Synthesis and Biological Evaluation of Targeted Transcriptional Activator with HDAC8 Inhibitory Activity
We demonstrated the activation of genes that played important roles in the early development process of living animals. To do that, we developed a new class of compounds known as SAHA-PIP, which is a combination of two functional domains. One is DNA minor groove-binding pyrrole–imidazole polyamide and the other one is histone deacetylase inhibitor HDACi called SAHA. In a previous study, we developed Sδ as one of such compound exhibiting both DNA-binding and HDAC-inhibitory activity. 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).
KeywordsBiomimetic synthesis DNA recognition HDAC8 inhibition Transcriptional activators Developmental genes
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