Hydroxy-substituted trans-cinnamoyl derivatives as multifunctional tools in the context of Alzheimer's disease
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
28810189
DOI
10.1016/j.ejmech.2017.07.058
PII: S0223-5234(17)30580-9
Knihovny.cz E-zdroje
- Klíčová slova
- Alzheimer's disease, Aβ aggregation, Glycogen synthase kinase 3β, Multitarget agents, Oxidative stress,
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- cinnamáty chemická syntéza chemie farmakologie MeSH
- kinasa glykogensynthasy 3beta antagonisté a inhibitory metabolismus MeSH
- molekulární struktura MeSH
- scavengery volných radikálů chemická syntéza chemie farmakologie MeSH
- stereoizomerie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cinnamáty MeSH
- kinasa glykogensynthasy 3beta MeSH
- scavengery volných radikálů MeSH
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 (Aβ), glycogen synthase kinase 3β (GSK-3β) 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-3β (IC50 = 24.36 ± 0.01 μM) and Aβ42 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.
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