Dehmel Florian, Weinbrenner Steffen, Julius Heiko, Ciossek Thomas, Maier Thomas, Stengel Thomas, Fettis Kamal, Burkhardt Carmen, Wieland Heike, Beckers Thomas
Nycomed GmbH, Therapeutic Area Oncology, Byk-Gulden-Strasse 2, D-78467 Konstanz, Germany.
J Med Chem. 2008 Jul 10;51(13):3985-4001. doi: 10.1021/jm800093c. Epub 2008 Jun 18.
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.
组蛋白脱乙酰酶（HDAC）抑制剂目前正被开发用于癌症治疗。这些抑制剂包括带有含硫头部基团的化合物，如缩肽、烷基硫醇、硫代羧酸盐以及在α位带有羰基的三硫代碳酸盐。在本研究中，我们报告了带有三硫代碳酸盐或二硫代碳酸盐基序的HDAC抑制剂的合成及全面的构效关系分析。此类三硫代碳酸盐可通过预制的或原位制备的α-卤代甲基芳基酮轻松获得。已证明特定类似物具有HDAC亚型选择性和底物竞争作用模式。对头部基团的探索表明，二硫代-α-羰基基序对于有效抑制HDAC是必要的。已鉴定出高效、底物竞争性的HDAC6选择性抑制剂（12ac：IC50 = 65 nM，Ki = 110 nM）。带有氨基喹啉取代的吡啶基-噻吩乙酰帽的三硫代碳酸盐类似物表现出与已获批的抗癌药物辛二酰苯胺异羟肟酸（SAHA）相当的细胞毒性谱和效力。
