RESUMO
Aminoglycoside-2"-O-nucleotidyltransferase ANT(2")-Ia is an aminoglycoside resistance enzyme prevalent among Gram-negative bacteria, and is one of the most common determinants of enzyme-dependant aminoglycoside-resistance. The following report outlines the use of our recently described oxidopyrylium cycloaddition/ring-opening strategy in the synthesis and profiling of a library of synthetic α-hydroxytropolones against ANT(2")-Ia. In addition, we show that two of these synthetic constructs are capable of rescuing gentamicin activity against ANT-(2")-Ia-expressing bacteria.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Gentamicinas/farmacologia , Nucleotidiltransferases/antagonistas & inibidores , Tropolona/farmacologia , Modelos Químicos , Estrutura Molecular , Nucleotidiltransferases/metabolismo , Tropolona/químicaRESUMO
Methoxytropolones are useful scaffolds for therapeutic development because of their known biological activity and established value in the synthesis of α-hydroxytropolones. Upon treatment with triflic acid, a series of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones rearrange rapidly and cleanly to form methoxytropolones. Interestingly, bicycles that are derived from dimethyl acetylenedicarboxylate (R(2) = R(3) = CO2Me) instead form furans as the major product.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Furanos/síntese química , Mesilatos/química , Furanos/química , Estrutura Molecular , Tropolona/análogos & derivados , Tropolona/químicaRESUMO
α-Hydroxytropolones are a class of molecules with therapeutic potential against several human diseases. However, structure-activity relationship studies on these molecules have been limited due to a scarcity of efficient synthetic methods to access them. It is demonstrated herein that α-hydroxytropolones can be generated through a BCl(3)-mediated ring-opening/aromatization/demethylation process on 8-oxabicyclo[3.2.1]octenes. Used in conjunction with an improved method based on established oxidopyrylium dipolar cycloadditions, several polysubstituted α-hydroxytropolones can be accessed in three steps from readily available α-hydroxy-γ-pyrones.