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 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.
Nycomed GmbH, Therapeutic Area Oncology, Byk-Gulden-Strasse 2, D-78467 Konstanz, Germany.
Florian
F
Dehmel
Steffen
S
Weinbrenner
Heiko
H
Julius
Thomas
T
Ciossek
Thomas
T
Maier
Thomas
T
Stengel
Kamal
K
Fettis
Carmen
C
Burkhardt
Heike
H
Wieland
Thomas
T
Beckers
D000107:Acetylation; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007527:Isoenzymes; D013871:Thiones; D006655:Histone Deacetylases; C013321:trithiocarbonic acid