RESUMO
Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core.
Assuntos
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Piridinas/farmacologia , Cromatografia Líquida de Alta Pressão , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Piridinas/químicaRESUMO
A new transition-metal-free, sodium metaperiodate (NaIO4)-mediated direct oxidation of methylarenes and benzylic bromides to the corresponding aromatic carboxylic acids is described. Under the same reaction conditions, benzylic alcohols are selectively oxidized to afford the corresponding aldehydes in good yields without undergoing overoxidation. Unprecedentedly, oxidation of benzyl bromide, toluene, or benzyl alcohol with NaIO4 underwent nuclear bromination followed by oxidation to give 4-bromobenzoic acid in 60-79% yields.
Assuntos
Álcoois/química , Derivados de Benzeno/química , Compostos de Benzil/química , Brometos/química , Cetonas/síntese química , Ácido Periódico/química , Cetonas/química , Estrutura Molecular , Oxirredução , Solventes/química , Estereoisomerismo , Água/químicaRESUMO
[reaction: see text] LiBr catalyzes efficiently the dihydroxylation of alkenes to afford syn and anti diols with excellent diastereoselectivity depending upon the use of NaIO(4) (30 mol %) or PhI(OAc)(2) (1 equiv), respectively, as the oxidants. The oxidation of non-benzylic halides has been achieved for the first time to afford the corresponding diols in excellent yields.