New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity.
One dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested in vitro as histone deacetylase (HDAC) inhibitors. The new molecules, as well as their sulfurated moieties, exhibited a much stronger inhibition of HDAC enzymatic and antiproliferative activities and histone hyperacetylation than VPA. ACS 2 is the most interesting compound among the new VPA derivatives and its sulfurated moiety, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, also known to be a metabolite of anethole trithione, seems to contribute significantly to its activity. This is the first time that HDAC inhibitory activity is described for dithiolethiones and thiosulfonates.
Perrino
Elena
E
Sulfidris s.r.l., Viale Gran Sasso 17, 20131 Milan, Italy.
Cappelletti
Graziella
G
Tazzari
Valerio
V
Giavini
Erminio
E
Del Soldato
Piero
P
Sparatore
Anna
A
D000107:Acetylation; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013886:Thiosulfonic Acids / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C529309:ACS2 compound; C529310:ACS33 compound; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D013886:Thiosulfonic Acids; D014635:Valproic Acid