Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease.
ChemMedChem
; 12(22): 1828-1838, 2017 11 22.
Article
en En
| MEDLINE
| ID: mdl-28990338
ABSTRACT
Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-ß (Aß), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool's reactivities toward multiple pathological facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. These compounds were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aß, reactive oxygen species (ROS), and free organic radicals. Our results show that although small molecules are structurally similar, they can interact with multiple factors associated with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chemical tools capable of regulating individual or interrelated pathological features in AD.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Bibliotecas de Moléculas Pequeñas
/
Enfermedad de Alzheimer
/
Antioxidantes
Límite:
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2017
Tipo del documento:
Article