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Abstract: The development of novel small molecules with effective catalytic antioxidant properties is highly sought after. A wide array of structurally diverse selenium- and tellurium-containing glutathione peroxidase mimics have been studied over the past two decades. Within this arena, organotellurium compounds generally exhibit higher catalytic properties with respect to selenium-containing analogues. Different mechanisms accounting for the thiol-peroxidase-like activity of various classes of organotellurium derivatives have been proposed. This review documents developments in this area and provides an overview of the catalytic mechanisms proposed for the various classes of telluriumcontaining thiol-peroxidase-like-catalysts.

With the aim to propose innovative antimicrobial agents able to not only selectively inhibit bacterial carbonic anhydrases (CAs) but also to be photoactivated by specific wavelengths, new heptamethine-based compounds decorated with a sulfonamide moiety were synthesized by means of different spacers. The compounds displayed potent CA inhibition and a slight preference for bacterial isoforms. Furthermore, minimal inhibitory and bactericidal concentrations and the cytotoxicity of the compounds were assessed, thus highlighting a promising effect under irradiation against S. epidermidis. The hemolysis activity test showed that these derivatives were not cytotoxic to human red blood cells, further corroborating their favorable selectivity index. This approach led to the discovery of a valuable scaffold for further investigations.

Nucleophilic sulfur- and selenium-containing reagents include versatile classes of compounds with broad application in organic and inorganic synthesis. In this chapter, synthetic applications of “unconventional” chalcogen nucleophilic reagents, containing chalcogen–boron, chalcogen–aluminium, chalcogen–silicon, and chalcogen–tin bonds, are reviewed. Focusing on more recent developments, reactions of these species with a variety of electrophilic partners are presented. Particular emphasis is devoted to advances in the field achieved over the last two decades.

Structural modifications of the resveratrol scaffold are valuable tools in order to develop new derivatives with potential biomedical and pharmacological applications. The investigation of the biological properties of resveratrol-derived semisynthetic systems and the study of their structure-activity relationships are attracting growing interest from medicinal chemists and biologists. In this context, the synthesis of novel resveratrol-derived systems characterisaed by elevated molecular complexity is highly sought after. Over the past years, a wide variety of resveratrol derivatives have been prepared and studied for their biological properties. Therefore, a number of stilbenoid-related potential anticancer, antioxidant, antiviral, analgesic, and anti-neurodegenerative systems have been investigated. This chapter focuses on recent studies related to the preparation and the study of semisynthetic resveratrol-derived systems.

Cognitive deficits are enduring and disabling symptoms for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. In this study, we reported the synthesis of β-arylchalcogeno amines bearing sulfurated, selenated, and tellurated moieties (2-4) which are structurally related to amphetamine with good activation properties for Carbonic Anhydrases (CAs) isoforms present in the cortical and hippocampal brain structures (hCA IV and hCA XIV). In addition, these compounds showed selective inhibition against the Monoamine oxidase (MAO) A isoform. In vivo evaluation of two derivatives (2a and 3a) revealed procognitive effects in the object recognition and social discrimination tests. Interestingly, these compounds, despite having a similar structure to amphetamine, did not caused hypophagia or hyperlocomotion, two effects often observed following the administration of amphetamine-like drugs. In this context, β-arylchalcogeno amines may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases such as attention deficit disorder, Parkinson's disease-related cognitive dysfunction and cognitive disorders associated with depression.

A study on the activity of selenocarbamates as a novel chemotype acting as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors is reported. Undergoing CA-mediated hydrolysis, selenocarbamates release selenolates behaving as zinc binding groups and effectively inhibiting CAs. A series of selenocarbamates characterised by high molecular diversity and complexity have been studied against different human CA isoforms such as hCA I, II, IX and XII. Selenocarbamates behave as masked selenols with potential biological applications as prodrugs for CAs inhibition-based strategies. X-ray studies provided insights into the binding mode of this novel class of CA inhibitors.

