Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aß complex mediated toxicity, oxidative stress and inflammation.
Bioorg Chem
; 109: 104710, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33611137
ABSTRACT
A series of 8-substituted sampangine derivatives have been designed, synthesized and tested for their ability to inhibit cholinesterase and penetrate the blood-brain barrier. Their chelating ability toward Zn2+ and other biologically relevant metal ions was also demonstrated by isothermal titration calorimetry. The new derivatives exhibited high acetylcholinesterase inhibitory activity, high blood-brain barrier penetration ability and high chelating selectivity for Zn2+. Moreover, compound 10 with the strongest binding affinity to Zn2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 10 suppressed the formation of Zn2+-Aß complexes, alleviated the Zn2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Zn2+ in Aß42 transgenic C. elegans. Furthermore, compound 10 also inhibited the expressions of pro-inflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1ß, induced by Zn2+ + Aß1-42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for Alzheimer's disease treatment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Zinco
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Peptídeos beta-Amiloides
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Caenorhabditis elegans
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Alcaloides
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Compostos Heterocíclicos de 4 ou mais Anéis
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Naftiridinas
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article