RESUMEN
A wide range of 3-selenylindoles were synthesized via an eco-friendly approach that uses Oxone® as the oxidant in the presence of a catalytic amount of iodine. This mild and economical protocol showed broad functional group tolerance and operational simplicity. A series of novel selenylindoles bearing a benzenesulfonamide moiety were also synthesized and evaluated as carbonic anhydrase inhibitors of the human (h) isoforms hCa I, II, IX, and XII, which are involved in pathologies such as glaucoma and cancer. Several derivatives showed excellent inhibitory activity towards these isoforms in the nanomolar range, lower than that shown by acetazolamide.
Asunto(s)
Bencenosulfonamidas , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Indoles , Yodo , Oxidación-Reducción , Sulfonamidas , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Humanos , Anhidrasas Carbónicas/metabolismo , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Yodo/química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
PhSeZnCl, which is also known as Santi's reagent, can catalyze the reduction of hydrogen peroxide by thiols with a GPx-like mechanism. In this work, the first step of this catalytic cycle, i.e., the reduction of H2O2 by PhSeZnCl, is investigated in silico using state-of-the-art density functional theory calculations. Then, the role of the metal is evaluated by replacing Zn with its group 12 siblings (Cd and Hg). The thermodynamic and kinetic factors favoring Zn are elucidated. Furthermore, the role of the halogen is considered by replacing Cl with Br in all three metal compounds, and this turns out to be negligible. Finally, the overall GPx-like mechanism of PhSeZnCl and PhSeZnBr is discussed by evaluating the energetics of the mechanistic path leading to the disulfide product.
RESUMEN
This review describes, from a chemical point of view, the top "blockbuster" small molecule orphan drugs according to their forecasted sales in 2026. Orphan drugs are intended for the treatment, prevention, or diagnosis of a rare disease or condition. These molecules are mostly addressed to the treatment of rare forms of cancer. The respiratory and central nervous systems represent other common therapeutic subcategories. This work will show how the orphan drugs market has significantly grown and will account for a consistent part of prescriptions by 2026.
Asunto(s)
Neoplasias , Producción de Medicamentos sin Interés Comercial , Humanos , Enfermedades Raras/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , ComercioRESUMEN
A new protocol for the synthesis of N-vinyl azoles using vinyl selenones and azoles in the presence of potassium hydroxide was developed. This reaction proceeded under mild and transition metal-free conditions through an addition/elimination cascade process. Both aromatic and aliphatic vinyl selenones and various mono-, bi- and tri-cyclic azoles can be tolerated and give terminal N-vinyl azoles in moderate to high yields. A plausible mechanism is also proposed.
RESUMEN
Here we report the reaction in the biphasic system of the in situ prepared selenols and thiols with 1,4-androstadiene-3,17-dione (1) or prednisone acetate (2) having α,ß-unsaturated ketone as an electrophilic functionalization. The Michael-type addition reaction resulted to be chemo- and stereoselective, affording a series of novel steroidal selenides and sulfides. This is an example of a one-step, eco-friendly process that bypasses some of the main concerns connected with the bad smell and the toxicity of these seleno- and thio-reagents. Furthermore, we demonstrated that the proposed methodology offers the possibility to prepare libraries of steroids variously and selectively decorated with different organochalcogen moieties at the C1 position starting from 1,4-androstadienic skeletons and leaving unaltered the C4-C5 unsaturation. Based on the data reported in the literature the introduction of an organoselenium or an organosulfur moiety in a steroid could provide new interesting pharmaceutically active entities exerting anticancer and antimicrobial activities. In this optic, new synthetic strategies to efficiently prepare this class of compounds could be strongly desirable.
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Cetonas , Esteroides , Compuestos de Sulfhidrilo , Sulfuros , ZincRESUMEN
This review describes the recent Food and Drug Administration (FDA)-approved drugs (in the year 2021) containing at least one halogen atom (covalently bound). The structures proposed throughout this work are grouped according to their therapeutical use. Their synthesis is presented as well. The number of halogenated molecules that are reaching the market is regularly preserved, and 14 of the 50 molecules approved by the FDA in the last year contain halogens. This underlines the emergent role of halogens and, in particular, of fluorine and chlorine in the preparation of drugs for the treatment of several diseases such as viral infections, several types of cancer, cardiovascular disease, multiple sclerosis, migraine and inflammatory diseases such as vasculitis.
