Synthesis of yakuchinone b-inspired inhibitors against islet amyloid polypeptide aggregation

Hui Kang Liu, Wei Jan Huang, Jui Yi Hsu, Ashish Rao Sathyan, Kai Cheng Hsu, Liang Chieh Chen, Cheng Chung Yen, Hui Ju Tseng, Kun Chang Wu

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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.

Original languageEnglish
Pages (from-to)1096-1103
Number of pages8
JournalJournal of Natural Products
Issue number4
Publication statusPublished - Apr 2021

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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