Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Adenocarcinoma / drug therapy
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Adenocarcinoma / enzymology
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Apoptosis / drug effects
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Blotting, Western
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Cell Proliferation / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology*
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Histone Deacetylase Inhibitors*
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / enzymology
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Molecular Structure
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Structure-Activity Relationship
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Thiosulfonic Acids / chemistry
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Tumor Cells, Cultured / drug effects
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Valproic Acid / analogs & derivatives*
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Valproic Acid / antagonists & inhibitors
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Valproic Acid / chemical synthesis
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Valproic Acid / chemistry*
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Valproic Acid / pharmacology
Substances
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ACS2 compound
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ACS33 compound
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Thiosulfonic Acids
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Valproic Acid