Treatment of substituted 1,3,5-trithianes with S2Cl2 and Na2S under mild conditions provides 3,5-disubstituted 1,2,4-trithiolanes, as mixture of diastereoisomers.

The one-pot multistep ethyltellurenylation reaction of epoxides with elemental tellurium and lithium triethylborohydride is described. The reaction mechanism was experimentally investigated. Dilithium ditelluride and triethyl borane, formed from elemental tellurium and lithium triethylborohydride, were shown to be the key species involved in the reaction mechanism. Epoxides undergo ring-opening reaction with dilithium ditelluride to afford β-hydroxy ditellurides, which are sequentially converted into the corresponding β-hydroxy-alkyl ethyl tellurides by transmetalation with triethyl borane, reasonably proceeding through the SH2 mechanism.

A series of benzoselenoates has been prepared and their inhibitory properties against the most relevant human Carbonic Anhydrases (CAs) isoforms, among which hCA I, II, IV, VII, IX, and XII were investigated. These inhibitors were designed considering the carboxylates and mono-/dithiocarbamates as lead and led to the observation that the COSe

Glutathione peroxidase (GPx) regulates cellular peroxide levels through glutathione oxidation. GPx-mimics based on 4,5-disubstituted fluorene diselenides, their oxides, and ditellurides show catalytic activities consistent with conformational restriction about the dichalcogen bond.

Platinum-based chemotherapy is widely used for the treatment of different tumors but is associated with serious side effects, among which neuropathic pain. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors have recently been validated as therapeutic agents in neuropathic pain and as antitumor agents. We report the synthesis of new organochalcogenides bearing the benzensulfonamide moiety acting as potent inhibitors of several human CA isoforms and, in particular, against hCA II and VII endowed with potent neuropathic pain attenuating effects. Moreover, in combination with cisplatin or doxorubicin, some of the new CA inhibitors enhanced the effects of the anticancer drugs capability in counteracting breast cancer MCF7 cell viability. The concomitant anti-neuropathic pain and antiproliferative effects of the new chalcogenide-based CA inhibitors represent an innovative approach for the counteraction and management of side effects associated with clinically platinum drugs as antitumor agents.

Symmetrical ditocopheryl disulfides (Toc)2 S2 and symmetrical and unsymmetrical ditocopheryl sulfides (Toc)2 S were simply prepared under remarkably mild conditions with complete control of the regiochemistry by using δ-, γ-, and β-tocopheryl-N-thiophthalimides (Toc-NSPht) as common starting materials. The roles of sulfur atom(s), H-bond and aryl ring substitution pattern on the antioxidant profile of these new compounds, which were assembled by linking together two tocopheryl units, are also discussed.

The reactivity of N-thiophthalimides with silyl chalcogenides is described. Treatment of N-thiophthalimides with bis(trimethylsilyl) sulfide [(Me3Si)2S] leads to the formation of a mixture of the corresponding disulfides and trisulfides. On the other hand, N-thiophthalimides react with bis(trimethylsilyl) selenide [(Me3Si)2Se] under TBAF catalysis to smoothly give variously substituted diaryl, divinyl, and dialkyl disulfides; formation of a selenotrisulfide (dithiaselane, RSSeSR) is rationalized as an intermediate. Exploiting the different chemical behavior of silyl chalcogenides, we have disclosed a novel, selective, and operationally simple method to access disulfides in good yields under mild conditions.

Stable aryl selenols were obtained through a convenient procedure. Selenols represent a new chemotype acting as carbonic anhydrase inhibitors (CAIs), inhibiting four human isoforms, CAs I, II, VII and the tumor-associated CA IX. X-ray crystallographic, physical and computational studies provided insights into the binding mode of this conceptually new class of CAIs.

