title: Exploiting the therapeutic potential of 8-β-d-glucopyranosylgenistein: synthesis, antidiabetic activity, and molecular interaction with islet amyloid polypeptide and amyloid β-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.
authors.affiliation: Center of Chemistry and Biochemistry, Department of Chemistry and Biochemistry, Faculdade de Ciências, Universidade de Lisboa , Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Jesus
authors.forename: Catarina
authors.initials: C
authors.lastname: Dias
authors.forename: Ana M
authors.initials: AM
authors.lastname: Matos
authors.forename: Rodrigo F M
authors.initials: RF
authors.lastname: de Almeida
authors.forename: Ana S
authors.initials: AS
authors.lastname: Viana
authors.forename: Filipa
authors.initials: F
authors.lastname: Marcelo
authors.forename: Rogério T
authors.initials: RT
authors.lastname: Ribeiro
authors.forename: Maria P
authors.initials: MP
authors.lastname: Macedo
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicotra
authors.forename: Alice
authors.initials: A
authors.lastname: Martins
authors.forename: Eurico J
authors.initials: EJ
authors.lastname: Cabrita
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Amélia P
authors.initials: AP
authors.lastname: Rauter
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry; D039761:Genista / Q000378:metabolism; D019833:Genistein / Q000031:analogs & derivatives* / Q000737:chemistry; D005960:Glucosides / Q000737:chemistry*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007328:Insulin / Q000097:blood; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D000939:Epitopes; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C415443:genistein-8-c-glucoside; C009462:thioflavin T; D013311:Streptozocin; D019833:Genistein; D010100:Oxygen