RESUMO
The SARS-CoV-2 life cycle is strictly dependent on the environmental redox state that influences both virus entry and replication. A reducing environment impairs the binding of the spike protein (S) to the angiotensin-converting enzyme 2 receptor (ACE2), while a highly oxidizing environment is thought to favor S interaction with ACE2. Moreover, SARS-CoV-2 interferes with redox homeostasis in infected cells to promote the oxidative folding of its own proteins. Here we demonstrate that synthetic low molecular weight (LMW) monothiol and dithiol compounds induce a redox switch in the S protein receptor binding domain (RBD) toward a more reduced state. Reactive cysteine residue profiling revealed that all the disulfides present in RBD are targets of the thiol compounds. The reduction of disulfides in RBD decreases the binding to ACE2 in a cell-free system as demonstrated by enzyme-linked immunosorbent and surface plasmon resonance (SPR) assays. Moreover, LMW thiols interfere with protein oxidative folding and the production of newly synthesized polypeptides in HEK293 cells expressing the S1 and RBD domain, respectively. Based on these results, we hypothesize that these thiol compounds impair both the binding of S protein to its cellular receptor during the early stage of viral infection, as well as viral protein folding/maturation and thus the formation of new viral mature particles. Indeed, all the tested molecules, although at different concentrations, efficiently inhibit both SARS-CoV-2 entry and replication in Vero E6 cells. LMW thiols may represent innovative anti-SARS-CoV-2 therapeutics acting directly on viral targets and indirectly by inhibiting cellular functions mandatory for viral replication.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Proteínas Virais/metabolismo , Células HEK293 , Ligação Proteica , Compostos de Sulfidrila/farmacologiaRESUMO
An unusual photoredox-catalyzed radical decarboxylative cyclization cascade reaction of γ,γ-dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to accomplish by more conventional procedures, enables the synthesis of ergot alkaloid precursors. In addition, this work describes a mild, environmentally friendly method to activate, reductively and oxidatively, natural carboxylic acids for decarboxylative C-C bond formation by exploiting the same photocatalyst.
RESUMO
The growing importance of structurally diverse and functionalized enantiomerically pure unnatural amino acids in the design of drugs, including peptides, has stimulated the development of new synthetic methods. This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone-based α-unnatural amino acids. The key to success was the design of a bifunctional primary amine-thiourea catalyst that combines H-bond-directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (>95 %â ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure α-amino-acid building blocks.
Assuntos
Aminoácidos , Cetonas , Alanina/análogos & derivados , Alquilação , Aminas/química , Aminoácidos/química , Catálise , Cetonas/química , Peptídeos/química , Estereoisomerismo , Tioureia/químicaRESUMO
We report the synthesis, chemical properties, and disulfide bond-reducing performance of a dithiol called NACMEAA, conceived as a hybrid of two biologically relevant thiols: cysteine and cysteamine. NACMEAA is conveniently prepared from inexpensive l-cystine in an efficient manner. As a nonvolatile, highly soluble, and neutral compound at physiological pH with the first thiol pKa value of 8.0, NACMEAA is reactive and user-friendly. We also demonstrate that NACMEAA reduces disulfide bonds in GSSG and lysozyme.
Assuntos
Cisteamina , Cisteína , Dissulfetos , Oxirredução , Substâncias Redutoras , Compostos de Sulfidrila , Tolueno/análogos & derivadosRESUMO
A practical and asymmetric synthesis of (R)-4-amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole, an enantiopure framework shared by most ergot alkaloids, was accomplished. Our method involves a Rh(i)-catalyzed 6-exo-trig intramolecular cyclization of an appropriate 4-pinacolboronic ester d-tryptophan aldehyde followed by the oxidation of the resulting secondary benzylic alcohol with a Cu(i)-ABNO catalyst and final deprotection under acidic conditions. This new procedure offers significant advantages over previous synthetic approaches, including brevity, mild reaction conditions, preservation of chiral integrity, and high overall yield and avoids the use of stoichiometric amounts of strongly basic and pyrophoric organometallic reagents.
