Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors.
Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors.
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DOI：
10.1016/j.ejmech.2016.05.031
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发表时间：
2016-10
影响因子：
6.7
通讯作者：
Koichi Narita;Keisuke Matsuhara;J. Itoh;Y. Akiyama;Singo Dan;T. Yamori;A. Ito;Minoru Yoshida;T. Katoh
中科院分区：
文献类型：
--
作者：
Koichi Narita;Keisuke Matsuhara;J. Itoh;Y. Akiyama;Singo Dan;T. Yamori;A. Ito;Minoru Yoshida;T. Katoh
以高度收敛和统一的方式有效合成了新型 C4 和 C7 修饰的 FK228 类似物。该合成的特点是含有甘氨酸-d-半胱氨酸的片段与含有缬氨酸的片段进行酰胺缩合，以直接组装相应的片段酸，片段酸是大环内酯的关键前体。合成类似物的 HDAC 抑制测定和细胞生长抑制分析揭示了它们结构-活性关系的新方面。这项研究表明，对 FK228 的 C4 和 C7 侧链进行简单修饰可有效提高 HDAC 抑制活性和异构体选择性；此外，还鉴定出了有效且高度异构体选择性的 I 类 HDAC1 抑制剂。
Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments withd-valine-containing segments for the direct assembly of the correspondingseco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship. This study demonstrated that simple modification at the C4 and C7 side chains in FK228 is effective for improving both HDAC inhibitory activity and isoform selectivity; moreover, potent and highly isoform-selective class I HDAC1 inhibitors were identified.