Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors

Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular endpoints with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-kappa B, STAT3, Nrf2, TGRS) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (Sb) was selected for further studies, and evaluation of its effect on HIF-la expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.