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.

Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential

“…Remarkably, the compound was able to inhibit human IAPP fibrillization, virtually preventing its aggregation into toxic amyloid oligomers—even prior to insoluble fibril formation. Additionally, nuclear magnetic resonance (NMR) studies pointed toward the same binding epitope in the presence of IAPP and Aβ 1‐42 polypeptides, suggesting potential neuroprotective effects as well . The results confirmed the already expected key role of both aromatic rings in the resulting interaction, and reinforced the importance of the sugar moiety in the antiamyloidogenic activity of this compound.…”

“…The 4′,5,7‐trihydroxyisoflavone analogue to apigenin is genistein, which C ‐glucosyl derivative in position 8, 8‐(β‐ d ‐glucosyl)genistein ( 26 , Fig. ), is the major component of the Portuguese plant Genista tenera ethyl acetate extract, recently revealed to be an extremely potent antidiabetic agent . The extract did not show toxicity toward human lymphocytes when tested at 2 mg/mL.…”

How Epigallocatechin‐3‐gallate and Tetracycline Interact with the Josephin Domain of Ataxin‐3 and Alter Its Aggregation Mode

“…Recently,w eh ave extensivelye xploited STD NMR spectroscopy [37][38][39][40] to characterize the binding of several natural [24,31,41,42] and synthetic ligands [43][44][45][46][47] to amyloid oligomers, thus demonstratingt he reliability and versatility of this technique. Moreover,M elacini and co-workersv alidated STD NMR methods in characterizing the amyloid oligomeri nteraction with soluble proteins (in particularA b peptide oligomers) [48,49] and in also mapping peptide early self-association events.…”

Isoflavones, their Glycosides and Glycoconjugates. Synthesis and Biological Activity

“…Recent work shows synthesis and analysis of biological activity of 8-β-D-glucopyranosyl genistein, a promising probe for study of amyloid related events associated with Alzheimer’s disease [164]. Genistein derivatives influence the course of immune processes by modulating IL-12, TNF-a, and NO production by macrophages and lung cancer cell lines [165].…”