title: Synthesis and Biological Evaluation of the First Example of NO-Donor Histone Deacetylase Inhibitor.
abstract: The NO-donor histone deacetylase inhibitor 2, formally obtained by joining Entinostat 1, a moderately selective Class I histone deacetylases (HDACs) inhibitor, to a 4-(methylaminomethyl)furoxan-3-carbonitrile scaffold, is described and its preliminary biological profile discussed. This hybrid regulates Classes I and II HDACs. Nitric oxide (NO) released by the compound activates soluble guanylate cyclase (sGC), causing Class II nuclear shuttling and chromatin modifications, with consequences on gene expression. The hybrid affects a number of micro-RNAs not modulated by its individual components; it promotes myogenic differentiation, inducing the formation of larger myotubes with significantly more nuclei per fiber, in a more efficient manner than the 1:1 mixture of its two components. The hybrid is an example of a new class of NO-donor HDACs now being developed, which should be of interest for treating a number of diseases.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Emily
authors.initials: E
authors.lastname: Borretto
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.affiliation: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS , Via Carlo Parea 4, 20138 Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spallotta
authors.affiliation: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS , Via Carlo Parea 4, 20138 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cencioni
authors.affiliation: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS , Via Carlo Parea 4, 20138 Milan, Italy.
authors.forename: Yuri
authors.initials: Y
authors.lastname: D'Alessandra
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
keywords: HDAC; NO-donor; epigenetics; histone deacetylase inhibitors; multitarget drugs