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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.
Bioorg Chem. 2021 08; 113:105022.BC

Abstract

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.

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Authors+Show Affiliations

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.

Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.

College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon 16499, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.

College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon 16499, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea. Electronic address: mdseo@ajou.ac.kr.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: jklee3984@khu.ac.kr.

College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: kimnj@khu.ac.kr.

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsBrainCatecholsDisease Models, AnimalDrug DesignIsoflavonesMaze LearningMiceMice, Inbred C57BLMice, TransgenicNeurofibrillary TanglesNeuroprotective AgentsPeptide FragmentsProtein Aggregatestau Proteins

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34098397

Citation

Son, Seung Hwan, et al. "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." Bioorganic Chemistry, vol. 113, 2021, p. 105022.

Son SH, Do JM, Yoo JN, et al. 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. Bioorg Chem. 2021;113:105022.

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, J. H., Inn, K. S., Seo, M. D., Lee, J. K., & Kim, N. J. (2021). 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. Bioorganic Chemistry, 113, 105022. https://doi.org/10.1016/j.bioorg.2021.105022

Son SH, et al. 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. Bioorg Chem. 2021;113:105022. PubMed PMID: 34098397.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - 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. AU - Son,Seung Hwan, AU - Do,Ji Min, AU - Yoo,Ji-Na, AU - Lee,Hyun Woo, AU - Kim,Nam Kwon, AU - Yoo,Hyung-Seok, AU - Gee,Min Sung, AU - Kim,Jong-Ho, AU - Seong,Ji Hye, AU - Inn,Kyung-Soo, AU - Seo,Min-Duk, AU - Lee,Jong Kil, AU - Kim,Nam-Jung, Y1 - 2021/05/26/ PY - 2020/11/05/received PY - 2021/04/03/revised PY - 2021/05/23/accepted PY - 2021/6/8/pubmed PY - 2021/10/26/medline PY - 2021/6/7/entrez KW - Alzheimer’s disease KW - Amyloid β KW - Catechol KW - Polyhydroxyisoflavone KW - Tau SP - 105022 EP - 105022 JF - Bioorganic chemistry JO - Bioorg Chem VL - 113 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/34098397/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_ DB - PRIME DP - Unbound Medicine ER -