Human liver microsomal metabolism of (+)-discodermolide.
The polyketide natural product (+)-discodermolide is a potent microtubule stabilizer that has generated considerable interest in its synthetic, medicinal, and biological chemistry. It progressed to early clinical oncology trials, where it showed some efficacy in terms of disease stabilization but also some indications of causing pneumotoxicity. Remarkably, there are no reports of its metabolism. Here, we examined its fate in mixed human liver microsomes. Due to limited availability of the agent, we chose a nanoflow liquid chromatography-electrospray ionization-mass spectrometry analytical approach employing quadrupolar ion trap and quadrupole-quadrupole-time-of-flight instruments for these studies. (+)-Discodermolide was rapidly converted to eight metabolites, with the left-side lactone (net oxidation) and the right-side diene (epoxidation followed by hydrolysis, along with an oxygen insertion product) being the most metabolically labile sites. Other sites of metabolism were the allylic and pendant methyl moieties in the C12-C14 region of the molecule. The results provide information on the metabolic soft spots of the molecule and can be used in further medicinal chemistry efforts to optimize discodermolide analogues.
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Yun
Y
Fan
Emanuel M
EM
Schreiber
Billy W
BW
Day
D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D002853:Chromatography, Liquid; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
D000473:Alkanes; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; C071229:discodermolide