Synthesis and biological evaluation of a targeted DNA-binding transcriptional activator with HDAC8 inhibitory activity

A Saha, GN Pandian, S Sato, J Taniguchi… - Bioorganic & medicinal …, 2013 - Elsevier
A Saha, GN Pandian, S Sato, J Taniguchi, K Hashiya, T Bando, H Sugiyama
Bioorganic & medicinal chemistry, 2013Elsevier
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 …
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).
Elsevier