Details

Autor(en) / Beteiligte

• Depetter, Yves
• Geurs, Silke
• Vanden Bussche, Flore
• De Vreese, Rob
• Franceus, Jorick
• Desmet, Tom
• De Wever, Olivier
• D'hooghe, Matthias

Titel

Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibitionElectronic supplementary information (ESI) available. See DOI: 10.1039/c8md00107c

Erscheinungsjahr

2018-06

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. The replacement of the hydroxamic acid zinc-binding group in benzohydroxamic acid HDAC6 inhibitors by a trifluoromethyl ketone function leads to severe reduction in enzymatic and cellular activity.