RÉSUMÉ
Seleninic acids and their precursors are well-known oxygen-transfer agents that can catalyze several oxidations with H2O2 as the final oxidant. Until very recently, the Se(iv) "peroxyseleninic" acid species has been considered the only plausible catalytic oxidant. Conversely, in 2020, the involvement of Se(vi) "peroxyselenonic" acid has been proposed for the selenium mediated epoxidation of alkenes. In this work, we theoretically probe different mechanisms of H2O2 activation and of Se(iv) to Se(vi) interconversion. In addition, we investigate through a combined theoretical (DFT) and experimental approach the mechanistic steps leading to the oxidation of aniline to nitrobenzene, when Se(iv) seleninic acid or Se(vi) selenonic acids are used as catalysts and H2O2 as the oxidant. This process encompasses three subsequent organoselenium mediated oxidations by H2O2. These results provide a mechanistic explanation of the advantages and disadvantages of both oxidation states (iv and vi) in the different stages of catalytic oxygen-transfer reactions: hydrogen peroxide activation and actual substrate oxidation. While the Se(vi) "peroxyselenonic" acid is found to be a better oxidant, the privileged role of "peroxyseleninic" acid as the main active species is assessed and its origin is identified in the lower catalyst-distortion that seleninic acid undergoes when activating H2O2. Conversely, the higher catalyst-distortion that characterizes the reaction of selenonic acid with H2O2 supports an inactivating role of Se(iv) to Se(vi) interconversion.
RÉSUMÉ
Novel chalcogen-containing amides and esters bearing the benzenesulfonamide moiety have been synthesised upon nucleophilic conjugate addition of thiols and selenols to suitable electron-deficient alkenes. The activity of the synthesised compounds as Carbonic Anhydrases inhibitors has been investigated inâ vitro and the inhibition mechanism has been elucidated by X-rays studies.
RÉSUMÉ
The absolute configuration of three chiral eugenol derivatives was assigned by a multi-step methodology based on enantioselective HPLC combined with spectroscopic and theoretical calculations. Milligram amounts of enantiopure forms used for stereochemical characterization were isolated by HPLC on the immobilized amylose-based chiral stationary phase Chiralpak IG using normal phase elution conditions. The absolute configuration was indirectly determined for one of the three compounds by 1H NMR via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (Mosher's acid). Comparison of the experimental and predicted electronic circular dichroism spectra confirmed the stereochemical assignment by Mosher's method and extended the absolute configuration assignment to two other chiral compounds.
RÉSUMÉ
INTRODUCTION: Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role in the onset and progression of several diseases, including cancer, immune-related and neurodegenerative disease, viral and parasitic infections, cysteine proteases represent an attractive drug target for the development of therapeutic tools. AREAS COVERED: Recent scientific and patent literature focusing on the design and study of cysteine protease inhibitors with potential therapeutic application has been reviewed. EXPERT OPINION: The discovery of a number of effective structurally diverse cysteine protease inhibitors opened up new challenges and opportunities for the development of therapeutic tools. Mechanistic studies and the availability of X-ray crystal structures of some proteases, alone and in complex with inhibitors, provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors as preclinical candidates for the treatment of different diseases.
Sujet(s)
Cysteine proteases , Maladies neurodégénératives , Humains , Inhibiteurs de la cystéine protéinase/pharmacologie , Inhibiteurs de la cystéine protéinase/composition chimique , Brevets comme sujet , Inhibiteurs de protéases/pharmacologie , Antiviraux/pharmacologieRÉSUMÉ
The implementation of innovative approaches is crucial in an ongoing endeavor to mitigate the impact of COVID-19 pandemic. The present study examines the strategic application of the SARS-CoV-2 Main Protease (Mpro) as a prospective instrument in the repertoire to combat the virus. The cloning, expression, and purification of Mpro, which plays a critical role in the viral life cycle, through heterologous expression in Escherichia coli in a completely soluble form produced an active enzyme. The hydrolysis of a specific substrate peptide comprising a six-amino-acid sequence (TSAVLQ) linked to a p-nitroaniline (pNA) fragment together with the use of a fluorogenic substrate allowed us to determine effective inhibitors incorporating selenium moieties, such as benzoselenoates and carbamoselenoates. The new inhibitors revealed their potential to proficiently inhibit Mpro with IC50-s in the low micromolar range. Our study contributes to the development of a new class of protease inhibitors targeting Mpro, ultimately strengthening the antiviral arsenal against COVID-19 and possibly, related coronaviruses.
