Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2011 May 1;21(9):2601-5. doi: 10.1016/j.bmcl.2011.01.134. Epub 2011 Feb 2.
We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified 'cap/linker/biasing element' structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds.
我们开发了一种在 96 孔板中高效合成候选组蛋白去乙酰化酶 (HDAC) 抑制剂的方法，可直接用于高通量筛选。我们选择了具有酰肼、醛基和羟肟酸官能团的砌块。酰肼在 DMSO 中与不同的醛偶联。得到的产物具有先前鉴定的有利于抑制 HDAC 的“帽/连接/偏置元件”结构。这些化合物未经进一步纯化就进行了检测。从这个新的化合物库中发现了 HDAC8 选择性抑制剂。
