Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacological profiles.

Abstract

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 alpha-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 alpha-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-alpha-carbonyl motif for potent HDAC inhibition. Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 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.

• Authors: Florian Dehmel, Steffen Weinbrenner, Heiko Julius, Thomas Ciossek, Thomas Maier, Thomas Stengel, Kamal Fettis, Carmen Burkhardt, Heike Wieland, Thomas Beckers
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 13 Pg. 3985-4001 (Jul 10 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18558669 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Histones
• Isoenzymes
• Thiones
• Histone Deacetylases
• trithiocarbonic acid

Topics

• Acetylation
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Histone Deacetylase Inhibitors
• Histone Deacetylases (metabolism)
• Histones (metabolism)
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• Kinetics
• Molecular Structure
• Structure-Activity Relationship
• Thiones (chemical synthesis, chemistry, pharmacology)