Synthesis and biological evaluation of oleanolic acid derivatives as inhibitors of protein tyrosine phosphatase 1B.

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.