Sujet(s)
COVID-19 , Protéases 3C des coronavirus , Sélénium , Humains , Sélénium/pharmacologie , Pandémies , Études prospectives , SARS-CoV-2 , Escherichia coliRÉSUMÉ
Chromatographic enantioseparation on polysaccharide-based chiral stationary phases has undergone explosive development over the last three decades as a method for separating the enantiomers of chiral compounds on an analytical and preparative scale. In this context, understanding the nature of the intermolecular interactions involved in retention and recognition processes is an interesting scientific challenge. In the present study, three eugenol derivatives were used as chiral references to elucidate some unexplored aspects of the enantioselective and retention properties of the Chiralpak IG-U chiral stationary phase based on amylose-tris(3-chloro-5-methylphenylcarbamate). The performance of the ultra-high performance liquid chromatography chiral packing material Chiralpak IG-U was evaluated using a two-step approach. First, binary mixtures containing variable proportions of alcohol (ethanol or 2-propanol) in n-hexane were used as mobile phases and the retention factors were recorded at three different temperatures. A rational analysis of this set of chromatographic data shows the leading role played by hydrogen bond between the OH group linked to the stereogenic centre of the analytes and the active sites of the chiral chromatographic material in obtaining a high degree of enantioseparation. The retention factors were then plotted against the percentage of alcohol modifiers to obtain retention maps with a non-linear performance trend with correlation factors >0.9990. The proposed retention map model was used to extrapolate and describe virtual chiral recognition of chiral analytes on the Chiralpak IG-U chiral stationary phase under extreme elution conditions with expected run times of hundreds or thousands of years. The presented virtual chiral recognition approach is based on a generic concept and therefore opens new possibilities for understanding the performance of other polysaccharide-based chiral stationary phases.
RÉSUMÉ
The antimicrobial properties of one of the most important secondary metabolites, Eugenol (EU), inspired us to design and synthesize three different series of derivatives enhancing its parent compound's anti-Helicobacter pylori activity. Thus, we prepared semisynthetic derivatives through (A) diazo aryl functionalization, (B) derivatization of the hydroxy group of EU, and (C) elongation of the allyl radical by incorporating a chalcogen atom. The antibacterial evaluation was performed on the reference NCTC 11637 strain and on three drug-resistant clinical isolates and the minimal inhibitory and bactericidal concentrations (MICs and MBCs) highlight the role of chalcogens in enhancing the antimicrobial activity (less than 4 µg/mL for some compounds) of the EU scaffold (32-64 µg/mL).
RÉSUMÉ
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.
Sujet(s)
Antinéoplasiques , Carbonic anhydrases , Humains , Relation structure-activité , Inhibiteurs de l'anhydrase carbonique/pharmacologie , Carbonic anhydrases/métabolisme , Antinéoplasiques/pharmacologie , Antibactériens/pharmacologie , Carbonic anhydrase IX/métabolisme , Structure moléculaireRÉSUMÉ
A scalable and operationally simple on water seleno-mediated reduction of nitroarenes to the respective aryl amines with NaBH4 is described. The reaction proceeds under transition metal-free conditions and is promoted by the formation of Na2 Se, which is the effective reducing agent involved in the mechanism. This mechanistic information enabled the development of a mild NaBH4 -free protocol for the selective reduction of nitro derivatives bearing labile moieties, including nitrocarbonyl compounds. The selenium-containing aqueous phase can be successfully reused up to four reduction cycles, thus further improving the efficiency of the protocol disclosed.
RÉSUMÉ
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 ß-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, ß-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.
Sujet(s)
Carbonic anhydrases , Humains , Carbonic anhydrases/métabolisme , Amines/pharmacologie , Monoamine oxidase , Isoformes de protéines , Inhibiteurs de l'anhydrase carbonique/composition chimique , Relation structure-activité , Carbonic anhydrase IX/métabolismeRÉSUMÉ
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- is a new zinc-binding group (ZBG) for metalloenzymes possessing zinc ions at their active site. The substitution pattern on aromatic ring of the benzoselenoates is the crucial structural element influencing selectivity towards various isoforms. We elucidated the binding mode of benzoselenoates to hCA I and hCA II by using X-ray crystallography. The negatively charged selenium atom from the new ZBG was observed coordinated to the zinc ion from the CA active site at a distance of 2.30-2.40 Å from it. Overall, these data might be useful for the development of new inhibitors with higher selectivity and efficacy for various hCAs.
Sujet(s)
Inhibiteurs de l'anhydrase carbonique , Carbonic anhydrases , Inhibiteurs de l'anhydrase carbonique/composition chimique , Inhibiteurs de l'anhydrase carbonique/pharmacologie , Carbonic anhydrases/métabolisme , Domaine catalytique , Humains , Isoformes de protéines/métabolisme , Relation structure-activitéRÉSUMÉ
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 hCAâ 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.
Sujet(s)
Carbonic anhydrases , Promédicaments , Antigènes néoplasiques/métabolisme , Carbonic anhydrase II , Carbonic anhydrase IX/métabolisme , Inhibiteurs de l'anhydrase carbonique/composition chimique , Carbonic anhydrases/métabolisme , Humains , Structure moléculaire , Promédicaments/pharmacologie , Relation structure-activitéRÉSUMÉ
Selenium is an essential microelement required for a number of biological functions. Selenium-and more specifically the amino acid selenocysteine-is present in at least 25 human selenoproteins involved in a wide variety of essential biological functions, ranging from the regulation of reactive oxygen species (ROS) concentration to the biosynthesis of hormones. These processes also play a central role in preventing and modulating the clinical outcome of several diseases, including cancer, diabetes, Alzheimer's disease, mental disorders, cardiovascular disorders, fertility impairments, inflammation, and infections (including SARS-CoV-2). Over the past years, a number of studies focusing on the relationship between selenium and such pathologies have been reported. Generally, an adequate selenium nutritional state-and in some cases selenium supplementation-have been related to improved prognostic outcome and reduced risk of developing several diseases. On the other hand, supra-nutritional levels might have adverse effects. The results of recent studies focusing on these topics are summarized and discussed in this review, with particular emphasis on advances achieved in the last decade.
