Design and synthesis of cyclopeptide analogues of the potent histone deacetylase inhibitor FR235222
Design and synthesis of cyclopeptide analogues of the potent histone deacetylase inhibitor FR235222
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DOI：
10.1002/cmdc.200700095
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发表时间：
2007-10-01
期刊：
影响因子：
3.4
通讯作者：
Sadoul, Karin
中科院分区：
文献类型：
--
作者：
Gomez-Paloma, Luigi;Bruno, Ines;Sadoul, Karin
FR 235222（1）是哺乳动物组蛋白去乙酰化酶的天然四肽抑制剂，我们用聚合方法制备了FR 235222（1）的各种结构修饰类似物。化合物的设计旨在研究参与酶结合的四肽核心的结构修饰的效果，以克服与天然产物1相关的一些合成困难。引入的修饰也可以帮助确定这些化合物作用机制中涉及的关键结构特征。制备的分子进行体外药理学试验，并在培养的细胞上测试其效力。发现该阵列的两种组分比母体化合物I更有效，并且几乎与阿司他汀A（TSA）一样有效。这些结果表明，可以使用市售氨基酸（除了2-氨基-8-氧代癸酸，Ahoda）合成高活性的环状四肽。环肽第二位残基的性质和Ahoda尾的立体化学对于这类环四肽类似物的抑制活性是重要的。
Various structurally modified analogues of FR235222 (1), a natural tetrapeptide inhibitor of mammalian histone deacetylases, were prepared in a convergent approach. The design of the compounds was aimed to investigate the effect of structural modifications of the tetrapeptide core involved in enzyme binding in order to overcome some synthetic difficulties connected with the natural product 1. The modifications introduced could also help identify key structural features involved in the mechanism of action of these compounds. The prepared molecules were subjected to in vitro pharmacological tests, and their potency was tested on cultured cells. Two of the components of the array were found to be more potent than the parent compound I and almost as efficient as trichostatin A (TSA). These results demonstrate that it is possible to synthesize highly active cyclic tetrapeptides using commercially available amino acids (with the exception of 2-amino-8-oxodecanoic acid, Ahoda). The nature of the residue in the second position of the cyclic peptide and the stereochemistry of the Ahoda tail are important for the inhibitory activity of this class of cyclic tetrapeptide analogues.