Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation

Type 2 diabetes mellitus (T2DM) is associated with pancreatic beta-cell dysfunction and insulin resistance. Islet amyloid polypeptide (IAPP) aggregation is found to induce islet beta-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-mu M range (IC60 = 0.7-0.8 mu M). The molecular docking analysis revealed crucial hydrogen bonds between the compounds and residues S19 and N22 and important hydrophobic interactions with residue 126. Notably, compounds 4g and 4h significantly protected beta-cells against IAPP-induced toxicity with EC50 values of 0.1 and 0.2 mu M, respectively. In contrast, the protective activities of compounds 4e and 4f were weak. Overall, these results suggest that the compounds exhibiting LAPP aggregation-inhibiting activity have the potential to treat T2DM.

Automated summary

Type 2 diabetes mellitus is linked to pancreatic beta-cell dysfunction and insulin resistance, with islet amyloid polypeptide aggregation leading to beta-cell death. Certain compounds have been found to inhibit IAPP aggregation, with compounds 4g and 4h showing significant protection against IAPP-induced toxicity in beta-cells.