RÉSUMÉ
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.
RÉSUMÉ
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.
Sujet(s)
Antinéoplasiques/pharmacologie , Inhibiteurs de l'anhydrase carbonique/pharmacologie , Carbonic anhydrases/métabolisme , Chalcogènes/pharmacologie , Cisplatine/pharmacologie , Névralgie/traitement médicamenteux , Administration par voie orale , Animaux , Antinéoplasiques/administration et posologie , Antinéoplasiques/composition chimique , Inhibiteurs de l'anhydrase carbonique/administration et posologie , Inhibiteurs de l'anhydrase carbonique/composition chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Chalcogènes/synthèse chimique , Chalcogènes/composition chimique , Cisplatine/administration et posologie , Cisplatine/composition chimique , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Isoenzymes/antagonistes et inhibiteurs , Isoenzymes/métabolisme , Cellules MCF-7 , Mâle , Souris , Structure moléculaire , Névralgie/induit chimiquement , Oxaliplatine , Stress oxydatif/effets des médicaments et des substances chimiques , Mesure de la douleur , Relation structure-activitéRÉSUMÉ
Differently substituted ß-hydroxy- and ß-amino dialkyl and alkyl-aryl tellurides and selenides have been prepared through ring-opening reactions of epoxides and aziridines with selenium- or tellurium-centered nucleophiles. The antioxidant properties and the cytotoxicity of such compounds have been investigated on normal human dermal fibroblasts. Most of the studied compounds exhibited a low cytotoxicity and a number of them proved to be non-toxic, not showing any effect on cell viability even at the highest concentration used (100 µM). The obtained results showed a significant antioxidant potential of the selected organotellurium compounds, particularly evident under conditions of exogenously induced oxidative stress. The antioxidant activity of selenium-containing analogues of active tellurides has also been evaluated on cells, highlighting that the replacement of Se with Te brought about a significant increase in the peroxidase activity.
Sujet(s)
Antioxydants/pharmacologie , Chalcogènes/pharmacologie , Dithiothréitol/métabolisme , Antioxydants/synthèse chimique , Antioxydants/composition chimique , Cellules cultivées , Chalcogènes/synthèse chimique , Chalcogènes/composition chimique , Relation dose-effet des médicaments , Humains , Structure moléculaire , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Inhibiteurs de l'anhydrase carbonique/pharmacologie , Carbonic anhydrases/métabolisme , Esterases/métabolisme , Composés du sélénium/pharmacologie , Carbonic anhydrase II/composition chimique , Carbonic anhydrases/composition chimique , Cristallographie aux rayons X , Esterases/composition chimique , Esters , Humains , Hydrolyse , Isoenzymes , Spectroscopie par résonance magnétique , Promédicaments , Composés du sélénium/métabolismeRÉSUMÉ
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-α and VchCA-ß), Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ), Mycobacterium tuberculosis (Rv3723-ß) and the Salmonella enterica serovar Typhimurium (StCA2-ß). 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.
Sujet(s)
Acétamides/composition chimique , Bactéries/effets des médicaments et des substances chimiques , Bactéries/pathogénicité , Infections bactériennes/traitement médicamenteux , Inhibiteurs de l'anhydrase carbonique/pharmacologie , Carbonic anhydrases/composition chimique , Sulfonamides/composition chimique , Bactéries/enzymologie , Infections bactériennes/microbiologie , Inhibiteurs de l'anhydrase carbonique/composition chimique , Relation dose-effet des médicaments , Humains , Structure moléculaire , Composés organiques du sélénium/composition chimique , Relation structure-activité , Thiols/composition chimique , Sulfonamides/pharmacologie ,RÉSUMÉ
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.
RÉSUMÉ
Functionalised aliphatic selenols, straightforwardly obtained through ring-opening reaction of strained heterocycles, represent a new chemotype acting as carbonic anhydrase inhibitors (CAIs). These compounds showed pronounced selectivity towards the cytosolic human (h) isoforms such as the hCA I, II and VII rather than the membrane tumor associate hCA IX. In addition, we reported for the first time the X-ray crystal structure of an aliphatic selenol bound to the hCA I zinc ion, and that afforded the opportunity to decipher in detail the inhibition mechanism underpinning such a new class of CAIs. In this context selenols are interesting leads worth developing for the obtainment of novel and efficient selective CAIs potentially useful for the management of a variety of diseases including glaucoma, retinitis pigmentosa, epilepsy and arthritis.