Metal-free ring opening reactions of activated and unactivated aziridines with different silyl chalcogenides are described. Judicious tuning of the reaction conditions enables the synthesis of chiral enantioenriched N-Ts and N-Boc 1,2-mercaptoamines in good yields from the corresponding aziridines and bis(trimethylsilyl)sulfide. N-Protected and N-H unactivated aziridines are efficiently converted into the corresponding β-arylchalcogeno amines upon treatment with suitable arylchalcogenosilanes. The silicon-mediated ring opening reactions proceed with excellent regioselectivity and stereospecificity, allowing to access a wide array of synthetically and biologically valuable enantioenriched chalcogenoamines.

An overview of the preparation and synthetic potentialities of functionalized organoselenium and organotellurium compounds is presented. Various methods to generate selenated or tellurated nucleophiles are described. Focusing on the more recent developments, in this Perspective reactions of selenium and tellurium nucleophiles with heterocycles (O-, N-, and S-containing) of different ring size (three, four, five, and six-membered) to access a variety of organo-chalcogen compounds, bearing different functional groups, are covered. Their application in organic synthesis and asymmetric catalysis is also reported, along with some novel methodologies derived thereof.

6-O-l-Ascorbyl selenoesters, thioesters and telluroesters can be efficiently and directly prepared from l-ascorbic acid and suitable functionalised chalcogenoesters through lipase-catalysed transesterification reactions. Novel synthesised l-ascorbyl derivatives exhibited remarkable chain breaking and glutathione peroxidase-like activities.

Several new molecules with different thio-scaffolds were designed, synthesised, and evaluated biologically as inhibitors of Carbonic Anhydrases (CAIs). The structure-activity relationship analysis identified thioether derivatives, here reported, as a potent and selective CAIs against hCA II and hCA IX. High resolution X-ray structure of inhibitor bound hCA II revealed extensive interactions with the hydrophobic pocket of active site and provided molecular insight into the binding properties of these new inhibitors.

International audience; Glutathione peroxidase (GPx) regulates cellular peroxide levels through glutathione oxidation. GPx-mimics based on 4,5-disubstituted fluorene diselenides, their oxides, and ditellurides show catalytic activities consistent with conformational restriction about the dichalcogen bond.

Selenium-catalysed oxidations are highly sought after in organic synthesis and biology. Herein, we report our studies on the on water selenium mediated oxidation of anilines. In the presence of diphenyl diselenide or benzeneseleninic acid, anilines react with hydrogen peroxide, providing direct and selective access to nitroarenes. On the other hand, the use of selenium dioxide or sodium selenite leads to azoxyarenes. Careful mechanistic analysis and 77Se NMR studies revealed that only Se(IV) species, such as benzeneperoxyseleninic acid, are the active oxidants involved in the catalytic cycle operating in water and leading to nitroarenes. While other selenium-catalysed oxidations occurring in organic solvents have been recently demonstrated to proceed through Se(VI) key intermediates, the on water oxidation of anilines to nitroarenes does not. These findings shed new light on the multifaceted nature of organoselenium-catalysed transformations and open new directions to exploit selenium-based catalysis.

Carbonic anhydrases (CAs, E.C. 4.2.1.1) are metalloenzymes expressed on a variety of cell types. Their overexpression leads to serious pathologies, including cancer. The discovery of a series of selenolesters with high structural diversity as novel CA inhibitors is reported here. These compounds show remarkable in vitro inhibition against a panel of human CA isoforms such as hCA I, II, IX and XII. We observed that they undergo a CA mediated hydrolysis, releasing different active selenol fragments, which act as CA inhibitors. Notably, to the best of our knowledge, this is the first example of an enzyme with selenolesterase activity. In addition, X-ray crystallographic data support the proposed mechanism, proving selenolesters as novel pro-drug inhibitors with potential pharmacological applications.

