Synthesis and Biological Evaluation of a Targeted DNA-Binding Transcriptional Activator with HDAC8 Inhibitory Activity
Synthesis and Biological Evaluation of a Targeted DNA-Binding Transcriptional Activator with HDAC8 Inhibitory Activity
复制标题
具有 HDAC8 抑制活性的靶向 DNA 结合转录激活剂的合成和生物学评价
DOI：
10.1016/j.bmc.2013.05.002
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
Saha;A.; Pandian;G. N.; Sato;S.; Taniguchi;J.; Hashiya;K.; Bando;T.;Sugiyama;H.
多功能转录激活因子的开发越来越重要，因为它们可以触发复杂的基因网络。最近，我们通过将组蛋白去乙酰化酶（HDAC）抑制剂SAHA与选择性DNA结合的吡咯-咪唑聚酰胺（PIP）偶联，开发了一种差异基因激活的多功能小分子SAHA-PIP（Sδ）。Sδ的表观遗传活性与SAHA的活性金属结合（-NHOH）结构域有关。我们合成了Sδ的衍生物Jδ，以评估SAHA的表面识别结构域（-苯基）在Sδ介导的转录激活中的作用。体外研究表明Jδ对HDAC 8具有较强的抑制活性。当单独使用和与Sδ组合使用时，Jδ保留了Sδ的多能性基因诱导能力;观察到多能性基因表达的显著增加。有趣的是，Jδ显著诱导HDAC 8控制的Otx 2和Lhx 1的表达。我们的研究结果表明，我们的多功能分子的表观遗传活性可以改变，以提高其作为复杂基因网络的转录激活因子的效率。
Development of multifunctional transcriptional activators is of increasing importance as they could trigger complicated gene networks. Recently, we developed a differential gene activating multifunctional small molecule SAHA-PIP (Sδ) by conjugating a histone deacetylase (HDAC) inhibitor, SAHA, to a selective DNA-binding pyrrole-imidazole polyamide (PIP). Epigenetic activity of Sδ was attributed to the active metal-binding (–NHOH) domain of SAHA. We synthesized a derivative of Sδ, called Jδ to evaluate the role of surface recognition domain (–phenyl) of SAHA in Sδ-mediated transcriptional activation. In vitro studies revealed that Jδ displayed potent inhibitory activity against HDAC8. Jδ retained the pluripotency gene-inducing ability of Sδ when used alone and in combination with Sδ; a notable increase in the pluripotency gene expression was observed. Interestingly, Jδ significantly induced the expression of HDAC8-controlled Otx2 and Lhx1. Our results suggest that the epigenetic activity of our multifunctional molecule could be altered to improve its efficiency as a transcriptional activator for intricate gene network(s).