Borretto Emily, Lazzarato Loretta, Spallotta Francesco, Cencioni Chiara, D'Alessandra Yuri, Gaetano Carlo, Fruttero Roberta, Gasco Alberto
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via Pietro Giuria 9, 10125 Torino, Italy.
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS , Via Carlo Parea 4, 20138 Milan, Italy.
ACS Med Chem Lett. 2013 Sep 4;4(10):994-9. doi: 10.1021/ml400289e. eCollection 2013 Oct 10.
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.
通过将适度选择性I类组蛋白脱乙酰酶（HDAC）抑制剂恩替诺特与4-（甲基氨基甲基）呋咱-3-腈支架连接而正式获得的一氧化氮供体型组蛋白脱乙酰酶抑制剂2被描述，并讨论了其初步生物学特性。这种杂合物调节I类和II类HDAC。该化合物释放的一氧化氮（NO）激活可溶性鸟苷酸环化酶（sGC），导致II类核穿梭和染色质修饰，从而影响基因表达。该杂合物影响许多不受其单个组分调节的微小RNA；它以比其两种组分的1:1混合物更有效的方式促进肌源性分化，诱导形成更大的肌管，每根纤维中的细胞核明显更多。该杂合物是目前正在开发的一类新型一氧化氮供体HDAC的一个例子，有望用于治疗多种疾病。
