title: 3,3',4',5,5'-Pentahydroxyflavone is a potent inhibitor of amyloid β fibril formation.
abstract: The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid β protein (Aβ). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease. To find even more effective drugs based on the structure of fisetin, we synthesized a series of fisetin analogues lacking the 7-hydroxyl group and compared their effects on Aβ fibril formation determined by the thioflavin T fluorescence assay. 3,3',4'-Trihydroxyflavone and 3',4'-dihydroxyflavone inhibited Aβ fibril formation more potently than fisetin or 3',4',7-trihydroxyflavone, suggesting that the 7-hydroxy group is not necessary for anti-amyloidogenic activity. 3,3',4',5'-Tetrahydroxyflavone and 3',4',5'-trihydroxyflavone inhibited Aβ fibril formation far more potently than 3,3',4'-trihydroxyflavone and 3',4'-dihydroxyflavone, suggesting that 3',4',5'-trihydroxyl group of the B ring is crucial for the anti-amyloidogenic activity of flavonoids. Based on the structure-activity relationship, we synthesized 3,3',4',5,5'-pentahydroxyflavone, and confirmed that this compound is the most potent inhibitor of Aβ fibril formation among fisetin analogues that have been tested. Cytotoxicity assay using rat hippocampal neuron cultures demonstrated that Aβ preincubated with 3,3',4',5,5'-pentahydroxyflavone was significantly less toxic than Aβ preincubated with vehicle. 3,3',4',5,5'-Pentahydroxyflavone could be a new therapeutic drug candidate for the treatment of Alzheimer's disease.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy and Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushikubo
authors.forename: Sayaka
authors.initials: S
authors.lastname: Watanabe
authors.forename: Yui
authors.initials: Y
authors.lastname: Tanimoto
authors.forename: Kazuho
authors.initials: K
authors.lastname: Abe
authors.forename: Aiki
authors.initials: A
authors.lastname: Hiza
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ogawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asakawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kan
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Akaishi
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D005419:Flavonoids; D044948:Flavonols; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C008775:peflavit; C040015:myricetin; C017875:fisetin