Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives.
Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives.
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DOI：
10.1016/j.bmc.2008.10.077
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发表时间：
2009-03-15
影响因子：
3.5
通讯作者：
Ireland, Chris M.
中科院分区：
文献类型：
--
作者：
McCulloch, Malcolm W. B.;Coombs, Gary S.;Banerjee, Nikhil;Bugni, Tim S.;Cannon, Kendell M.;Harper, Mary Kay;Veltri, Charles A.;Virshup, David M.;Ireland, Chris M.
关键词：
Wnt信号通路调节后生动物的细胞生长和发育，因此对药物发现感兴趣。通过在基于细胞的Wnt信号传导测定中筛选5，808种预分级海洋提取物的文库，观察到几种信号传导激活剂和抑制剂。基于LCMS的分级快速鉴定了来自Pseudoceratina purpurea的活性化合物为psammaplin A，一种已知的HDAC抑制剂。其他HDAC抑制剂在该测定中类似地激活信号传导，表明HDAC抑制剂将通过许多基于细胞的报告基因测定来鉴定。在大规模的P. purpurea分析中，鉴定了三种以前未描述的基于溴酪氨酸的天然产物;其中一种的结构通过合成得到证实。此外，还制备了三种其他的Psammaplin A衍生物：一种混合二硫化物和两种亚磺酸酯。最后，证据支持的结构重新分配的psammaplin我从砜的异构亚磺酸酯。
The Wnt signaling pathway regulates cell growth and development in metazoans, and is therefore of interest for drug discovery. By screening a library of 5,808 pre-fractionated marine extracts in a cell-based Wnt signaling assay, several signaling activators and inhibitors were observed. LCMS based fractionation rapidly identified an active compound from Pseudoceratina purpurea as psammaplin A, a known HDAC inhibitor. Other HDAC inhibitors similarly activated signaling in this assay, indicating HDAC inhibitors will be identified through many cell-based reporter assays. In a large scale analysis of P. purpurea, three previously undescribed bromotyrosine based natural products were identified; the structure of one of these was confirmed by synthesis. Additionally, three other derivatives of psammaplin A were prepared: a mixed disulfide and two sulfinate esters. Finally, evidence to support a structural reassignment of psammaplin I from a sulfone to the isomeric sulfinate ester is presented.
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