Highly fluorescent and HDAC6 selective scriptaid analogues

Cassandra L Fleming; Anthony Natoli; Jeannette Schreuders; Mark Devlin; Prusothman Yoganantharajah; Yann Gibert; Kathryn G Leslie; Elizabeth J New; Trent D Ashton; Frederick M Pfeffer

doi:10.1016/j.ejmech.2018.11.020

Highly fluorescent and HDAC6 selective scriptaid analogues

Eur J Med Chem. 2019 Jan 15:162:321-333. doi: 10.1016/j.ejmech.2018.11.020. Epub 2018 Nov 9.

Affiliations

¹ School of Life & Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia.
² Peter MacCallum Cancer Centre, Parkville, Melbourne, Victoria, 3000, Australia.
³ School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia.
⁴ School of Chemistry, The University of Sydney, Sydney, New South Wales, 2006, Australia.
⁵ School of Life & Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
⁶ School of Life & Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia. Electronic address: fred.pfeffer@deakin.edu.au.

PMID: 30448419
DOI: 10.1016/j.ejmech.2018.11.020

Abstract

Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6 > 500) and potency (HDAC6 IC₅₀ < 5 nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to Φ_F = 0.83 in DMSO and 0.38 in aqueous buffer) makes them ideally suited for cellular imaging and visualisation of their cytoplasmic localisation was readily accomplished. Whole organism imaging in zebrafish confirmed both the vascular localisation of the new inhibitors and the impact of HDAC6 inhibition on in vivo development.

Keywords: 4MS; Fluorescence; HDAC; Imaging; Naphthalimide; Scriptaid; Zebrafish.

MeSH terms

Animals
Blood Vessels / diagnostic imaging
Blood Vessels / metabolism
Cytoplasm / metabolism
Diagnostic Imaging / methods
Fluorescence
Histone Deacetylase 6 / antagonists & inhibitors*
Histone Deacetylase Inhibitors / pharmacokinetics
Histone Deacetylase Inhibitors / therapeutic use
Hydroxylamines / chemical synthesis
Hydroxylamines / chemistry*
Hydroxylamines / pharmacokinetics
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacokinetics
Zebrafish / metabolism

Substances

Histone Deacetylase Inhibitors
Hydroxylamines
Quinolines
scriptaid
Histone Deacetylase 6