TY - JOUR
T1 - New Benzodihydrofuran Derivatives Alter the Amyloid β Peptide Aggregation
T2 - Strategies To Develop New Anti-Alzheimer Drugs
AU - Sánchez, Yaíma
AU - Castillo, Carolina
AU - Fuentealba, Jorge
AU - Sáez-Orellana, Francisco
AU - Burgos, Carlos Felipe
AU - López, Jhon J.
AU - F. de la Torre, Alexander
AU - Jiménez, Claudio A.
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/8/2
Y1 - 2023/8/2
N2 - Alzheimer’s disease is a neurodegenerative disorder that is the leading cause of dementia in elderly patients. Amyloid-β peptide (1-42 oligomers) has been identified as a neurotoxic factor, triggering many neuropathologic events. In this study, 15 chalcones were synthesized employing the Claisen-Schmidt condensation reaction, starting from a compound derived from fomannoxine, a natural benzodihydrofuran whose neuroprotective activity has been proven and reported, and methyl aromatic ketones with diverse patterns of halogenated substitution. As a result, chalcones were obtained, with good to excellent reaction yields from 50 to 98%. Cytotoxicity of the compounds was assessed, and their cytoprotective effect against the toxicity associated with Aβ was evaluated on PC-12 cells. Out of the 15 chalcones obtained, only the 4-bromo substituted was cytotoxic at most tested concentrations. Three synthesized chalcones showed a cytoprotective effect against Aβ toxicity (over 37%). The 2,4,5-trifluoro substituted chalcone was the most promising series since it showed a cytoprotective impact with more than 60 ± 5% of recovery of cellular viability; however, 3-fluoro substituted compound also exhibited important values of recovery (50 ± 6%). The fluorine substitution pattern was shown to be more effective for cytoprotective activity. Specifically, substitution with fluorine in the 3,5-positions turned out to be particularly effective for cytoprotection. Furthermore, fluorinated compounds inhibited the aggregation rate of Aβ, suggesting a dual effect that can be the starting point of new molecules with therapeutic potential.
AB - Alzheimer’s disease is a neurodegenerative disorder that is the leading cause of dementia in elderly patients. Amyloid-β peptide (1-42 oligomers) has been identified as a neurotoxic factor, triggering many neuropathologic events. In this study, 15 chalcones were synthesized employing the Claisen-Schmidt condensation reaction, starting from a compound derived from fomannoxine, a natural benzodihydrofuran whose neuroprotective activity has been proven and reported, and methyl aromatic ketones with diverse patterns of halogenated substitution. As a result, chalcones were obtained, with good to excellent reaction yields from 50 to 98%. Cytotoxicity of the compounds was assessed, and their cytoprotective effect against the toxicity associated with Aβ was evaluated on PC-12 cells. Out of the 15 chalcones obtained, only the 4-bromo substituted was cytotoxic at most tested concentrations. Three synthesized chalcones showed a cytoprotective effect against Aβ toxicity (over 37%). The 2,4,5-trifluoro substituted chalcone was the most promising series since it showed a cytoprotective impact with more than 60 ± 5% of recovery of cellular viability; however, 3-fluoro substituted compound also exhibited important values of recovery (50 ± 6%). The fluorine substitution pattern was shown to be more effective for cytoprotective activity. Specifically, substitution with fluorine in the 3,5-positions turned out to be particularly effective for cytoprotection. Furthermore, fluorinated compounds inhibited the aggregation rate of Aβ, suggesting a dual effect that can be the starting point of new molecules with therapeutic potential.
KW - Alzheimer’s disease
KW - amyloid-β peptide
KW - chalcones
KW - cytoprotective effect
UR - http://www.scopus.com/inward/record.url?scp=85166394592&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.2c00778
DO - 10.1021/acschemneuro.2c00778
M3 - Article
C2 - 37480555
AN - SCOPUS:85166394592
SN - 1948-7193
VL - 14
SP - 2590
EP - 2602
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 15
ER -