RESUMO
Aminoglycoside-antibiotics represent important tools for studying the biological functions of RNA. An orthogonal protection strategy applied on 2-deoxystreptamine (2-DOS) revealed a series of key intermediates that enable its regioselective functionalization. Our approach allowed the construction of selected representatives of triazole-containing analogues with diverse molecular frameworks for biological evaluation regarding their binding and antibacterial potencies.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Triazóis/química , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Hexosaminas/síntese química , Hexosaminas/química , Hexosaminas/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Relação Estrutura-AtividadeAssuntos
Bactérias/efeitos dos fármacos , Éteres Cíclicos/síntese química , Éteres Cíclicos/farmacologia , Ribossomos/química , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Sítios de Ligação , Química Click , Éteres Cíclicos/química , Modelos Moleculares , Estrutura Molecular , Ribossomos/metabolismo , Compostos de Espiro/químicaRESUMO
The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.
Assuntos
Desenho de Fármacos , RNA Ribossômico/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Alcenos/química , Sequência de Bases , Glicosídeos/química , Hidroxilação , Cetonas/química , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/química , RNA Bacteriano/química , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , RNA Ribossômico/química , RNA Ribossômico/genética , Compostos de Espiro/síntese química , Eletricidade EstáticaRESUMO
Previous work from our group described the synthesis and biological evaluation of new rigid, 6,6- and 6,7-spiro aminoglycosidic scaffolds targeting the bacterial ribosome. Herein we describe an improved synthetic protocol for their construction, and extend our study by further amino-functionalization of their 6,7-spiro analogs. The synthetic strategy, preparation and evaluation of some representative examples are reported.
