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

Yves Depetter (UGent) , Silke Geurs (UGent) , Flore Vanden Bussche (UGent) , Rob De Vreese (UGent) , Jorick Franceus (UGent) , Tom Desmet (UGent) , Olivier De Wever (UGent) and Matthias D'hooghe (UGent)
(2018) MEDCHEMCOMM. 9(6). p.1011-1016
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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.
Keywords
HISTONE-DEACETYLASE INHIBITORS, POTENT, CELLS, ACID, TUBASTATIN, ANALOGS, DESIGN, FAMILY

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Chicago
Depetter, Yves, Silke Geurs, Flore Vanden Bussche, Rob De Vreese, Jorick Franceus, Tom Desmet, Olivier De Wever, and Matthias D’hooghe. 2018. “Assessment of the Trifluoromethyl Ketone Functionality as an Alternative Zinc-binding Group for Selective HDAC6 Inhibition.” Medchemcomm 9 (6): 1011–1016.
APA
Depetter, Y., Geurs, S., Vanden Bussche, F., De Vreese, R., Franceus, J., Desmet, T., De Wever, O., et al. (2018). Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition. MEDCHEMCOMM, 9(6), 1011–1016.
Vancouver
1.
Depetter Y, Geurs S, Vanden Bussche F, De Vreese R, Franceus J, Desmet T, et al. Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition. MEDCHEMCOMM. 2018;9(6):1011–6.
MLA
Depetter, Yves, Silke Geurs, Flore Vanden Bussche, et al. “Assessment of the Trifluoromethyl Ketone Functionality as an Alternative Zinc-binding Group for Selective HDAC6 Inhibition.” MEDCHEMCOMM 9.6 (2018): 1011–1016. Print.
@article{8572189,
  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.},
  author       = {Depetter, Yves and Geurs, Silke and Vanden Bussche, Flore and De Vreese, Rob and Franceus, Jorick and Desmet, Tom and De Wever, Olivier and D'hooghe, Matthias},
  issn         = {2040-2503},
  journal      = {MEDCHEMCOMM},
  language     = {eng},
  number       = {6},
  pages        = {1011--1016},
  title        = {Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition},
  url          = {http://dx.doi.org/10.1039/c8md00107c},
  volume       = {9},
  year         = {2018},
}

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