Exploiting the Therapeutic Potential of 8-beta-D-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid beta-Peptide (1-42)

Ana R. Jesus, Catarina Dias, Ana M Matos, Rodrigo F. M. de Almeida, Ana S. Viana, Filipa Margarida Barradas Morais Marcelo, Rogério T Ribeiro, Maria P Macedo, Cristina Airoldi, Francesco Nicotra, Alice Martins, Eurico J Cabrita, Jesus Jimenez-Barbere, Amelia P. Rauter

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Abstract

8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease.
Original languageEnglish
Pages (from-to)9463-9472
Number of pages10
JournalJournal Of Medicinal Chemistry
Volume57
Issue number22
DOIs
Publication statusPublished - 27 Nov 2014

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Islet Amyloid Polypeptide
Hypoglycemic Agents
Amyloid
Genista
Atomic Force Microscopy
Hyperglycemia
Insulin Resistance
Epitopes
Fasting
Alzheimer Disease
Therapeutics
Fluorescence
Insulin
Glucose
Peptides
genistein-8-c-glucoside
amyloid beta-protein (1-42)

Keywords

    Cite this

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    title = "Exploiting the Therapeutic Potential of 8-beta-D-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid beta-Peptide (1-42)",
    abstract = "8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease.",
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    author = "Jesus, {Ana R.} and Catarina Dias and Matos, {Ana M} and {de Almeida}, {Rodrigo F. M.} and Viana, {Ana S.} and Marcelo, {Filipa Margarida Barradas Morais} and Ribeiro, {Rog{\'e}rio T} and Macedo, {Maria P} and Cristina Airoldi and Francesco Nicotra and Alice Martins and Cabrita, {Eurico J} and Jesus Jimenez-Barbere and Rauter, {Amelia P.}",
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    Exploiting the Therapeutic Potential of 8-beta-D-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid beta-Peptide (1-42). / Jesus, Ana R.; Dias, Catarina; Matos, Ana M; de Almeida, Rodrigo F. M. ; Viana, Ana S.; Marcelo, Filipa Margarida Barradas Morais; Ribeiro, Rogério T; Macedo, Maria P; Airoldi, Cristina; Nicotra, Francesco; Martins, Alice; Cabrita, Eurico J; Jimenez-Barbere, Jesus; Rauter, Amelia P.

    In: Journal Of Medicinal Chemistry, Vol. 57, No. 22, 27.11.2014, p. 9463-9472.

    Research output: Contribution to journalArticle

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    T1 - Exploiting the Therapeutic Potential of 8-beta-D-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid beta-Peptide (1-42)

    AU - Jesus, Ana R.

    AU - Dias, Catarina

    AU - Matos, Ana M

    AU - de Almeida, Rodrigo F. M.

    AU - Viana, Ana S.

    AU - Marcelo, Filipa Margarida Barradas Morais

    AU - Ribeiro, Rogério T

    AU - Macedo, Maria P

    AU - Airoldi, Cristina

    AU - Nicotra, Francesco

    AU - Martins, Alice

    AU - Cabrita, Eurico J

    AU - Jimenez-Barbere, Jesus

    AU - Rauter, Amelia P.

    PY - 2014/11/27

    Y1 - 2014/11/27

    N2 - 8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease.

    AB - 8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease.

    KW - NATURAL-PRODUCTS

    KW - MASS-SPECTROMETRY

    KW - IN-VITRO

    KW - MECHANICS

    KW - SPECTROSCOPY

    KW - TRANSFER DIFFERENCE NMR

    KW - LIGAND-BINDING

    KW - PLANT GENISTA-TENERA

    KW - DISEASE

    KW - GLYCOSIDES

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    DO - 10.1021/jm501069h

    M3 - Article

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    SP - 9463

    EP - 9472

    JO - Journal Of Medicinal Chemistry

    JF - Journal Of Medicinal Chemistry

    SN - 0022-2623

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