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Issue 6, 2018
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Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition

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Abstract

Recent studies point towards the possible disadvantages of using hydroxamic acid-based zinc-binding groups in HDAC inhibitors due to e.g. mutagenicity issues. In this work, we elaborated on our previously developed Tubathian series, a class of highly selective thiaheterocyclic HDAC6 inhibitors, by replacing the benzohydroxamic acid function by an alternative zinc chelator, i.e., an aromatic trifluoromethyl ketone. Unfortunately, these compounds showed a reduced potency to inhibit HDAC6 as compared to their hydroxamic acid counterparts. In agreement, the most active trifluoromethyl ketone was unable to influence the growth of SK-OV-3 ovarian cancer cells nor to alter the acetylation status of tubulin and histone H3. These data suggest that replacement of the zinc-binding hydroxamic acid function with a trifluoromethyl ketone zinc-binding moiety within reported benzohydroxamic HDAC6 inhibitors should not be considered as a standard strategy in HDAC inhibitor development.

Graphical abstract: Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition

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Publication details

The article was received on 26 Feb 2018, accepted on 04 May 2018 and first published on 18 May 2018


Article type: Research Article
DOI: 10.1039/C8MD00107C
Citation: Med. Chem. Commun., 2018,9, 1011-1016
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    Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition

    Y. Depetter, S. Geurs, F. Vanden Bussche, R. De Vreese, J. Franceus, T. Desmet, O. De Wever and M. D'hooghe, Med. Chem. Commun., 2018, 9, 1011
    DOI: 10.1039/C8MD00107C

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