RESUMO
Systematic alanine scanning of the linear peptide bisebromoamide (BBA), isolated from a marine cyanobacterium, was enabled by solid-phase peptide synthesis of thiazole analogues. The analogues have comparable cytotoxicity (nanomolar) to that of BBA, and cellular morphology assays indicated that they target the actin cytoskeleton. Pathway inhibition in human colon tumour (HCT116) cells was explored by reverse phase protein array (RPPA) analysis, which showed a dose-dependent response in IRS-1 expression. Alanine scanning reveals a structural dependence to the cytotoxicity, actin targeting and pathway inhibition, and allows a new readily synthesised lead to be proposed.
Assuntos
Actinas/metabolismo , Alanina/análise , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Tiazóis/química , Sobrevivência Celular/efeitos dos fármacos , Cianobactérias/química , Citoesqueleto/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Estrutura Molecular , Oligopeptídeos/síntese química , Peptídeos/síntese química , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
The mono ortho-bromination of phenolic building blocks by NBS has been achieved in short reaction times (15-20 min) using ACS-grade methanol as a solvent. The reactions can be conducted on phenol, naphthol and biphenol substrates, giving yields of >86% on gram scale. Excellent selectivity for the desired mono ortho-brominated products is achieved in the presence of 10 mol % para-TsOH, and the reaction is shown to be tolerant of a range of substituents, including CH3, F, and NHBoc.
Assuntos
Compostos de Bifenilo/química , Metanol/química , Naftóis/química , Fenol/química , Benzenossulfonatos/química , Bromosuccinimida/química , Halogenação , Cinética , SolventesRESUMO
A range of 4-substituted prolines can be rapidly synthesized from a protected glycine Schiff base in only four steps and in 27-55% overall yield. Phase transfer catalysis allows direct access to both enantiomeric series, and the relative stereochemistry at the 4-position is readily controlled (>10:1 dr) through the choice of hydrogenation conditions.
