterparts containing sulfur. Currently, it is possible to consider that chemists have managed to master the preparative chemistry of tellurium-and selenium-containing compounds, and their biological applications are quite widespread. This can be seen in the increase in the number of publications dedicated to organoselenium and organotellurium compounds. [23][24][25] It is important to show that organoselenium compounds have already proven to be valuable reagents in various chemical reactions, such as selenylation, selenocyclization, selenoxide elimination, cross-coupling reactions and 2,3-sigmatropic rearrangement processes, as well as in asymmetric catalysis. [26][27][28][29][30][31] The biological profile of selenium compounds is established, and their use as bioactive molecules is emerging as an even more attractive field of research. The selenide ALT2074 (3) was identified as a glutathione peroxidase (GPx)-mimic able to prevent endothelial changes and myocardial ischemia-reperfusion injury. 32 In addition, ethaselen (4) is in phase II of clinical trials for the treatment of non-small cell lung cancers with overexpression thioredoxin reductase (TrxR). 33 One of the most important organoselenium compound is ebselen (5), which exhibits hydroperoxide-and peroxynitritereducing activity, acting as a glutathione peroxidase and peroxiredoxin enzyme mimetic ( Figure 2). This compound has become even more interesting due to its promising potential to inhibit the main protease (M pro ) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 34,35 The large number of studies showing the applications of hybrid compounds between quinones and organochalcogens demonstrate the great interest in the development of synthetic methods toward compounds containing these two moieties in the same structure, aiming at superior additive or synergistic biological effects. Thus, this review has the proposal of emphasizing studies related to quinone structures functionalized with organochalcogens, their synthesis, as well as biological applications. The systematic arrangement of this review explores the possibility of providing practical guidance to synthetic chemists for further research, while emphasizing the possible biological applications of quinones functionalized with organochalcogens.
Ueno and co-workers 37 discovered an innovative method of selenylation to obtain selenonaphthoquinones a n d s e l e n o q u i n o l i n e q u i n o n e s b y a d d i t i o n o f phenylselenolate ion in chloroquinones. The selenolate ions were obtained by reaction of the corresponding diselenides, tributylphosphine (Bu 3 P), and sodium hydroxide, with tetrahydrofuran (THF) as solvent. The different selenoquinones 11 were produced from naphthoquinones 9 with yields varying from 68 to 98% (Scheme 2a). The two selenoquinolinequinones 13a-13b were synthesized from chloroquinoline quinones 12a and 12b, in 47 and 38% yield, respectively (Scheme 2b). As a mechanistic suggestion, the authors believe that the phenylselenolate ion (nucleophile of the reaction) is generated from the breakdown of diphenyl diselenides for the complexation of phenylselenide with Bu 3 P and its subsequent release in the basic medium. This ion then performs substitution at the C-2 and/or C-3 of the quinone, depending on the position of the halogen (Scheme 2c).  Tetrachloro-1,4-benzoquinone 14 and 2,3-dichloro-1,4-naphthoquinone 9g are versatile compounds with reactive chlorine atoms, and their chemistry is of great synthetic interest. They have been widely used as reagents in nucleophilic substitution. Quinone compounds containing an organoselenium moiety were obtained through reactions of chloroquinones with selenolates. Initially, using route 1, compound 14 was treated with aryl and alkyl selenolates, generated by the reaction of Grignard reagents and selenium powder to provide 16a-16c in yields of 55-72% and 11g and 17a in yields of 59 and 72%, respectively. However, when 9g was reacted with phenyl and benzyl selenolate, in the route 2, generated by the reduction of diselenides with NaBH 4 , compounds 11g and 17b were also obtained in good yields of 59 and 72%, respectively. However, using diselenides 10, the products 11g and 17b were also obtained in good yields (Scheme 3). 38 Joseph and co-workers 39 have successfully demonstrated another method to introduce selenium atoms through a reaction between benzeneseleninic anhydride and hexamethyldisilazane (Scheme 4). This methodology provides a reactive intermediate, oligomeric (PhSeN) 4 , that oxidizes the phenol derivatives to selenoiminoquinones 21.
