Son, S.H. Do, J.M. Yoo, J.-N. Lee, H.W. Kim, N.K. Yoo, H.-S. Gee, M.S. Kim, J.-H. Seong, Ji hye Inn, K.-S. Seo, M.-D. Lee, J.K. Kim, N.-J. 2024-01-19T14:03:30Z 2024-01-19T14:03:30Z 2021-09-02 2021-08 0045-2068 https://pubs.kist.re.kr/handle/201004/116665 In this study, polyhydroxyisoflavones that directly prevent the aggregation of both amyloid β (Aβ) and tau were expediently synthesized via divergent Pd(0)-catalyzed Suzuki-Miyaura coupling and then biologically evaluated. By preliminary structure？activity relationship studies using thioflavin T (ThT) assays, an ortho-catechol containing isoflavone scaffold was proven to be crucial for preventing both Aβ aggregation and tau-mediated neurofibrillary tangle formation. Additional TEM experiment confirmed that ortho-catechol containing isoflavone 4d significantly prevented the aggregation of both Aβ and tau. To investigate the mode of action (MOA) of 4d, which possesses an ortho-catechol moiety, 1H-15N HSQC NMR analysis was thoroughly performed and the result indicated that 4d could directly inhibit both the formation of Aβ42 fibrils and the formation of tau-derived neurofibrils, probably through the catechol-mediated nucleation of tau. Finally, 4d was demonstrated to alleviate cognitive impairment and pathologies related to Alzheimer's disease in a 5XFAD transgenic mouse model. ？ 2021 Elsevier Inc. English Academic Press Inc. Identification of ortho catechol-containing isoflavone as a privileged scaffold that directly prevents the aggregation of both amyloid β plaques and tau-mediated neurofibrillary tangles and its in vivo evaluation Article 10.1016/j.bioorg.2021.105022 1 Bioorganic Chemistry, v.113 Bioorganic Chemistry 113 N scie scopus 000663790400008 2-s2.0-85108709897 Biochemistry & Molecular Biology Chemistry, Organic Biochemistry & Molecular Biology Chemistry Article ALZHEIMERS FLAVONOIDS GENISTEIN DEMENTIA (-)-EPIGALLOCATECHIN-3-GALLATE IMMUNOTHERAPY REACTIVITY PATHWAY CELLS EGCG Alzheimer&apos s disease Amyloid β Catechol Polyhydroxyisoflavone Tau