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Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation

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journal contribution
posted on 22.11.2019, 21:08 by Barbara Vergani, Giovanni Sandrone, Mattia Marchini, Chiara Ripamonti, Edoardo Cellupica, Elisabetta Galbiati, Gianluca Caprini, Gianfranco Pavich, Giulia Porro, Ilaria Rocchio, Maria Lattanzio, Marcello Pezzuto, Malgorzata Skorupska, Paola Cordella, Paolo Pagani, Pietro Pozzi, Roberta Pomarico, Daniela Modena, Flavio Leoni, Raffaella Perego, Gianluca Fossati, Christian Steinkühler, Andrea Stevenazzi
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.