In addition, these selenoiminoquinones were investigated, and both spectroscopic and crystallographic studies proved that the oxygen from the carbonyl group is involved in an attractive interaction with the selenium atom. Therefore, the electronic structure around the selenium atom can be described in terms of the model with a 3-center and 4-electron connection and correlated with other hypervalent molecules.
In the same year, Henriksen 41 studied the first o-oxidation of phenols using benzeneselenenyl acid 26 as a specific oxidizing agent, producing 28 after subsequent reactions of dehydration and rearrangement. Intermediate 28 was oxidized in a final step to give a mixture of three compounds (benzoquinone 6 and selenium-quinones 29a and 29b), in the proportion 3:4:3 (Scheme 6).
As a further expansion of this promising area of research, a simple and efficient method for the synthesis of selenocyanoquinones has been described. Quinone imines 31a-31e were reacted with triselenodicyanide in a one-pot selenocyanation reaction in a quinoid kernel of pyridobenzimidazole system and showed selectivity at C-9 due to the presence of the electron-donor substituent in the ortho position (Scheme 7). The method involves an aromatic electrophilic substitution reaction in the quinoidal structure and presented several advantages, such as mild reaction conditions, simple procedure, and good yields (66-96%). 42 Selenium-lapachol derivatives can be synthetized via a solvent-free and metal-free methodology, as reported by Braga and co-workers in 2015. 43 The synthesis involved the use of molecular iodine as a catalyst, dimethyl sulfoxide (DMSO) as a stoichiometric oxidizing agent and diselenides as nucleophiles, under microwave irradiation. Lapachol (32) and C-allyl lawsone (34) were employed  as substrates for the seleno-functionalization. This system allows the formation of PhSeI species, which is the source of electrophilic selenium for the formation of the seleniranium intermediate 32a. When 32 was used, the respective 3-selenophenyl-β-lapachone 33a was obtained in 65% yield in a 6-endo-trig fashion (Scheme 8a). Applying the chalcogenylation method to C-allyl lawsone (34), the selenium product 35a was obtained in 80% yield (Scheme 8b). The compounds were obtained through β-cyclization; however, α-cyclization is also possible. In general, β-lapachone analogs are synthesized preferentially in reactions without heating and in a shorter reaction time than α-lapachone derivatives (thermodynamic product). 43 Sykes and co-workers 44 described the synthesis of 1,8-anthraquinone-18-crown-5 containing chalcogenides 37a-37b and their application as sensors for the selective recognition of Pb II . The structure of these macrocycles is formed by a fluorescent anthraquinone moiety that has a cyclic polyether chain as a receptor. Compounds 37a-37b were synthesized by the reaction of disodium selenide or disodium telluride with 1,8-bis-(2-bromoethylethylenoxy) anthracene-9,10-dione (36) in the proportion of 1:1, in yields of 10 and 25%, respectively (Scheme 9). Several studies have been carried out in relation to optical properties, X-ray diffraction, cyclic voltammetry and nuclear magnetic resonance (NMR) spectroscopy. From these results, it was found that 37a acts as a luminescent sensor for the selective recognition of Pb II in acetonitrile via internal charge transfer. However, compound 37b does not show the same result, as it does not change luminescence with the addition of lead. 44 The first methodology that described the C-H phenylselenylation of quinones was described in 2016 by da Silva Junior and co-workers. 45 The reaction was carried out under Rh-catalysis and using N-(phenylseleno)phthalimide (100 mol%) as an electrophile. Selenobenzoquinones 40a-40c were obtained in satisfactory yields that varied from 61 to 74% (Scheme 10a), and the selenonaphthoquinone 42a in 86% yield (Scheme 10b). Increasing the loading of N-(phenylseleno)-phthalimide to 250 mol% enabled the selective generation of bis-functionalization adduct 40b in 73% yield. Seleniumcontaining quinones possess significant antitumor activity, which may be due to their ability to generate intracellular ROS and induce cell death. 45 In 2005, Jacob and co-workers 46 reported the synthesis of compounds containing a chalcogen and a naphthoquinone as selective enhancers of oxidative stress. Cancer cells proliferate under conditions of oxidative stress and might therefore be selectively targeted by redox catalysts. Scheme 11 describes the synthetic methodology for obtaining tellurium-menadione compounds 45a and 45b using NaBH 4 as reducing agent and ditellurides 44, in yields of 9 and 75%, respectively. These compounds combine the specific electrochemical features of quinones and tellurium, and respond to the presence of oxidative stress. The high efficiency and selectivity shown by compounds 45a-45b make them interesting in the development of anticancer drugs.