RESUMO
The first total synthesis of natural (-)-clavicipitic acid from γ,γ-dimethylallyltryptophan (DMAT), its biosynthetic precursor, is described. This is done by regio- and chemoselective, remote, nondirected C(sp3)-H hydroxylation followed by aminocyclization. This study also features regio- and chemoselective Pd(0)-catalyzed linear prenylation at C4 of l-tryptophan boronic pinacol ester derivate, the latter obtained by a Lewis acid-promoted aziridine amino acid ring opening with 4-boronated indole. In addition, these results support the hypothesis that oxidative cyclization between amino acid nitrogen and the prenyl chain during clavicipitic acid biosynthesis can occur through the transient hydroxylated intermediate.
Assuntos
Carbono/química , Alcaloides de Claviceps/química , Alcaloides de Claviceps/síntese química , Hidrogênio/química , Triptofano/química , Catálise , Técnicas de Química Sintética , Ciclização , HidroxilaçãoRESUMO
The concise and convergent total syntheses of (+)- and (-)-Fumimycin have been achieved by taking advantage of strategies for the asymmetric aza-Friedel-Crafts reaction of a highly substituted hydroquinone and N-fumaryl ketimine generated from the corresponding dehydroalanine. The enantiomerically pure natural product and its enantiomer were prepared in seven steps and 22% overall yield by employing both enantiomers of a BINOL-derived chiral phosphoric acid (CPA) catalyst.
RESUMO
N-Acetyl ketimine generated from methyl 2-acetamidoacrylate was explored to develop an unprecedented domino aza-Friedel-Crafts/lactonization reaction with naphthols and phenols (including 5-hydroxyindoles). This novel method requires a catalyst loading of only 5 mol % of a phosphoric acid catalyst and provides a new series of 3-NHAc-naphtho- and benzofuranone derivatives bearing tetra-substituted stereogenic centers in moderate-to-good yields. The enantioselective variant using BINOL-derived phosphoric acids was also explored with 1-naphthol, providing the desired product with moderate enantioselectivities (up to 99:1 following recrystallization).
RESUMO
We present the coupling of primary and secondary benzyl alcohols with indoles to form 3-benzylated indoles and H2O that is catalyzed, for the first time, by a complex of earth-abundant iron. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, sustainability, high functional-group tolerance, and amenability to gram-scale synthesis. On the basis of the preliminary experimental observations, we propose that the reaction proceeds through a borrowing hydrogen process.
RESUMO
The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.
Assuntos
Alquilantes/química , Amino Álcoois/química , Indóis/química , Irídio/química , Compostos Organometálicos/química , Triptaminas/síntese química , Catálise , Estrutura Molecular , Triptaminas/químicaRESUMO
A new and short synthesis of racemic cis-clavicipitic acid was achieved by taking advantage of the double nucleophilic character of indole-4-pinacolboronic ester. Key to the success of the synthesis were an efficient and selective C-3 indole Friedel-Crafts alkylation and the development of an unprecedented intramolecular rhodium-catalyzed 1,2-addition of an aryl pinacolboronic ester to an unactivated imine.
Assuntos
Ácidos Borônicos/química , Ácidos Borônicos/síntese química , Alcaloides de Claviceps/síntese química , Iminas/química , Indóis/química , Indóis/síntese química , Ródio/química , Alquilação , Catálise , Ésteres , Estrutura Molecular , EstereoisomerismoRESUMO
The reaction of 3-substituted indoles with dehydroalanine (Dha) derivatives under Lewis acid-mediated conditions has been investigated. The formation of 2-substituted tryptophans is proposed to occur through a selective alkylative dearomatization-cyclization followed by C3- to C2-alkyl migration and rearomatization.
RESUMO
Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C-C, C-H, and C-N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N-H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.
RESUMO
The synthetic efforts toward the concise synthesis of (-)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C-N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (-)-epi-indolactam V and its enantiomer have been accomplished.
