948837-87-4Relevant academic research and scientific papers
Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacolozgical profiles
Dehmel, Florian,Weinbrenner, Steffen,Julius, Heiko,Ciossek, Thomas,Maier, Thomas,Stengel, Thomas,Fettis, Kamal,Burkhardt, Carmen,Wieland, Heike,Beckers, Thomas
experimental part, p. 3985 - 4001 (2009/05/11)
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 Ki = 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.
Trithiocarbonates-Exploration of a new head group for HDAC inhibitors
Dehmel, Florian,Ciossek, Thomas,Maier, Thomas,Weinbrenner, Steffen,Schmidt, Beate,Zoche, Martin,Beckers, Thomas
, p. 4746 - 4752 (2008/12/21)
Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn2+ complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.