The same research group reported the synthesis of redox-active multifunctional selenium and tellurium compounds and the evaluation of their cytotoxicity against cancer cells. 47 The synthetic methodology employed involved the use of multicomponent of Passerini and Ugi reactions, showing that it is an excellent synthetic route for obtaining highly functionalized molecules (Scheme 12). The Passerini reaction is a three-component reaction combining an acid, an aldehyde, and an isonitrile, while the Ugi reaction is a four-component reaction (acid, aldehyde, isonitrile, and amine). It is worth mentioning that acids, aldehydes and amines as building blocks are accessible and variable, which can bring more functionality to multicomponent reaction products. Thus, compounds containing selenium and tellurium were obtained with two to four redox centers, 1,4-naphthoquinone always being one of them. All compounds were evaluated against cancer cells, with 49 and 54 being the most active. In both compounds, the selenium atom is linked directly to the quinonic ring, and this can result in a synergistic effect between the two redox sites. 47 In 2010, Jacob and co-workers 48 reported a very simple synthesis of a variety of multifunctional redox catalysts designed to target cancer cells by modulating intracellular levels of ROS. Scheme 13 describes the synthetic methodology for obtaining quinone-chalcogen compounds using NaBH 4 as a diselenide reducing agent, giving rise to sodium phenylselenolates-reaction nucleophiles . Compounds 61, 63, 65 and 67 were obtained with yields ranging from 18 to 44%. Compound 67 has been shown to decrease the proliferation of carcinoma cells. According to human treatment protocols, 67 was combined with other drugs and the result was promising, as it worked in conjunction with these drugs to inhibit the growth of cancer cells and did not increase the toxicity of the drugs. 46,48 Selenium-containing compounds can be used as potential redox-modulating agents, an effect which may be used for the selective targeting of cancer cells, which are naturally under oxidative stress. As macrophages also generate an environment rich in ROS, they may represent a target for such redox-modulating agents. Thus, seleniumcontaining quinones have been synthesized and tested in macrophage culture. Scheme 14 reports the methodology used to obtain the compounds 69a-69d using NaBH 4 as a reducing agent, in yields varying from 8 to 34%. All compounds were synthesized and subsequently tested in macrophage culture. While tellurium analogs may enable the resolute, effective and fairly selective targeting of macrophages, the selenium agents could act less severely, but equally effectively, by interfering with inflammatory signaling molecules. The studies offer ample opportunities for future investigations in the field of the chemistry and biochemistry of organochalcogens (selenium and tellurium), redox modulation and planning of antiinflammatories. 49 In 2015, da Silva Junior and co-workers 50 reported a fast, efficient and green methodology for obtaining compounds containing two redox centers-quinone and chalcogen. Selenium-containing β-lapachone derivatives 33 were synthesized in moderate to high yields, using I 2 /DMSO as a catalytic system and microwave radiation (Scheme 15). The methodology employed allowed the preparation of the compounds from lapachol, passing through the intermediate chalcogeniranium ion 32a, within a few minutes in a green approach. These compounds were evaluated against several human cancer cell lines (leukemia, colon carcinoma, prostate, ovary, central nervous system In the following year, da Cruz et al. 51 reported the synthesis of selenium-containing quinone-based 1,2,3-triazoles 72 using a copper catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (Scheme 16). All compounds were evaluated for antitumor activity in vitro using several human cancer cell lines. The results showed most compounds to be highly active against all cancer cell lines evaluated, the o-quinones were more active than the p-quinones. In general, the most potent compounds showed IC 50 values below 0.3 μM, being more active than the β-lapachone and doxorubicin, a standard clinical agent used against several types of cancers. Compound 72d (p-quinone) showed IC 50 values varying from 0.62 to 2.42 µM in the evaluated cancer cell lines. The most active o-quinones, 72a-72c, presented IC 50 values between 0.07 and 2.52 µM. 51 The synthesis of selenonaphthoquinone pseudopeptides was described in 2016 by Wessjohann and co-workers. 52 Initially, the diselenides were reduced in situ to give the corresponding sodium selenolate upon treatment with NaBH 4 . The attack of nucleophilic selenolate on 2-bromo-3methyl-1,4-naphthoquinone (43) resulted in selenium-based quinone-peptidomimetics 73 with excellent yields (up to 93%, Scheme 17). The cytotoxic activity of these compounds was evaluated in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines, with 73a and 73c being the most potent compounds and with the more pronounced cytotoxicity in the case of MCF-7 compared to HepG2cells, with IC 50 values of 6 and 7 μM, respectively. Of the tested compounds, selenium-based quinones 73a, 73b and 73c were among the most active, exhibiting good free radical scavenging activity. In addition, compounds 73b and 73c exhibited equipotent activity to ampicillin, an antibiotic used in clinical medicine against a range of bacterial infections. On the other hand, compound 73e showed moderate activity: 68% of that of ampicillin.
