RESUMO
RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.
Assuntos
Proteínas , Quimera de Direcionamento de Proteólise , RNA , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas/metabolismo , Proteólise , RNA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Aptâmeros de Nucleotídeos , Quimera de Direcionamento de Proteólise/químicaRESUMO
The 1,5-benzodiazepines are important skeletons frequently contained in medicinal chemistry. Herein, we described an unexpected tandem cyclization/transfer hydrogenation reaction for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The enolizable aryl aldehydes were chosen as substrates to react with symmetric and unsymmetric o-phenylenediamines. The unforeseen tandem reaction occurred among many possible latent side reactions under chiral phosphoric acid catalysis and affords the corresponding products in moderate yields and regioselectivities, good diastereoselectivities, and enantiomeric ratio (up to 99:1).
Assuntos
Benzodiazepinas , Substâncias Redutoras , Catálise , Ciclização , EstereoisomerismoRESUMO
N-Substituted tetrahydroquinoxalines (37 examples) were step-economically obtained in good yield (<97%) and ee (<99%) with readily available substrates. The reaction proceeds through an interesting regioselective Heyns rearrangement/enantioselective transfer hydrogenation in one pot. The substrate scope and the reaction mechanism were systematically investigated.