PT  - JOURNAL ARTICLE
AU  - Andreas Fredenhagen
AU  - Matthias Kittelmann
AU  - Lukas Oberer
AU  - Anton Kuhn
AU  - Jürgen Kühnöl
AU  - Thierry Délémonté
AU  - Reiner Aichholz
AU  - Ping Wang
AU  - Peter Atadja
AU  - Michael D. Shultz
TI  - Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)
AID  - 10.1124/dmd.111.043620
DP  - 2012 May 01
TA  - Drug Metabolism and Disposition
PG  - 1041--1050
VI  - 40
IP  - 5
4099  - http://dmd.aspetjournals.org/content/40/5/1041.short
4100  - http://dmd.aspetjournals.org/content/40/5/1041.full
SO  - Drug Metab Dispos2012 May 01; 40
AB  - 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 MS2 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.