The synthesis of sulfur- and selenium-containing isosters of triacyl glycerols is herein described. Regioselective fluoride-induced ring-opening reaction of suitable substituted thiiranes with bis(trimethyl)silyl selenide, followed by in situ S- and Se-acylation with fatty acid acyl chlorides, enables the one pot synthesis of mixed chalcogeno esters in good yield. The key step of this methodology is the functionalization of S-Si and Se-Si bonds of silyl chalcogenides, generated in situ under mild conditions. A related procedure for the synthesis of functionalized selenides, bearing two thiol ester and two ester moieties, was also developed through a fine tuning of the reaction conditions. The physico-chemical properties of these novel fatty acid chalcogeno esters have been investigated through DSC, SAXS, WAXS, FTIR and polarized optical microscopy, and compared to those of the common triglycerides in order to highlight the effect of the replacement of oxygen with other chalcogen elements in the polar head of the lipid.

A series of 2-thio- and 2-seleno-acetamides bearing the benzenesulfonamide moiety were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against different pathogenic bacteria such as the Vibrio cholerae (VchCA-&alpha, and VchCA-&beta, ), Burkholderia pseudomallei (BpsCA-&beta, and BpsCA-&gamma, ), Mycobacterium tuberculosis (Rv3723-&beta, ) and the Salmonella enterica serovar Typhimurium (StCA2-&beta, ). The molecules represent interesting leads worth developing as innovative antibacterial agents since they possess new mechanism of action and isoform selectivity preferentially against the bacterial expressed CAs. The identification of potent and selective inhibitors of bacterial CAs may lead to tools also useful for deciphering the physiological role(s) of such proteins.

The effect of eight potassium salts (KF, K3PO4, KOCN, K2CO3, KCl, K2SO4, KBr and KI) on glycerol carbonate (GC) is studied through NMR, DSC, solubility and ATR-FTIR experiments. From the solubility data, the main thermodynamic functions of solution and solvation are estimated, and the mean molal activity coefficients are calculated. The results suggest that the capability of an anion to establish hydrogen bonds with the solvent molecules (or behave as a base, as in the case of fluoride, phosphate, cyanate and carbonate) is the most important structural feature that determines its effects on the solvent structure. On the other hand potassium iodide behaves in an anomalous way, due to the large polarizability of the anion that can form non-electrostatic, van der Waals dispersive intermolecular interactions.

Isomeric fluorinated α‐bromoenones react with dinucleophilic β‐mercaptoalcohols in CH2Cl2 at room temperature in the presence of Et3N in a multistep process. Depending on the position of the CF3 group, different O,S‐heterocycles or non‐cyclic products were obtained. With 3‐bromo‐1,1,1‐trifluorobut‐3‐en‐2‐ones derivatives of 1,4‐oxathianes were formed, but isomeric 2‐bromo‐4,4,4‐trifluorobut‐2‐en‐1‐ones yielded 1,3‐oxathiolanes or non‐cyclic sulfides. The thia‐Michael addition is proposed as the initial step of the reaction, and the final heterocyclization is governed by the location of the CF3 group.

A series of tellurides was evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) carbonic anhydrase isoforms hCA I, II, IV, VII and IX, involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors. These compounds, which are the first tellurium-containing derivatives acting as inhibitors of carbonic anhydrase enzymes, showed effective inhibition against all isoforms investigated and some of them were selective for inhibiting the cytosolic or the membrane-bound CAs. Thus, these carbonic anhydrase inhibitors are interesting leads for the development of isoform-selective inhibitors.

1,2-Mercapto alcohols and 1,2-mercapto amines proved to be useful reagents towards Michael acceptors, such as α,β-ethylenic ketones, esters and nitriles leading to variously polyfunctionalized unsy...

A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for the inhibition of five human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, VII, and IX. These enzymes are involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors. The investigated compounds showed potent inhibitory action against hCA II, VII, and IX, in the low nanomolar range, thus making them of interest for the development of isoform-selective inhibitors and as candidates for biomedical applications.

