Root-Extracted lignanamides from Limonium gmelinii (Willd.) Kuntze with a potential PTP1B inhibitory activity by regulating PI3K/AKT signaling pathway

The phytochemical study of Limonium gmelinii roots resulted in the isolation of five lignanamides (1–5). Among them, limoniumins J, K, and M (1, 2, and 4) are undescribed compounds, limoniumin L (3) is a new naturally occurring lignanamide, and limoniumin B (5) is a known compound which showed PTP1B inhibition activity with an IC50 value of 5.05 ± 2.44 μM in our previous work. Spectroscopic data analysis, including 1D and 2D NMR and HRESIMS experiments, established the chemical structures of limoniumins J − M (1–4). Compounds 1–4 showed PTP1B inhibition activity, among which compound 3 showed the most potent PTP1B inhibition with an IC50 value of 2.07 ± 0.05 μM. Compounds 3 and 5 could significantly increase cellular glucose consumption and glucose uptake in L6 muscle cells and could synergize with insulin to promote glucose consumption and glucose uptake in a concentration-dependent manner. The treatment of compound 3 also promoted glycogen synthesis in skeletal muscle cells. Western blot analysis demonstrated that the good hypoglycemic effect of compounds 3 and 5 was achieved by activating PI3K/AKT signaling pathway to promote glucose consumption, glucose uptake, and glycogen synthesis. Furthermore, studies on molecular docking revealed the potent interactions between these bioactive substances and the PTP1B protein.