Oleanolic Acid Amide Derivatives as 20s Proteasome Stimulators

Oleanolic acid (OA), a pentacyclic triterpenoid natural product, is previously identified as a proteasome stimulator using purified proteasome. Structure-activity relationship studies are carried out on OA at the C₂₈ and C₃ positions to determine if modifications at these positions can change proteasome stimulation activity. Ten amide derivatives are synthesized and tested in cells. These findings indicate that replacing the carboxylic acid with an amide at position C₂₈ does not diminish the stimulating effect, with certain functional groups making stimulation more potent. Amides with increased steric hinderance stimulate the proteasome the best, particularly amides with ortho substituted benzyl or isopropyl moieties. OA is further derivatized at the C₃ position by acylating the hydroxyl group. Changes at this position affect solubility of the derivatives, but do not dramatically diminish proteasome stimulation. These modifications highlight that the structure of OA can be modified to include linkers or covalent cross-linking moieties to expand upon the available proteasome probes.