Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors

Alberto Minassi, Federica Rogati, Cristina Cruz, M. Eugenia Prados, Nuria Galera, Carla Jinénez, Giovanni Appendino, M. Luz Bellido, Marco A. Calzado, Diego Caprioglio, Eduardo Muñoz

Research output: Contribution to journalArticlepeer-review


Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points 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-κB, STAT3, Nrf2, TGR5) 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 (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.

Original languageEnglish
Pages (from-to)2235-2243
Number of pages9
JournalJournal of Natural Products
Issue number10
Publication statusPublished - 26 Oct 2018


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