RESUMEN
Starting from substituted 9-chloroacridines, a series of quinacrine and spacered dimeric acridine compounds was prepared. Their ability to interrupt the protein association of prion- and Alzheimer-specific proteins and Ab peptides was explored using a fast screening system based on FACS analysis. The bis-acridines displayed a higher activity than the corresponding monomers. Among these derivatives, best results were obtained with the 2,4-dimethoxy-6-nitro compound 7h for Abeta-peptides and the 2-methoxy-6-nitro compound 7f for PrP.
Asunto(s)
Acridinas/síntesis química , Acridinas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedades por Prión/tratamiento farmacológico , Acridinas/farmacología , Péptidos beta-Amiloides/efectos de los fármacos , Dimerización , Evaluación Preclínica de Medicamentos/métodos , Humanos , Técnicas In Vitro , Estructura Molecular , Priones/efectos de los fármacosRESUMEN
The synthesis of dimeric compounds derived from quinazolin-2-one and 1,4-benzodiazepin-2-one possessing a piperazine or homopiperazine spacer was investigated. In addition, a piperazine spacered bis-isoalloxazine and a bis-riboflavin compound were prepared and their ability to interrupt the association of prion proteins and Alzheimer-specific Abeta peptides was investigated using a fast screening system based on flow cytometry. The bis-isoalloxazine 14 was identified as a new lead structure.