title: Synthesis and biological evaluation of a targeted DNA-binding transcriptional activator with HDAC8 inhibitory activity.
abstract: 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).
authors.affiliation: Department of Science, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Saha
authors.forename: Ganesh N
authors.initials: GN
authors.lastname: Pandian
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Sato
authors.forename: Junichi
authors.initials: J
authors.lastname: Taniguchi
authors.forename: Kaori
authors.initials: K
authors.lastname: Hashiya
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry*; D016503:Drug Delivery Systems; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009757:Nylons / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; C585735:JAHA-PIP-delta; D009757:Nylons; D011758:Pyrroles; C585734:SAHA-PIP-delta; D004247:DNA; D006655:Histone Deacetylases