ABSTRACT
Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.
Subject(s)
Antiviral Agents , COVID-19 , Animals , Humans , Mice , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , SARS-CoV-2 , Kinetin/pharmacology , Inflammation/drug therapy , Nucleotides , Virus ReplicationABSTRACT
Alkylation of thiopurine derivatives with alcohols by the Mitsunobu reaction are reported in moderated to good yields. The method was applied in synthesis of number of thiopurine and thiopurine ribosides derivatives.
Subject(s)
Alcohols , Mercaptopurine , Alkylation , Magnetic Resonance SpectroscopyABSTRACT
New acylhydrazone-based palladacycles are prepared and evaluated as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.
ABSTRACT
A configurationally simple and robust semibatch apparatus for the in situ on-demand generation of anhydrous solutions of diazomethane (CH2N2) avoiding distillation methods is presented. Diazomethane is produced by base-mediated decomposition of commercially available Diazald within a semipermeable Teflon AF-2400 tubing and subsequently selectively separated from the tubing into a solvent- and substrate-filled flask (tube-in-flask reactor). Reactions with CH2N2 can therefore be performed directly in the flask without dangerous and labor-intensive purification operations or exposure of the operator to CH2N2. The reactor has been employed for the methylation of carboxylic acids, the synthesis of α-chloro ketones and pyrazoles, and palladium-catalyzed cyclopropanation reactions on laboratory scale. The implementation of in-line FTIR technology allowed monitoring of the CH2N2 generation and its consumption. In addition, larger scales (1.8 g diazomethane per hour) could be obtained via parallelization (numbering up) by simply wrapping several membrane tubings into the flask.
ABSTRACT
A straightforward and stereoselective synthesis of the alkaloid preussin is described starting from decanal and diethyl 3-diazo-2-oxopropylphosphonate. The key steps are an aza-Michael reaction from an α,ß-unsaturated diazoketone followed by a highly stereoselective Cu-catalyzed ylide formation and then a [1,2]-Stevens rearrangement. This strategy is feasible for extension to preussin analogues, demonstrating its utility for the rapid construction of all-cis-substituted pyrrolidines.
Subject(s)
Aldehydes/chemistry , Anisomycin/analogs & derivatives , Anisomycin/chemical synthesis , Anisomycin/chemistry , Molecular Structure , StereoisomerismABSTRACT
The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield).
Subject(s)
Amino Acids/chemistry , Anhydrides/chemistry , Anti-Retroviral Agents/chemical synthesis , Anti-Retroviral Agents/pharmacology , Diazomethane/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Hydrocarbons, Halogenated/chemical synthesis , Ketones/chemical synthesis , Anti-Retroviral Agents/chemistry , Diazomethane/chemistry , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Hydrocarbons, Halogenated/chemistry , Ketones/chemistry , Ketones/pharmacology , Molecular StructureABSTRACT
The coupling between cyclic and acyclic α-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide is achieved after two or three steps from these amino acid derivatives.
Subject(s)
Amino Acids/chemistry , Indolizines/chemical synthesis , Iodides/chemistry , Quinolizines/chemical synthesis , Samarium/chemistry , Acrylates/chemistry , Indolizines/chemistry , Molecular Structure , Quinolizines/chemistry , StereoisomerismABSTRACT
A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,ß-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.
Subject(s)
Alkaloids/chemistry , Alkaloids/chemical synthesis , Diazonium Compounds/chemistry , Indolizidines/chemistry , Indolizines/chemistry , Indolizines/chemical synthesis , Hydroxylation , Molecular Structure , StereoisomerismABSTRACT
A new method for the preparation of α,ß-unsaturated diazoketones from aldehydes and a Horner-Wadsworth-Emmons reagent is reported. The method was applied to the short synthesis of two substituted pyrrolidines.