In 2017, selenoquinones were first tested against Trypanosoma cruzi, a protozoan that causes Chagas disease. da Silva Junior and co-workers 53 reported the synthesis of selenium-containing quinones by activating the rhodiumcatalyzed C-H bond, using species with the electrophilic nature of chalcogen. Reaction of benzoquinone (6) with 150 mol% N-(phenylseleno)phthalimide (74) produced a mixture of 40a and the bisquinone 40b. However, using 100 mol% of 74, 40a was obtained in good yield and high selectivity. Compound 40b could be accessed in 74% yield by using a large excess (250 mol%) of 74 (Scheme 18a). Application of the C-H functionalization conditions under Rh-catalysis to 1,4-naphthoquinone provided 42a in 86% yields (Scheme 18b). Taking advantage of the success of the previously established methodology, other seleniumquinone hybrid compounds with potential antitumor activity were also obtained via Rh-catalyzed C-H bond activation (Scheme 18c). 54 Among these compounds, the naphthoquinone substituted at C-2 with selenium (42a, IC 50 1.13 μM, selectivity index (SI) 11.2) was 8.5-fold more active than benznidazole, often the first-line treatment for Chagas disease in most countries. 53 In the following year, the same group demonstrated, 55 the efficient use of stable phenyl selenolate as a nucleophilic reagent in various organic transformations. For example, the A-ring selenylation of naphthoquinones and anthraquinones using copper catalysts (Scheme 19a). The reaction between iodo-quinone 75 and ArSeCl in presence of zinc, copper(I) thiophene-2-carboxylate (CuTC) and dimethylacetamide (DMAc), provided 76a-76j in yields varying from 42 to 81% (Scheme 19b). Copper complexes and carbon nanotube-copper ferrite in the presence of RSeAg salts efficiently catalyze the reaction and provide the products in high yield (Schemes 19c and 19d). All compounds were evaluated against T. cruzi, with 76c (IC 50 13,3 μM) and 76d (IC 50 13,4 μM) being the most potent, about eight-fold more active than benznidazole, a positive control and one of the medicines used against T. cruzi. 55 The use of electrochemistry in the synthesis of selenium-containing quinone hybrid molecules has been widely explored by several research groups, offering an efficient, ecological, fast and reliable methodology that avoids the use of chemical oxidants. The reactivity of lapachol 32 toward electrophilic selenated species has been described previously 50 in an I 2 /DMSO oxidative system. However, this type of oxidative cyclization is also possible in an electrochemical cell. Thus, da Silva Junior and co-workers, 56 motivated by the positive results of previous studies, described a range of selenium-functionalized quinones using electrochemical selenylation. They also analyzed the reaction through cyclic voltammetry to investigate the mechanism, and it was possible to confirm the formation of the cationic intermediate, coming from an electrophilic addition of selenium, followed by a nucleophilic cyclization (Scheme 20). Some of the compounds produced exhibited considerable biological activity against five cancer cell lines and T. cruzi, such as 33c, which is active against HCT-116 and B16F10 cancer cells with IC 50 values of 0.95 and 0.98 μM, respectively (doxorubicin: IC 50 values of 0.19 and 1.34 μM, respectively), and against T. cruzi with an IC 50 of 38.3 μM (benznidazole: IC 50 of 103.6 μM). 56 Derivatizations of 33a were also investigated to demonstrate the usefulness of the selenated naphthoquinones. Reaction of 33a with hydroxylamine hydrochloride, o-phenylenediamine and phenylhydrazine hydrochloride provided 79, 80 and 81 in yields of 60, 72 and 70%, respectively (Scheme 21). Lapachone derivatives have several applications, such as fluorescent sensors for images of living cells and lipid droplets and for imaging of NQO1 activity in tumor tissues. 56 Recently, Nascimento and co-workers 57 developed a series of seleno-1,4-naphthoquinones 84 against Mycobacterium tuberculosis H37Rv, a bacterium that causes tuberculosis. Seleno-functionalization of menadione was performed rapidly and economically. The synthetic approach used to obtain selenium-containing menadione derivatives was based on a two-step pathway Vol. 00, No. 00, 2021 Scheme 21. Synthesis of lapachone derivatives (adapted from reference 56).