Asunto(s)
HalógenosRESUMEN
A three-component synthesis of novel spirooxindole-tetrahydropyrrolizines from secondary α-aminoacids, isatins and vinyl selenones has been disclosed. Products were formed in good yields and high diastereoselectivity by 1,3-dipolar cycloaddition of in situ generated azomethine ylides followed by spontaneous elimination of benzeneseleninic acid. Good regioselectivities with aryl substituted vinyl selenones were observed. The method showed good functional group tolerance, providing a direct approach to biologically relevant spirooxindoles under mild reaction conditions.
RESUMEN
The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 µM and 8 µM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.
Asunto(s)
Antivirales/química , Quercetina/química , SARS-CoV-2/metabolismo , Selenio/química , Proteínas de la Matriz Viral/antagonistas & inhibidores , Animales , Antivirales/metabolismo , Antivirales/farmacología , Sitios de Unión , COVID-19/patología , COVID-19/virología , Dominio Catalítico , Chlorocebus aethiops , Humanos , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Quercetina/metabolismo , Quercetina/farmacología , SARS-CoV-2/aislamiento & purificación , Selenio/metabolismo , Células Vero , Proteínas de la Matriz Viral/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
The selenophene derivatives are an important class of selenium-based heterocyclics. These compounds play an important role in prospecting new drugs, as well as in the development of new light-emitting materials. During the last years, several methods have been emerging to access the selenophene scaffold, employing a diversity of cyclization-based synthetic strategies, involving specific reaction partners and particularities. This review presents a comprehensive discussion on the recent advances in the synthesis of selenophene-based compounds, starting from different precursors, highlighting the main differences, the advantages, and limitations among them.
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Técnicas de Química Sintética , Compuestos Heterocíclicos/síntesis química , Compuestos de Organoselenio/síntesis química , Técnicas de Química Sintética/métodos , Técnicas de Química Sintética/tendencias , Ciclización , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Estructura Molecular , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacologíaRESUMEN
A novel approach to regioselectively substituted and stereoselectively α-trifluoromethylated tryptamines is reported based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)- or (S)-tert-butanesulfinyltrifluoroacetaldimine. Boc- and sulfinylamido-protected α-trifluoromethyltryptamines are obtained in 60-70% yield and 85/15 dr by just heating equimolar amounts of the two reaction partners at 80-90 °C for 2-3 h without a solvent. The absolute configuration of the amino α-carbon has been assigned based on the vibrational circular dichroism (VCD) spectral analysis. The two protecting group can be chemoselectively removed allowing further regio- and stereoselective elaboration of the ene products to various biologically interesting compounds.
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Alquenos/química , Iminas/química , Triptaminas/química , EstereoisomerismoRESUMEN
In 2017, the 200th anniversary of the discovery of selenium was celebrated. In 1817, the Swedish chemists, Berzelius and Gahn, on roasting 200 kg of sulfur from a pyrite from the Falun mine, obtained about 3 g of a precipitate that they first wrongly identified as tellurium. Berzelius doubted this result and repeated the analysis some months later realizing that a new element was in his hands and he named this element Selenium (Greek: Selene, moon) in consideration of its resemblance to Tellurium (Latin: Tellus, earth). Several events were organized in the year for this special celebration and this Special Issue would like to be an additional contribution to the success of a research that, especially during the last decades, rapidly grew in different fields: synthesis, medicinal chemistry, biology, material, and environment. These studies are strongly characterized by multi- and interdisciplinary connections, and, for this reason, we collected here contributions coming from different areas and disciplines, not exclusively synthetic organic chemistry.
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Compuestos de Selenio/química , Selenio/química , Catálisis , Tecnología Química Verde/métodos , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Selenio/historia , Compuestos de Selenio/historiaRESUMEN
Herein we describe the synthesis of organoselanyl and organotellanyl alkynes by the addition of lithium alkynylchalcogenolate (Se and Te) to tosyl solketal, easily obtained from glycerol. The alkynylchalcogenolate anions were generated in situ and added to tosyl solketal in short reaction times, furnishing in all cases the respective products of substitution in good yields. Some of the prepared compounds were deprotected using an acidic resin to afford new water-soluble 3-organotellanylpropane-1,2-diols. The synthetic versatility of the new chalcogenyl alkynes was demonstrated in the iodocyclization of 2,2-dimethyl-1,3-dioxolanylmethyl(2-methoxyphenylethynyl)selane 3f, which afforded 3-iodo-2-(2,2-dimethyl-1,3-dioxolanylmethyl) selenanylbenzo[b]furan in 85% yield, opening a new way to access water-soluble Se-functionalized benzo[b]furanes.
