RESUMO
The electrophilic potential of diazirines has been utilized to obtain N-substituted diaziridines that are directly hydrolyzed to produce monosubstituted hydrazines. The hydrazines can undergo the Fisher process with enolizable carbonyls to yield multiple indole derivatives in moderate to high yields. The N-metalated diaziridine intermediates can undergo isomerization prior to electrophilic substitution, to form N,N-disubstituted hydrazones. The latter react with enolizable carbonyls to produce N-protected indole derivatives in a single step. This protocol was used to efficiently synthesize indomethacin, an anti-inflammatory drug.
RESUMO
Aminoacyl-tRNAs serve as amino acid donors in many reactions in addition to protein synthesis by the ribosome, including synthesis of the peptidoglycan network in the cell wall of bacterial pathogens. Synthesis of analogs of aminoacylated tRNAs is critical to further improve the mechanism of these reactions. Here we have described the synthesis of two non-isomerizable analogues of Ala-tRNA(Ala) containing an amide bond instead of the isomerizable ester that connects the amino acid with the terminal adenosine in the natural substrate. The non-isomerizable 2' and 3' regioisomers were not used as substrates by FemX(Wv), an alanyl-transferase essential for peptidoglycan synthesis, but inhibited this enzyme with IC50 of 5.8 and 5.5 µM, respectively.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Transferases de Grupos Nitrogenados/antagonistas & inibidores , RNA de Transferência de Alanina/síntese química , RNA de Transferência de Alanina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Modelos Moleculares , Conformação Molecular , Transferases de Grupos Nitrogenados/metabolismo , RNA de Transferência de Alanina/química , Relação Estrutura-AtividadeRESUMO
Even after more than 50 years since its discovery, the electrophilic potential of diazirines was never truly exploited. This longstanding limitation has been resolved. N-Monosubstituted diaziridines and hydrazones are obtained by nucleophilic additions. They release, under hydrolysis conditions, the corresponding monosubstituted hydrazines. The latter were converted to pyrazoles in high yields. The adamantanone can be recovered in 80-100% yields. This work demonstrates the potential of diazirines as electrophilic nitrogen sources with recoverable protecting groups.