2. Academic Validation
  3. Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors

Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors

  • J Med Chem. 2019 Feb 14;62(3):1138-1166. doi: 10.1021/acs.jmedchem.8b01090.
Katharina Vögerl 1,  Nghia Ong 1,  Johanna Senger 2,  Daniel Herp 2,  Karin Schmidtkunz 2,  Martin Marek 3,  Martin Müller 1,  Karin Bartel 1,  Tajith B Shaik 3,  Nicholas J Porter 4,  Dina Robaa 5,  David W Christianson 4,  Christophe Romier 3,  Wolfgang Sippl 5,  Manfred Jung 2,  Franz Bracher 1
Affiliations

Affiliations

  • 1 Department of Pharmacy-Center for Drug Research , Ludwig-Maximilians University Munich , Butenandtstr. 5-13 , 81377 Munich , Germany.
  • 2 Institute of Pharmaceutical Sciences , University of Freiburg , Albertstraße 25 , 79104 Freiburg , Germany.
  • 3 Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC) , Université de Strasbourg (UDS), CNRS, INSERM , 67404 Illkirch Cedex , France.
  • 4 Department of Chemistry , University of Pennsylvania , 231 South 34th Street , Philadelphia , Pennsylvania 19104-6323 , United States.
  • 5 Institute of Pharmacy , Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale , Germany.
PMID: 30645113 DOI: 10.1021/acs.jmedchem.8b01090
Abstract

The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC Enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various Cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.

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