Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells

被引：153
|
作者：
Marek, Linda [1 ]
Hamacher, Alexandra [1 ]
Hansen, Finn K. [1 ]
Kuna, Krystina [1 ]
Gohlke, Holger [1 ]
Kassack, Matthias U. [1 ]
Kurz, Thomas [1 ]
机构：
[1] Univ Dusseldorf, Inst Pharmazeut & Med Chem, D-40225 Dusseldorf, Germany
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 02期
关键词：
SUBEROYLANILIDE HYDROXAMIC ACID; CISPLATIN RESISTANCE; CRYSTAL-STRUCTURE; DOCKING; BINDING; COMBINATIONS; PREDICT;
D O I：
10.1021/jm301254q
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 191 (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.
引用
收藏
页码：427 / 436
页数：10
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