P. R. Watson, Jacob Hooker, D. Christianson
May 1, 2022
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Quality indicators
Journal
The FASEB Journal
Abstract
Fluorine is increasingly being incorporated into pharmaceuticals to modulate their physical properties. Furthermore, 18F can be utilized in positron emission tomography (PET) probes for in vivo imaging. Bavarostat is a selective inhibitor of histone deacetylase 6 (HDAC6), and when derivatized with 18F is used to map out HDAC6 localisation within the brain. As HDAC6 is implicated in Alzheimer’s disease due to its function as a Tau deacetylase, it may serve as an effective biomarker for this disease. The active site cavity of HDAC6 contains two phenylalanine residues that form an aromatic crevice, F583 and F643, that engage in offset π‐π interactions with phenylhydroxymate binding groups. Moreover, the fluoroaromatic ring of Bavarostat orientates such that the C–F group binds in the aromatic crevice instead of being exposed to solvent. Structure activity relationships were determined for a series of fluorophenylhydroxymates to inform the design of fluorinated inhibitors of HDAC6 as well PET probes. Our studies show the aromatic crevice of HDAC6 preferentially binds C–F groups in this series of inhibitors. The inhibitors show differences in zinc binding orientations, likely due to the electronic influence of fluorine on the hydroxymate zinc‐binding group.