Hydroxy-substituted trans-cinnamoyl derivatives as multifunctional tools in the context of Alzheimer's disease.
Eur J Med Chem
; 139: 378-389, 2017 Oct 20.
Article
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| MEDLINE
| ID: mdl-28810189
ABSTRACT
Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Aß), glycogen synthase kinase 3ß (GSK-3ß) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments. We designed compound 3 which demonstrated the ability to inhibit both GSK-3ß (IC50 = 24.36 ± 0.01 µM) and Aß42 self-aggregation (IC50 = 9.0 ± 1.4 µM), to chelate copper (II) and to act as exceptionally strong radical scavenger (kinh = 6.8 ± 0.5 · 105 M-1s-1) even in phosphate buffer at pH 7.4 (kinh = 3.2 ± 0.5 · 105 M-1s-1). Importantly, compound 3 showed high-predicted blood-brain barrier permeability, did not exert any significant cytotoxic effects in immature cortical neurons up to 50 µM and showed neuroprotective properties at micromolar concentration against toxic insult induced by glutamate.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Depuradores de Radicales Libres
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Cinamatos
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Enfermedad de Alzheimer
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Glucógeno Sintasa Quinasa 3 beta
Límite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Año:
2017
Tipo del documento:
Article
País de afiliación:
Italia