Aliphatic and aromatic thiols react smoothly with dialkyl dicyanofumarates in CH2Cl2 at room temperature to give the corresponding disulfides in excellent yields. Aliphatic 1,2-, 1,3-, and 1,4-dithiols afford cyclic disulfides. Analogous reaction courses were observed starting with selenols, and the required diselenides were also formed in nearly quantitative yields. In all of the reactions, dialkyl dicyanosuccinates formed as a 1:1-mixture of diastereoisomers as the only other product. Cysteamine (2-mercaptoethylamine) behaved differently; the Michael addition of the primary amine group led to complete consumption of the dicyanofumarate, and the formation of the disulfide containing the enamine moiety occurred without the formation of dicyanosuccinate.

A series of benzenesulfonamides bearing selenourea moieties was obtained considering the ureido-sulfonamide SLC-0111, in Phase I clinical trials as antitumor agent, as a lead molecule. All compounds showed interesting inhibition potencies against the physiologically relevant human (h) carbonic anhydrase (hCAs, EC 4.2.1.1) isoforms I, II, IV, and IX. The most flexible analogues in the series 14–19 showed low nanomolar inhibition constants against hCA I, II, and IX. We assessed selected compounds on the in vitro antioxidant properties and binding modes and evaluated ex vivo human prostate (PC3), breast (MDA-MB-231), and colon-rectal (HT-29) cancer cell lines both in normoxic and hypoxic conditions.

We have synthetized a novel series of β-hydroxy tellurides bearing the benzenesulfonamide group as potent inhibitors of carbonic anhydrase enzymes. In a one pot procedure, we discovered both the ring opening reaction of the three-membered ring and the cleavage of the sulfonamide protecting moiety at the same time. Moreover, the first X-ray co-crystallographic structure of a β-hydroxy telluride derivative with hCA II is reported. The potent effects of these compounds against the tumor-associated hCA IX with low nanomolar constant inhibition values give the possibility to evaluate their activity in vitro using a breast cancer cell line (MDA-MB-231). Compounds 7e and 7g induced significant toxic effects against tumor cells after 48 h incubation in normoxic conditions killing over 50% of tumor cells at 3 μM, but their efficacy decreased in hypoxic conditions reaching the 50% of the tumor cell viability only at 30 μM. These unusual features make them interesting lead compounds to act as antitumor agents, not only as Carbonic Anhydrase IX inhibitors, but reasonably in different pathways, where hCA IX is not overexpressed.

A novel series of thio- and seleno-acetamides bearing benzenesulfonamide were synthetized and tested as human carbonic anhydrase inhibitors. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX/XII). Several derivatives showed potent inhibition activity in low nanomolar range such as 3a, 4a, 7a and 8a. Furthermore, based on the tail approach we explain the interesting and selective inhibition profile of compound such as 5a and 9a, which were more selective for hCA I, 9b which was selective for hCA II, 3f selective for hCA IX and finally, 3e and 4b selective for hCA XII, over the other three isoforms. They are interesting leads for the development of more effective and isoform-selective inhibitors.

A new methodology for the synthesis of small molecules containing the S-Se bond is reported. Aryl- and alkyl-selenols react smoothly with N-thiophthalimides to afford the corresponding selenenylsulfides through a clean SN2 path occurring at the sulfur atom. The reaction proceeds under very mild conditions in DMF in absence of catalysts for most of the substrates. The scope of the reaction was found to be broad, allowing a wide series of selenols and N-thiophtalimides to be efficiently employed in this procedure. Owing to the instability of the S-Se bond, selenenylsulfides exhibited a remarkable tendency to disproportionate to the corresponding symmetric diselenides and disulfides. Preliminary evaluation of the catalytic antioxidant properties of novel selenenylsulfides showed their behaviour as GPx mimics.

A new series of β-aminochalcogenides were designed and synthesized to identify new carbonic anhydrase activator (CAA) agents as novel tools for the management of several neurodegenerative and metabolic disorders which represent a clinical challenge without effective therapies available. Some β-aminoselenides and β-aminotellurides showed effective CA activating effects and a potent antioxidant activity. CAAs may have applications for memory therapy and CA deficiency syndromes.