oleanonic-acid and Obesity

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator in the process of insulin signaling and a promising drug target for diabetes and obesity. Derivatives of oleanolic acid were synthesized and evaluated as PTP1B inhibitors. Several derivatives exhibited moderate to good inhibitory activities against PTP1B, with 25f displaying the most promising inhibition (IC(50) = 3.12 μM). Structure-activity relationship analyses of these derivatives demonstrated that the integrity of the A ring and 12-ene moieties was important in the retention of PTP1B enzyme inhibitory activities. In addition, hydrophilic and acidic groups as well as the distance between the oleanene and acid moieties were associated with PTP1B inhibitory activities. Possible binding modes of 25f were explored by molecular docking simulations.

Topics: Diabetes Mellitus; Drugs, Chinese Herbal; Escherichia coli; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Obesity; Oleanolic Acid; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Structure-Activity Relationship

Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, a series of competitive inhibitors were optimized from oleanolic acid, a natural triterpenoid identified against PTP1B by screening libraries of traditional Chinese medicinal herbs. Modifying at 3 and 28 positions, we obtained compound 13 with a K(i) of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin.

Topics: Animals; Cell Line; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus; Drugs, Chinese Herbal; Enzyme Inhibitors; Humans; Insulin; Obesity; Oleanolic Acid; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptor, Insulin; Structure-Activity Relationship; T-Lymphocytes