RESUMO
Starting from a FPP analogue with nanomolar inhibitory activity against isolated FPTase, yet lacking activity in cellular assays, structural modifications were performed to enhance cellular activity by removing all acidic functionalities. Overall, these changes resulted in the transformation of a pure FPP to a mixed FPP and CAAX competitive inhibitor with nanomolar activity on isolated FPTase and micromolar inhibitory activity in the farnesylation of H-Ras in cultured DLD-1 cells.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfatos de Poli-Isoprenil/química , Fosfatos de Poli-Isoprenil/farmacologia , Alquil e Aril Transferases/metabolismo , Animais , Ligação Competitiva , Bovinos , Humanos , Concentração Inibidora 50 , Proteínas de Membrana/química , Modelos Moleculares , Prenilação de Proteína/efeitos dos fármacos , Sesquiterpenos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteínas ras/efeitos dos fármacos , Proteínas ras/metabolismoRESUMO
An efficient process for the solid-phase synthesis of hydantoins has been developed. The amino acid starting material is anchored to the resin from its carboxylic acid end through formation of a very stable amide bond. After introduction of different functional groups, the cleavage/cyclization step can be performed in acidic or basic conditions.
