Exploiting the Therapeutic Potential of 8-尾-d-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amy
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- 作者：Ana R. Jesus ; Catarina Dias ; Ana M. Matos ; Rodrigo F. M. de Almeida ; Ana S. Viana ; Filipa Marcelo ; Rog茅rio T. Ribeiro ; Maria P. Macedo ; Cristina Airoldi ; Francesco Nicotra ; Alice Martins ; Eurico J. Cabrita ; Jes煤s Jim茅nez-Barbero ; Am茅lia P. Rauter
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：November 26, 2014
- 年：2014
- 卷：57
- 期：22
- 页码：9463-9472
- 全文大小：434K
- ISSN：1520-4804
文摘
8-尾-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 尾-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 A尾1鈥?2 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鈥?geometry resulting from interaction with A尾1鈥?2 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-尾-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer鈥檚 disease.