tubastatin-a and benzohydroxamic-acid

This paper provides an overview of the synthesis and biological activity of the most representative benzohydroxamic acid-based histone deacetylase inhibitors published to date. Benzohydroxamic acids comprise an important class of HDAC inhibitors, and recently several of these structures have been evaluated in clinical trials for the treatment of a variety of cancers. In this overview, benzohydroxamic acids were divided in four different classes based on their reported selectivity towards zinc-dependent HDACs: a first and major class consists of HDAC6 selective inhibitors, a second class deals with pan-HDAC inhibitors, a third class comprises HDAC8 selective inhibitors and a fourth, minor class includes dual HDAC6/8 selective inhibitors. Through this approach, structure-activity relationships were identified for each class, which could help future researchers in the design and development of novel benzohydroxamic acid-based HDAC inhibitors.

Topics: Dose-Response Relationship, Drug; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Molecular Structure; Structure-Activity Relationship

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.

Topics: Acetylation; Animals; Catalytic Domain; Cells, Cultured; Crystallography, X-Ray; Histone Deacetylase 6; Histone Deacetylase Inhibitors; HL-60 Cells; Humans; Hydroxamic Acids; In Vitro Techniques; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Phenothiazines; Structure-Activity Relationship; Zebrafish

Histone deacetylase 6 (HDAC6) is a peculiar HDAC isoform whose expression and functional alterations have been correlated with a variety of pathologies such as autoimmune disorders, neurodegenerative diseases, and cancer. It is primarily a cytoplasmic protein, and its deacetylase activity is focused mainly on nonhistone substrates such as tubulin, heat shock protein (HSP)90, Foxp3, and cortactin, to name a few. Selective inhibition of HDAC6 does not show cytotoxic effects in healthy cells, normally associated with the inhibition of Class I HDAC isoforms. Here, we describe the design and synthesis of a new class of potent and selective HDAC6 inhibitors that bear a pentaheterocyclic central core. These compounds show a remarkably low toxicity both in vitro and in vivo and are able to increase the function of regulatory T cells (Tregs) at well-tolerated concentrations, suggesting a potential clinical use for the treatment of degenerative, autoimmune diseases and for organ transplantation.

Topics: Animals; Cell Survival; Drug Design; Gene Expression Regulation, Enzymologic; Histone Deacetylase 6; Histones; Hydroxamic Acids; Mice; Protein Isoforms; Spleen; T-Lymphocytes, Regulatory; Tubulin