title: Chemical modification of a synthetic small molecule boosts its biological efficacy against pluripotency genes in mouse fibroblasts.
abstract: A synthetic transcriptional activator encompassing both sequence-specific pyrrole-imidazole polyamides (PIPs) and an epigenetic activator (suberoylanilide hydroxamic acid) was recently shown to induce the endogenous expression of core pluripotency genes in mouse embryonic fibroblasts (MEFs). Microarray data analysis suggested Oct-3/4 as the probable target pathway of the activator. However, the expression levels in MEFs treated with the activator were relatively lower than those in mouse embryonic stem cells. Herein, we report studies carried out to improve the efficacy of the activator and show that the biological activity was significantly (p<0.05) improved against the core pluripotency genes after the incorporation of an isophthalic acid (IPA) at the C terminus. The resultant IPA conjugate dramatically induced Oct-3/4 and demonstrated a new chemical strategy for developing PIP conjugates as next-generation genetic switches.
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: Yusuke
authors.initials: Y
authors.lastname: Kawamoto
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: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet
keywords: biological activity; cellular uptake; gene expression; polyamides; transcription