Assuntos
Indóis/síntese química , Lactamas/síntese química , Ciclização , Indóis/química , Lactamas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Fluorescent ligands are imperative to many facets of chemical biology and medicinal chemistry. Herein, we report the syntheses of two fluorescent melatonin-based derivatives as potential ligands of melatonin receptors. The two compounds, namely, 4-cyano and 4-formyl melatonin (4CN-MLT and 4CHO-MLT, respectively), which differ from melatonin by only two/three atoms that are very compact in size, were prepared using the selective C3-alkylation of indoles with N-acetyl ethanolamines involving the "borrowing hydrogen" strategy. These compounds exhibit absorption/emission spectra that are red-shifted from those of melatonin. Binding studies on two melatonin receptor subtypes showed that these derivatives have a modest affinity and selectivity ratio.
RESUMO
An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin.
Assuntos
Indóis/química , Triptaminas/síntese química , Alquilação , Estrutura Molecular , Estereoisomerismo , Triptaminas/químicaRESUMO
An efficient and practical approach for the synthesis of all four stereoisomers of the MT(2) melatonin receptor ligand 4-phenyl-2-propionamidotetralin (4-P-PDOT), each in enantiomerically pure form (ee > 99.9%), was developed. The strategy involved an optical resolution procedure of the key precursor (±)-4-phenyl-2-tetralone with the unusual resolving agent (S)-mandelamide, through the formation of four dihydronaphtalene-spiro-oxazolidin-4-one diastereomers. Interestingly, NMR experimental observations in combination with geometric calculations, provided unambiguous configuration assignments of all stereocenters of the key spiro stereoisomers. Cleavage of each single spiro diastereomer under acidic conditions gave enantiopure (R)- or (S)-4-phenyl-2-tetralone, which were then converted to each 4-P-PDOT single enantiomer by using stereoselective reactions.
Assuntos
Tetra-Hidronaftalenos/síntese química , Tetralonas/química , Ligantes , Conformação Molecular , Fenômenos Ópticos , Receptores de Melatonina/química , Estereoisomerismo , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologiaRESUMO
A small library of 8-substituted 9-deazaxanthines has been prepared by late-stage diversification of an 8-bromo-9-deazaxanthine. By utilizing palladium-catalyzed cross-coupling reactions a single key precursor can be transformed into a variety of 8-substituted-9-deazaxanthine compounds. Three key 8-bromo-9-deazaxanthine intermediates were efficiently prepared from commercially available 6-chlorouracil in six steps.
Assuntos
Compostos Aza/síntese química , Xantinas/síntese química , Compostos Aza/química , Catálise , Halogenação , Paládio/química , Uracila/análogos & derivados , Uracila/síntese química , Uracila/química , Xantinas/químicaRESUMO
A new, robust, and reliable method has been developed for the selective reductive N-alkylation of primary and secondary aromatic amines with some functionalized acetals using TFA/Et(3)SiH as a reagent combination. A variety of unsymmetrically substituted ethylenediamines can be synthesized in a one-pot procedure in excellent yields at room temperature. This new procedure offers significant advantages over previous synthetic approaches, including brevity, mild reaction conditions, excellent yields, and high functional group tolerance.
Assuntos
Acetais/química , Compostos de Anilina/química , Etilenodiaminas/química , Etilenodiaminas/síntese química , Silanos/química , Ácido Trifluoracético/química , Alquilação , Catálise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , OxirreduçãoRESUMO
The scope and limitations of using palladium-catalyzed cross-coupling reactions of diverse butyl metal species with two different 2-halopurines were evaluated. While tributylboranes reacted readily and regioselectively with both 2-chloro-6-dibenzylaminopurines and 2-iodo-6-chloropurines, all the other alkyl metal species were much less reactive and gave very poor yield and/or selectivity of the desired product. This protocol was applied to the synthesis of an important adenosine A(2A) receptor antagonist, ST1535.