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Chemical Modification of a Synthetic Small Molecule Boosts Its Biological Efficacy against Pluripotency Genes in Mouse Fibroblasts
Author(s) -
Saha Abhijit,
Pandian Ganesh N.,
Sato Shinsuke,
Taniguchi Junichi,
Kawamoto Yusuke,
Hashiya Kaori,
Bando Toshikazu,
Sugiyama Hiroshi
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402117
Subject(s) - activator (genetics) , embryonic stem cell , chemistry , gene , conjugate , epigenetics , microbiology and biotechnology , biology , biochemistry , mathematical analysis , mathematics
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.