Scheme 22.
Seleno-functionalization of menadione (adapted from reference 57). entailing the use of commercial menadione 82. First was the insertion of the −CH 2 Cl group into menadione in excellent yield (95%) followed by the selenofunctionalization of 83 by means of a reaction with the respective selenocarboxylate generated in situ, obtaining the compounds in yields varying from 24 to 75% (Scheme 22). All compounds were evaluated against M. tuberculosis H37Rv, with 84a, 84c and 84f showing the best minimum inhibitory concentration (MIC) values 2.1, 8.0 and 8.1 μM, respectively. These compounds were also tested in vitro against multidrug-resistant clinical isolates (CDCT-16 and CDCT-27) and showed remarkable values from 0.8 to 3.1 μM. A final analysis was carried out exploring its toxicity against the Vero cell lines, where 84a and 84f proved to be non-toxic. Therefore, the new selenium-menadione conjugates were shown to be a promising class of anti-tuberculosis agents, mainly in combating the multidrug-resistant event.
In the same year, da Silva Junior and co-workers 58 published the synthesis and biological evaluation against several cancer cell lines of 48 new compounds containing two redox centers (combinations of selenium and naphthoquinones) linked by a triazole ring. The authors reported that selenonaphthoquinones 87a-87h, 91a-91h, 93a-93j and 96a-96d, were synthesized by an accessible synthetic approach, making it possible to obtain selenated beta-lapachone-triazoles and selenated nor-betalapachone-triazoles (Schemes 23a and 23b) containing a spacer between the redox centers, and selenated β-lapachone-triazoles and selenated nor-α-lapachonetriazoles (Schemes 23c and 23d) without this space. Furthermore, it was reported that the antitumor activity of these compounds was generally satisfactory with IC 50 values below 0.5 μM, significantly lower cytotoxicity in the L929 control cell line and good selectivity index. Thus, the wide range of compounds synthesized, in addition to showing good initial results, serves as an inspiration for the discovery of new antitumor drugs. 58

Final Remarks
In recent decades the scientific community has devoted its efforts to the study of tellurium-and selenium-containing quinones, which is an important class of compounds with different relevant biological properties. A selenium or tellurium atom can be introduced into quinones as an electrophile, using an appropriate nucleophilic carbon such as double bond, and dichalcogenides or arylchalcogenyl halides. On the other hand, chalcogencontaining quinones can also be prepared through the reaction of quinones containing electrophiles with different nucleophilic selenium or tellurium species generated through diverse methodologies. The choice of method is guided by the structure of the quinone derivatives that react with the chalcogen source. Due to the high potential of quinones containing an organochalcogen moiety as bioactive structures, we believe that new investigations into the design, synthesis and biological evaluation of these molecules can lead to new biochemical tools and consequent new successes in drug development. We visualize that this review and perspectives described herein will stimulate further efforts from researchers across the quinone and organochalcogen community.