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
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Published : 2019
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 ΦF = 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.
CLF and TDA thank the Centre for Molecular and Medical research at Deakin University for a top up scholarship and a salary contribution respectively. The work performed by YG was supported by grants from the Centre for Molecular and Medical research at Deakin University. YG and PY thank the Deakin University zebrafish facility. We thank Westpac Bicentennial Foundation for a Research Fellowship (EJN) and the Australian government for a Research Training Program Scholarship (KGL). The authors acknowledge Alexander P. Ray for helping with the in vivo experiments in zebrafish and the scientific and technical assistance of the Australian Microscopy and Microanalysis Research Facility at the Australian Centre for Microscopy and Microanalysis at the University of Sydney.