The diastereoselective synthesis of highly substituted pyrrolidines has been accomplished using a six‐carbon building block bearing carbon atoms with different reactivities. In this reaction, the ...building block acts a 1,3‐dipole and undergoes cyclization with imines formed in situ to give pyrrolidine derivatives.
Highly functionalized pyrrolidine and γ‐lactam derivatives were synthesized using a six‐carbon building block.
Gold‐catalysed generation of diol equivalents from epoxides and their intramolecular reaction with C≡C bonds to generate bicyclic ketals is presented. This reaction essentially involves the formation ...of an acetonide, which subsequently cyclises on the alkyne intramolecularly under gold catalysis conditions. This method could be extended to make optically pure bicyclic ketals. Deuterium incorporation experiments were carried out to ascertain the mechanism of the reaction.
Sequential activation of epoxide and alkyne moieties by a gold catalyst in acetone as solvent has been achieved. This strategyhas been employed to synthesise bicyclic ketals from epoxy alkynes.
Generation of diol equivalent from epoxide under gold catalysis for the intermolecular reaction with terminal alkynes to generate 1,3-dioxolane has been achieved. Oxo- and alkynophilicities of gold ...catalyst play important role in tandem to effect this transformation.
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Regioselective hydration of α‐alkynyl esters and ketones by using a cationic NHC–Au
I
catalyst results in β‐keto esters and β‐diketones, respectively. Controlled release of water in acetone by aldol ...self‐condensation under the reaction conditions makes acetone as better solvent than 1,4‐dioxane/water for the hydration of α‐alkynyl esters having sensitive ester moieties.
Regioselective hydration of α‐alkynyl esters and ketones by using a cationic NHC–AuI catalyst results in β‐keto esters and β‐diketones, respectively. Controlled release of water in acetone by aldol ...self‐condensation under the reaction conditions makes acetone as better solvent than 1,4‐dioxane/water for the hydration of α‐alkynyl esters having sensitive ester moieties.
A cationic NHC–AuI catalyst opens the way to regioselective hydration of α‐alkynyl esters and ketones to afford β‐keto esters and β‐diketones, respectively.
Regioselective hydration of alpha-alkynyl esters and ketones by using a cationic NHC-AuI catalyst results in beta-keto esters and beta-diketones, respectively. Controlled release of water in acetone ...by aldol self-condensation under the reaction conditions makes acetone as better solvent than 1,4-dioxane/water for the hydration of alpha-alkynyl esters having sensitive ester moieties.
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•Four TGK-series compounds related to homoserine γ-lactone were synthesized and fully characterized.•TGK-series compounds inhibit quorum sensing activity in a AHL-regulated E. coli ...Top 10 QS biosensor strain.•Modelling results revealed that the TGK-series compounds bind TraR protein with greater affinity than do 3OC6HSL.
Quorum sensing (QS) is a density-dependent form of cell-cell communication that triggers the functional coordination of cooperative behaviors such as the production of virulence factors and biofilm formation. Quorum quenching (QQ) refers to all processes involved in the disruption of QS and is regarded as a promising strategy for treating bacterial infections. Herein, four compounds with closely related chemical structures to homoserine γ-lactone were synthesized and fully characterized. The compounds are termed TGK-series compounds. These compounds were subsequently tested in their QS inhibition activity using an E. coli Top 10 QS biosensor strain, a GFP QS reporter, that probes the capacity of bacteria to detect their cognate autoinducer N-(3-oxohexanoyl)-homoserine lactone (3OC6HSL) substrate by means of a single intracellular protein LuxR. All TGK-series compounds were found to significantly inhibit the ability of bacteria to produce GFP but without exerting toxicity when applied at a concentration of 50 µM. In parallel, the interaction of TGK-series compounds with LuxR were studied by molecular docking simulations. These studies revealed that TGK-series compounds bound to the natural substrate N-(3-oxo-octanoyl)-l-homoserine lactone (OOHL) binding site and that the binding ability of the compounds with the TraR protein (a surrogate of LuxR) was even more favorable in comparison with the natural substrate. It was also uncovered that TGK-series compounds form stronger hydrophobic interactions with the TraR protein than 3OC6HSL does, thus providing a rationale for the enhancement of the QQ activity of the synthetic TGK-series compounds. This study will serve to guide future works aimed to design promising novel QS inhibitor candidates on a rational basis.
An enantioselective conjugate addition of 2‐acylimidazoles with nitroalkenes catalyzed by chiral‐at‐metal rhodium(III) complex under mild reaction conditions was developed, affording versatile ...γ‐nitro ketone skeletons in good yields with excellent enantioselectivities (up to >99% ee).
Superoxide radicals and other reactive oxygen species (ROS) are implicated in influenza A virus-induced inflammation. In this in vitro study, we evaluated the effects of TG6-44, a novel ...quinazolin-derived myeloperoxidase-specific ROS inhibitor, on influenza A virus (A/X31) infection using THP-1 lung monocytic cells and freshly isolated peripheral blood mononuclear cells (PBMC). TG6-44 significantly decreased A/X31-induced ROS and virus-induced inflammatory mediators in THP-1 cells (IL-6, IFN-gamma, MCP-1, TNF-alpha, MIP-1beta) and in human PBMC (IL-6, IL-8, TNF-alpha, MCP-1). Interestingly, TG6-44-treated THP-1 cells showed a decrease in percent cells expressing viral nucleoprotein, as well as a delay in translocation of viral nucleoprotein into the nucleus. Furthermore, in influenza A virus-infected cells, TG6-44 treatment led to suppression of virus-induced cell death as evidenced by decreased caspase-3 activation, decreased proportion of Annexin V.sup.+ PI.sup.+ cells, and increased Bcl-2 phosphorylation. Taken together, our results demonstrate the anti-inflammatory and anti-infective effects of TG6-44.
Abstract
Acute lung injury (ALI) and its more severe form acute respiratory distress (ARD) can result from infectious agents, including several strains of influenza A virus. Recent evidence suggests ...that excessive production of reactive oxygen species (ROS) is a major contributor to ALI caused by influenza. We evaluated the effects of TG6-44, a novel inhibitor of ROS production, in in vitro and in vivo models of influenza A virus infection. In vitro, using the monocytic cells (THP-1) and human PBMC infected with influenza A virus (X31), we found that TG6-44 treatment decreased virus-induced ROS and inflammatory markers in THP1 (IL6, IFNγ , MCP1, TNFα , MIP1β) and in PBMC (IL6, IL8, TNFα , MCP1). Also, in influenza A virus-infected THP1 cells, TG6-44 treatment led to a reduction in virus-induced cell death as evidenced by decreased Caspase3 activation, decreased proportion of Annexin V+/PI+ cells, and increased Bcl2 phosphorylation. Notably, TG6-44-treatment decreased the proportion of THP1 cells expressing viral nucleoprotein and delayed its translocation into the nucleus. Moreover, mice infected with a lethal dose of influenza A virus (PR8) and given TG6-44 had both reduced levels of virus-induced inflammatory markers in lungs and a higher survival rate compared to controls. Taken together, our results demonstrate anti-inflammatory and anti-infective effects of TG6-44, and suggest ROS-inhibitors as valuable adjunct therapeutics to reduce ALI/ARD caused by influenza A virus infection.
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