Asunto(s)
Alquinos/química , Glicerol/química , Compuestos Organometálicos/química , Compuestos de Organoselenio/química , Química Orgánica , Fenómenos Químicos OrgánicosRESUMEN
Even if water is the natural environment for bioorganic reactions, its use in organic chemistry is often severely limited by the high insolubility of the organic derivatives. In this review, we introduce some examples of the use of water to perform organoselenium chemistry. We mainly discuss the advantages of this medium when the recyclability is demonstrated and when the water can control the selectivity of a reaction or enhance the reaction rate.
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Compuestos de Organoselenio/química , Agua/química , Catálisis , Química Orgánica/métodosRESUMEN
The stoichiometric use of hydrogen peroxide in the presence of a selenium-containing catalyst in water is here reported as a new ecofriendly protocol for the synthesis of variously functionalized carboxylic acids and esters. The method affords the desired products in good to excellent yields under very mild conditions starting directly from commercially available aldehydes. Using benzaldehyde as a prototype the gram scale synthesis of benzoic acid is described, in which the aqueous medium and the catalyst could be recycled at last five times while achieving an 87% overall yield.
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Aldehídos/química , Oxidación-Reducción , Selenio/química , Ácidos Carboxílicos/síntesis química , Catálisis , Ésteres/síntesis química , Tecnología Química VerdeRESUMEN
Pseudo-oligosaccharides have attracted much interest as scaffolds for the synthesis of sugar mimics endowed with very similar biological properties but structurally and synthetically simpler than their natural counterparts. Herein, the synthesis of pseudo-oligosaccharides using the cross-metathesis reaction between distinct sugar-olefins followed by intramolecular selenocyclization of the obtained heterodimer as key steps is first investigated. This methodology has been then applied to the preparation of structural analogues of the trisaccharide repeating unit from Streptococcus pneumoniae 19F. The inhibition abilities of the synthetic molecules were evaluated by a competitive ELISA assay using a rabbit polyclonal anti-19F serum.
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Compuestos de Organoselenio/química , Polisacáridos/síntesis química , Streptococcus pneumoniae/química , Ciclización , Estructura Molecular , Polisacáridos/químicaRESUMEN
This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug.
RESUMEN
The reactions of readily available vinyl selenones with enantiopure 1,2-diols, N-protected-1,2-aminoalcohols, and diamines gave substituted enantiopure 1,4-dioxanes, morpholines, and piperazines, respectively, in good to excellent yields. The same procedure was extended to the synthesis of thiomorpholine, benzodiazepine, and benzoxazepine. The reactions proceeded in one pot, in the presence of base, through a simple and novel application of the Michael-initiated, ring-closure (MIRC) reactions. The formed heterocycles constitute a framework that is observed in a large number of pharmaceutical compounds.
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Amino Alcoholes/química , Diaminas/química , Dioxanos/síntesis química , Morfolinas/síntesis química , Piperazinas/síntesis química , Compuestos de Vinilo/química , Dioxanos/química , Estructura Molecular , Morfolinas/química , Piperazinas/química , EstereoisomerismoRESUMEN
The reaction of readily available (5R)-5-but-3-en-1-ylpyrrolidin-2-one with aryl bromides, chlorides, or triflates in the presence of Pd(2)(dba)(3), Xphos, and Cs(2)CO(3) in 1,4-dioxane at 120 degrees C affords (5R,7aR)-5-aryl hexahydropyrrolizidin-3-ones in good to high yields through a diastereoselective carboamination reaction. Aryl iodides are less successful substrates than bromides and chlorides.
Asunto(s)
Paladio/química , Pirrolidinas/síntesis química , Pirrolidinonas/síntesis química , Aminación , Catálisis , Pirrolidinas/química , Pirrolidinonas/química , EstereoisomerismoRESUMEN
In the last decades, organoselenium compounds gained interest due to their important biological features. However, the lack of solubility, which characterizes most of them, makes their actual clinical exploitability a hard to reach goal. Selenosugars, with their intrinsic polarity, do not suffer from this issue and as a result, they can be conceived as a useful alternative. The aim of this review is to provide basic knowledge of the synthetic aspects of selenosugars, selenonium salts, selenoglycosides, and selenonucleotides. Their biological properties will be briefly detailed. Of course, it will not be a comprehensive dissertation but an analysis of what the authors think is the cream of the crop of this interesting research topic.
RESUMEN
Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity.