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.
Bibliographical noteFunding Information:
We gratefully appreciate the financial support from the NIH (Grants T32-GM08700 and F31-CA203039-01, S.K.C), American Foundation for Pharmaceutical Education (D.S.H. and S.K.C.), the University of Minnesota’s Vince and McKnight Endowed Chairs (G.I.G.), and the Engebretson Drug Design and Development Grant (G.I.G. and H.L.W.). The authors are indebted to Dr. Peter Villalta and Xun Ming of the Analytical Biochemistry Core for their assistance with the mass spectrometer, Dr. Fred Schendel and the Biotechnology Institute at the University of Minnesota for performing the bacteria fermentation, Dr. Amy P. N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for providing cells, and Dr. Natalia Y. Tretyakova for reading and editing of the manuscript. We also thank Dr. Dee Hua Huang at Scripps Research for NMR analysis of demethylpironetin (M5).