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.
journal_name
Medchemcommjournal_title
MedChemCommauthors
Depetter Y,Geurs S,Vanden Bussche F,De Vreese R,Franceus J,Desmet T,De Wever O,D'hooghe Mdoi
10.1039/c8md00107csubject
Has Abstractpub_date
2018-05-18 00:00:00pages
1011-1016issue
6eissn
2040-2503issn
2040-2511pii
c8md00107cjournal_volume
9pub_type
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