Trithiocarbonates as a Novel Class of HDAC Inhibitors: SAR Studies, Isoenzyme Selectivity, and Pharmacological Profiles

Inhibitors of histone deacetylases (HDAC) are currently developed for the treatment of cancer. These include compounds with a sulfur containing head group like depsipeptide, alkylthiols, thiocarboxylates, and trithiocarbonates with a carbonyl group in the α-position. In the present investigation, we report on the synthesis and comprehensive SAR analysis of HDAC inhibitors bearing a tri- or dithiocarbonate motif. Such trithiocarbonates are readily accessible from either preformed or in situ prepared α-halogenated methylaryl ketones. A HDAC isotype selectivity and a substrate competitive mode-of-action is shown for defined analogues. Exploration of the head group showed the necessity of the dithio-α-carbonyl motif for potent HDAC inhibition. Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug.