In vitro antiamyloidogenic properties of 1,4-naphthoquinones

• Published in: Biochemical and biophysical research communications Vol. 400; no. 1; pp. 169 - 174
• Main Authors: Bermejo-Bescós, Paloma, Martín-Aragón, Sagrario, Jiménez-Aliaga, Karim L., Ortega, Andrea, Molina, María Teresa, Buxaderas, Eduardo, Orellana, Guillermo, Csákÿ, Aurelio G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2010
• Subjects: 1,4-Naphthoquinones; Alzheimer Disease - enzymology; Alzheimer’s disease; Amyloid aggregation; Amyloid beta-Protein Precursor - antagonists & inhibitors; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aβ fibrils; Cell Line, Tumor; Humans; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; β-Secretase (BACE); 1,4-Naphthoquinones; Alzheimer’s disease; β-Secretase (BACE); Aβ fibrils; Amyloid aggregation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.08.038

► 1,4-NQ with OH groups at the quinoid or benzenoid rings were BACE inhibitors. ► 2- and 3-Aryl 1,4-NQ derivatives showed BACE inhibitory activity. ► Halogenated 1,4-NQ inhibited the amyloid aggregation. ► 1,4-Naphthoquinone, 6-OH-1,4-naphthoquinone and 2-(3,4-dichlorophenyl)-1,4-naphthoquinone were active on amyloid aggregation process. ► Juglone and 3-( p-OH-phenyl)-5-methoxy-1,4-napththoquinone were active on all targets. The aim of this study is to find out whether several 1,4-naphthoquinones (1,4-NQ) can interact with the amyloidogenic pathway of the amyloid precursor protein processing, particularly targeting at β-secretase (BACE), as well as at β-amyloid peptide (Aβ) aggregation and disaggregating preformed Aβ fibrils. Compounds bearing hydroxyl groups at the quinoid ( 2) or benzenoid rings ( 5, 6) as well as some 2- and 3-aryl derivatives ( 11– 15) showed BACE inhibitory activity, without effect on amyloid aggregation or disaggregation. The halogenated compounds 8 and 10 were selective for the inhibition of amyloid aggregation. On the other hand, 1,4-naphthoquinone ( 1), 6-hydroxy-1,4-naphthoquinone ( 4) and 2-(3,4-dichlorophenyl)-1,4-naphthoquinone ( 26) did not show any BACE inhibitory activity but were active on amyloid aggregation and disaggregation preformed Aβ fibrils. Juglone (5-hydroxy-1,4-naphthoquinone ( 3), and 3-( p-hydroxyphenyl)-5-methoxy-1,4-napththoquinone ( 19) were active on all the three targets. Therefore, we suggest that 1,4-NQ derivatives, specially 3 and 19, should be explored as possible drug candidates or lead compounds for the development of drugs to prevent amyloid aggregation and neurotoxicity in Alzheimer’s disease.