Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation
| Autor: | Jui Yi Hsu, Hui Ju Tseng, Cheng Chung Yen, Hui Kang Liu, Wei Jan Huang, Kun Chang Wu, Kai Cheng Hsu, Ashish Rao Sathyan, Liang Chieh Chen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
Amyloid Pharmaceutical Science Protein Aggregation Pathological 01 natural sciences Cell Line Analytical Chemistry Hydrophobic effect chemistry.chemical_compound Residue (chemistry) Insulin resistance Diarylheptanoids Insulin-Secreting Cells Drug Discovery medicine Animals IC50 Pharmacology geography geography.geographical_feature_category 010405 organic chemistry Chemistry Organic Chemistry Islet medicine.disease Islet Amyloid Polypeptide Rats 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Complementary and alternative medicine Biochemistry Toxicity Molecular Medicine Insulin Resistance Lead compound |
| Zdroj: | Journal of Natural Products. 84:1096-1103 |
| ISSN: | 1520-6025 0163-3864 |
| Popis: | Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction and insulin resistance. Islet amyloid polypeptide (IAPP) aggregation is found to induce islet β-cell death in T2DM patients. Recently, we demonstrated that yakuchinone B derivative 1 exhibited inhibitory activity against IAPP aggregation. Thus, in this study, a series of synthesized yakuchinone B-inspired compounds were tested for their anti-IAPP aggregation activity. Four of these compounds, 4e-h, showed greater activity than the lead compound 1, in the sub-μM range (IC50 = 0.7-0.8 μM). The molecular docking analysis revealed crucial hydrogen bonds between the compounds and residues S19 and N22 and important hydrophobic interactions with residue I26. Notably, compounds 4g and 4h significantly protected β-cells against IAPP-induced toxicity with EC50 values of 0.1 and 0.2 μM, respectively. In contrast, the protective activities of compounds 4e and 4f were weak. Overall, these results suggest that the compounds exhibiting IAPP aggregation-inhibiting activity have the potential to treat T2DM. |
| Databáze: | OpenAIRE |
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