RESUMO
Natural products form attractive leads for the development of chemical probes and drugs. The antibacterial lipopeptide Brabantamide A contains an unusual enol cyclocarbamate and we used this scaffold as inspiration for the synthesis of a panel of enol cyclocarbamate containing compounds. By equipping the scaffold with different groups, we identified structural features that are essential for antibacterial activity. Some of the derivatives block incorporation of hydroxycoumarin carboxylic acid-amino d-alanine into the newly synthesized peptidoglycan. Activity-based protein-profiling experiments revealed that the enol carbamates inhibit a specific subset of penicillin-binding proteins in B. subtilis and S. pneumoniae.
Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Relação Dose-Resposta a Droga , Cetonas/química , Cetonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The detection of protein lysine acylations remains a challenge due to lack of specific antibodies for acylations with various chain lengths. This problem can be addressed by metabolic labeling techniques using carboxylates with reactive functionalities. Subsequent chemoselective reactions with a complementary moiety connected to a detection tag enable the visualization and quantification of the protein lysine acylome. In this study, we present EDTA-Pd(II) as a novel catalyst for the oxidative Heck reaction on protein-bound alkenes, which allows employment of fully aqueous reaction conditions. We used this reaction to monitor histone lysine acylation in vitro after metabolic incorporation of olefinic carboxylates as chemical reporters.
Assuntos
Alcenos/metabolismo , Fenômenos Químicos , Histonas/metabolismo , Coloração e Rotulagem , Acetilação , Acilação , Animais , Anticorpos/metabolismo , Química Click , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Lisina/metabolismo , Camundongos , Oxirredução , Células RAW 264.7 , Solubilidade , ÁguaRESUMO
A sequence of oxidative cleavage/reductive amination/hydrogenolysis enables the preparation of N-substituted cis-3,5-diaminopiperidines from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to RNA-friendly fragments with a good chemical diversity.