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Bioorg Med Chem Lett. 2017 Apr 1;27(7):1508-1512. doi: 10.1016/j.bmcl.2017.02.050. Epub 2017 Feb 21.

Perfluorinated hydroxamic acids are potent and selective inhibitors of HDAC-like enzymes from Pseudomonas aeruginosa.

Author information

1
Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Haardtring 100, 64295 Darmstadt, Germany.
2
Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Haardtring 100, 64295 Darmstadt, Germany. Electronic address: franz-josef.meyer-almes@h-da.de.

Abstract

A series of perfluorinated SAHA (PFSAHA) was prepared and profiled against a panel of human and bacterial members of the Histone deacetylase (HDAC) family. Some of the active substances show nanomolar inhibitory activity and several hundred fold selectivity for the HDAC like enzyme PA3774 from P. aeruginosa. The extraordinary selectivity against human HDACs results from the distinct oligomeric state of PA3774 which consists of two head-to-head dimers. The binding pocket is defined by the surface of both opposite monomers confining the access of ligands to the active site. In addition, the aromatic cap group of PFSAHA undergoes an edge-to-face aromatic interaction with phenylalanine from the opposite monomer.

KEYWORDS:

HDAC inhibitors; Perfluorinated hydroxamic acids; Pseudomonas aeruginosa; Selectivity

PMID:
28259626
DOI:
10.1016/j.bmcl.2017.02.050
[Indexed for MEDLINE]

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