Identification of the Metabolic Profile of the α-Tubulin-Binding Natural Product (-)-Pironetin

  • J Med Chem. 2019 Feb 14;62(3):1684-1689. doi: 10.1021/acs.jmedchem.8b01774.
Sara K Coulup  1 ,  David S Huang  1 ,  Henry L Wong  1 ,  Gunda I Georg  1
Affiliations
  • 1. Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
PMID: 30693770 DOI: 10.1021/acs.jmedchem.8b01774
Abstract

Pironetin, the only crystallographically confirmed natural product to target α-tubulin, displays potent cytotoxic activity against sensitive and resistant A2780 ovarian Cancer cell lines but is only marginally active in vivo. We now report that pironetin has a short half-life (<7 min) in human liver microsomes, suggesting that its limited in vivo efficacy is due to rapid metabolism. Further, we describe the discovery of epoxypironetin as pironetin's major metabolite in human liver microsomes.