Biocatalytic synthesis and structure elucidation of cyclized metabolites of the deacetylase inhibitor panobinostat (LBH589)

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Andreas FredenhagenMichael D Shultz

Abstract

Panobinostat (LBH589) is a novel pan-deacetylase inhibitor that is currently being evaluated in phase III clinical trials for treatment of Hodgkin's lymphoma and multiple myeloma. Under catalysis of recombinant human CYP3A4 and CYP2D6 coexpressed with human cytochrome P450 reductase in Escherichia coli JM109, five metabolites of panobinostat were produced via whole-cell biotransformation. The structures of the metabolites were elucidated with the spectroscopic methods mass spectrometry (MS) and NMR and revealed an oxidative cyclization of the ethyl-amino group to the methylindole moiety. The MS(2) spectrum of the cyclized metabolite showed a base peak, where the closed ring is reopened and that, taken as sole base for structure proposals, would have lead to wrong conclusions. The metabolites were substantially less potent deacetylase inhibitors than the parent compound.

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Citations

Aug 13, 2014·European Journal of Medicinal Chemistry·Samir MehndirattaJing-Ping Liou
Oct 22, 2016·Pharmacogenomics·Andrew Kl GoeyWilliam D Figg
Mar 31, 2018·Angewandte Chemie·Margit WinklerAnton Glieder
Oct 23, 2018·Chembiochem : a European Journal of Chemical Biology·Andreas FredenhagenAldo Meishammer
Jul 2, 2017·Clinical Pharmacokinetics·Mathilde Van VeggelPaul Hamberg

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