title: Biocatalytic synthesis and structure elucidation of cyclized metabolites of the deacetylase inhibitor panobinostat (LBH589).
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.
authors.affiliation: Global Ciscovery Chemistry, Novartis Institutes for BioMedical Research, WKL-122.P.37, CH-4002 Basel, Switzerland. andreas.fredenhagen@novartis.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Fredenhagen
authors.forename: Matthias
authors.initials: M
authors.lastname: Kittelmann
authors.forename: Lukas
authors.initials: L
authors.lastname: Oberer
authors.forename: Anton
authors.initials: A
authors.lastname: Kuhn
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kühnöl
authors.forename: Thierry
authors.initials: T
authors.lastname: Délémonté
authors.forename: Reiner
authors.initials: R
authors.lastname: Aichholz
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055162:Biocatalysis; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles; D008968:Molecular Conformation; D000077767:Panobinostat; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human