Assuntos
Produtos Biológicos/química , Inibidores Enzimáticos/química , Manosidases/antagonistas & inibidores , Pirrolidinas/química , Alcaloides/química , Alcaloides/metabolismo , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Manosidases/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
The preparation of natural product-like polyhydroxylated pyrrolidine and piperidine alkaloids using a combination of solid- and solution-phase organic synthesis is described. The key intermediates, enantiopure five- or six-membered tri-O-benzyl cyclic nitrones, were efficiently prepared on solid support from accessible chiral furanosides and pyranosides, respectively. The substituent diversity was achieved by a diastereoselective addition of a variety of Grignard reagents to the cyclic nitrones in solution-phase synthesis. All reaction steps and work-up procedures were modified to allow the use of automated equipment. A 36-membered demonstration library with three diversity elements (core, configuration, and substituent) was prepared in good yield and purity.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Produtos Biológicos/química , Piperidinas/química , Pirrolidinas/química , Hidroxilação , Óxidos de Nitrogênio/síntese química , Óxidos de Nitrogênio/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Soluções , VolatilizaçãoRESUMO
Inspired by polyhydroxylated pyrrolidine alkaloid natural products, a 18-membered library of 2-aryl polyhydroxylated pyrrolidines has been efficiently prepared in two or three synthetic steps from the known chiral cyclic nitrones with high yield and purity and excellent stereoselectivity. The inhibitory activity of all these compounds against various glycosidase enzymes was evaluated. Interestingly, 15 and 19 show better inhibitory activities than radicamine A (20) and B (18) against alpha-glucosidases. The IC(50) values of 15 and 19 are 1.1 and 0.5 microM, respectively. In this study, we also discovered the substituent(s) on the aryl ring could affect the inhibition potency and selectivity against glycosidases.
