Synthesis, evaluation and absolute configuration assignment of novel dihydropyrimidin-2-ones as picomolar sodium iodide symporter inhibitors
Synthesis, evaluation and absolute configuration assignment of novel dihydropyrimidin-2-ones as picomolar sodium iodide symporter inhibitors
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DOI：
10.1016/j.ejmech.2013.01.043
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发表时间：
2013-04-01
影响因子：
6.7
通讯作者：
Ambroise, Yves
中科院分区：
文献类型：
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作者：
Lacotte, Pierre;Buisson, David-Alexandre;Ambroise, Yves
合成了一个小的二氢嘧啶-2-酮(DHPM)文库，并对其阻断碘在大鼠甲状腺细胞中的包封性进行了评价。合成采用多组分的Biginelli反应。通过细胞实验检测了12个化合物对钠碘同向转运体(NIS)的抑制作用。一种新合成的衍生物显示出非常强的活性，其半数最大抑制浓度(IC50)为65 pM用手性高效液相色谱法进一步从外消旋体中拆分了三个DHPM，并用圆二色光谱对其绝对构型进行了归属。生物评价表明，大部分抗NIS活性存在于一种对映体中。这项研究为抗甲状腺药物的开发以及合成新的药理工具提供了新的见解，这些工具旨在研究细胞和分子水平上的碘转运机制。(C)2013年爱思唯尔·马森公司。版权所有。
A small library of dihydropyrimidin-2-ones (DHPMs) was synthesized and evaluated for their potency to block iodide entrapment in rat thyroid cells. Synthesis was achieved using the multicomponent Biginelli reaction. Twelve compounds were tested for the inhibition of sodium iodide symporter (NIS) in a cell-based assay. One newly synthesized derivative exhibited a remarkably strong activity, with a half-maximum inhibitory concentration value (IC50) of 65 pM. Three DHPMs were further resolved from racemates using chiral HPLC and absolute configurations were assigned using circular dichroism spectroscopy. Biological evaluation showed that most of the activity against NIS resides in one enantiomer. This study provides new insights for the development of anti-thyroid drugs, as well as for the synthesis of novel pharmacological tools designed to investigate iodide transport mechanisms at cellular and molecular levels. (C) 2013 Elsevier Masson SAS. All rights reserved.