New aryldithiolethione derivatives as potent histone deacetylase inhibitors

Abstract

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodelling and gene transcription and there is a growing interest in inhibitors of HDAC as a promising class of anticancer agents. Recently we have found that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) and its valproic acid ester ACS 2 potently inhibited in vitro HDAC enzymatic activity as well as A549 cell proliferation with increased levels of hyperacetylated histone H4-acetylation [1]. On this ground and with the aim to explore further the anticancer potentialities of dithiolethiones, we designed and synthesized novel derivatives taking as a model the chemical structure of the well known and recently marketed HDAC inhibitor SAHA. In our new compounds the aryldithiolethione moiety is linked to an alkyl chain by mean of an ester or an ether linkage. All compounds exhibited in vitro HDAC inhibitory activity, sometimes comparable or higher than SAHA (IC50<0.1\u3bcM). A discussion on structure-activity relationships of the synthesized compounds will be performed. Data on inhibition of cellular proliferation and on histone hyperacetylation by the most active compounds will be also reporte