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

Fredenhagen, Andreas and Kittelmann, Matthias and Oberer, Lukas and Kuhn, Anton and Kuehnoel, Juergen and Delemonte, Thierry and Aichholz, Reiner and Wang, Ping and Atadja, Peter and Shultz, Michael (2012) Biocatalytic synthesis and structure elucidation of cyclized metabolites of the deacetylase inhibitor Panobinostat (LBH589). Drug Metabolism and Disposition, 40 (5). pp. 1041-1050. ISSN 0090-9556

Abstract

Panobinostat (LBH589) is a novel pan-deacetylase inhibitor that is currently being evaluated in clinical phase III trials for treatment of Hodgkin’s lymphoma and multiple myeloma. Under catalysis of recombinant human cytochrome P450 3A4 and 2D6 co-expressed with human P450 reductase in E. coli JM109, five metabolites of panobinostat were produced via whole cell biotransformation. The structures of the metabolites were elucidated with the spectroscopic methods MS and NMR and revealed an oxidative cyclization of the ethyl-amino-group to the methylindole moiety. The MS2 spectrum of a 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.

Item Type: Article
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Keywords: Biocatalysis, CYP, Panobinostat,metabolism, LBH589
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6006

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