Chemical Modification of a Synthetic Small Molecule Boosts Its Biological Efficacy Against Pluripotency Genes in Mouse Fibroblast

Chapter
Part of the Springer Theses book series (Springer Theses)

Abstract

Our synthetic transcriptional activator SAHA-PIP, Sδ (described here as 1), encompassing both sequence-specific pyrrole–imidazole polyamides (PIPs) and an epigenetic activator (SAHA) was shown to induce the endogenous expression of core pluripotency genes in mouse embryonic fibroblasts (MEFs). However, the expression levels of pluripotency genes by 1 in MEFs were relatively lesser than that in mouse embryonic stem (ES) cells. Here, in this chapter, we carried out studies to improve the efficacy of 1 and show that the biological activity of 1 got significantly (P ≤ 0.05) improved against the core pluripotency genes after the incorporation of an isophthalic acid (IPA) in its C-terminus. The resultant IPA conjugate 2 dramatically induced Oct-3/4 to demonstrate a new chemical strategy for developing PIP conjugates as next-generation genetic switches.

Keywords

Biological activity Cellular uptake Gene expression Polyamides Transcription 

References

  1. 1.
    Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, Zhao Y, Deng H (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341:651–654.  https://doi.org/10.1126/science.1239278 CrossRefGoogle Scholar
  2. 2.
    (a) Wu YL, Pandian GN, Ding YP, Zhang W, Tanaka Y, Sugiyama H (2013) Clinical grade iPS cells: need for versatile small molecules and optimal cell sources. Chem Biol 20:1311–1322.  https://doi.org/10.1016/j.chembiol.2013.09.016; (b) Pandian GN, Sugiyama H (2012) Programmable genetic switches to control transcriptional machinery of pluripotency. Biotechnol J 7:798–809.  https://doi.org/10.1002/biot.201100361
  3. 3.
    Ohtsuki A, Kimura MT, Minoshima M, Suzuki T, Ikeda M, Bando T, Nagase H, Shinohara K, Sugiyama H (2009) Synthesis and properties of PI polyamide—SAHA conjugate. Tetrahedron Lett 50:7288–7292.  https://doi.org/10.1016/j.tetlet.2009.10.034 CrossRefGoogle Scholar
  4. 4.
    Wähnert U, Zimmer O, Luck G, Pitra O (1975) (dA-dT) Dependent inactivation of the DNA template properties by interaction with netropsin and distamycin A. Nucleic Acids Res 2:391–404CrossRefGoogle Scholar
  5. 5.
    Kopka ML, Yoon C, Goodsell D, Pjura P, Dickerson RE (1985) Binding of an antitumor drug to DNA, Netropsin and C-G-C-G-A-A-T-T-BrC-G-C-G. Mol Biol 183:553–563CrossRefGoogle Scholar
  6. 6.
    Dervan PB (2001) Molecular recognition of DNA by small molecules. Bioorg Med Chem 9:2215–2235CrossRefGoogle Scholar
  7. 7.
    Han L, Pandian GN, Junetha S, Sato S, Anandhakumar C, Taniguchi J, Saha A, Bando T, Nagase H, Sugiyama H (2013) A synthetic small molecule for targeted transcriptional activation of germ cell genes in a human somatic cell. Angew Chem Int Ed 52:13410–13413.  https://doi.org/10.1002/anie.201306766 CrossRefGoogle Scholar
  8. 8.
    (a) Pandian GN, Taniguchi J, Junetha S, Sato S, Han L, Saha A, AnandhaKumar C, Bando T, Nagase H, Vaijayanthi T, Taylor RD, Sugiyama H (2014) Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts. Sci Rep 4:3843.  https://doi.org/10.1038/srep03843; (b) Pandian GN, Sugiyama H (2012) Strategies to modulate heritable epigenetic defects in cellular machinery: lessons from nature. Pharmaceuticals 6:1–24.  https://doi.org/10.3390/ph6010001
  9. 9.
    Pandian GN, Shinohara K, Ohtsuki A, Nakano Y, Masafumi M, Bando T, Nagase H, Yamada Y, Watanabe A, Terada N, Sato S, Morinaga H, Sugiyama H (2011) Synthetic small molecules for epigenetic activation of pluripotency genes in mouse embryonic fibroblasts. Chem BioChem 12:2822–2828.  https://doi.org/10.1002/cbic.201100597 Google Scholar
  10. 10.
    Pandian GN, Nakano Y, Sato S, Morinaga H, Bando T, Nagase H, Sugiyama H (2012) A synthetic small molecule for rapid induction of multiple pluripotency genes in mouse embryonic fibroblasts. Sci Rep 2:544.  https://doi.org/10.1038/srep00544 CrossRefGoogle Scholar
  11. 11.
    Saha A, Pandian GN, Sato S, Taniguchi J, Hashiya K, Bando T, Sugiyama H (2013) Synthesis and biological evaluation of a targeted DNA-binding transcriptional activator with HDAC8 inhibitory activity. Bioorg Med Chem 21:4201–4209.  https://doi.org/10.1016/j.bmc.2013.05.002 CrossRefGoogle Scholar
  12. 12.
    Jacobs CS, Dervan PB (2009) Modifications at the C-terminus to improve pyrrole-imidazole polyamide activity in cell culture. J Med Chem 52:7380–7388.  https://doi.org/10.1021/jm900256f CrossRefGoogle Scholar
  13. 13.
    Hargrove AE, Raskatov JA, Meier JL, Montgomery DC, Dervan PB (2012) Characterization and solubilization of pyrrole-imidazole polyamide aggregates. J Med Chem 55:5425–5432.  https://doi.org/10.1021/jm300380a CrossRefGoogle Scholar
  14. 14.
    (a) Belitsky JM, Leslie SJ, Arora PS, Beerman TA, Dervan PB (2002) Cellular uptake of N-methylpyrrole/N-methylimidazole polyamide-dye conjugates. Bioorg Med Chem 10:3313–3318; (b) Vaijayanthi T, Bando T, Hashiya K, Pandian GN, Sugiyama H (2013) Design of a new fluorescent probe: pyrrole/imidazole hairpin polyamides with pyrene conjugation at their γ-turn. Bioorg Med Chem 21:852–855.  https://doi.org/10.1016/j.bmc.2012.12.018
  15. 15.
    Nickols NG, Jacobs CS, Farkas ME, Dervan PB (2007) Improved nuclear localization of DNA-binding polyamides. Nucleic Acids Res 35:363–370.  https://doi.org/10.1093/nar/gkl1042 CrossRefGoogle Scholar
  16. 16.
    Adlington RM, Baldwin JE, Becker GW, Chen B, Cheng L, Cooper SL, Hermann RB, Howe TJ, McCoull W, McNulty AM, Neubauer BL, Pritchard GJ (2001) Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen. J Med Chem 44:1491–1508CrossRefGoogle Scholar
  17. 17.
    Chenoweth DM, Harki DA, Dervan PB (2009) Solution-phase synthesis of pyrrole-imidazole polyamides. J Am Chem Soc 131:7175–7181.  https://doi.org/10.1021/ja901307m CrossRefGoogle Scholar
  18. 18.
    Nishijima S, Shinohara K, Bando T, Minoshima M, Kashiwazaki G, Sugiyama H (2010) Cell permeability of Py-Im-polyamide-fluorescein conjugates: influence of molecular size and Py/Im content. Bioorg Med Chem 18:978–983.  https://doi.org/10.1016/j.bmc.2009.07.018 CrossRefGoogle Scholar
  19. 19.
    Meier JL, Montgomery DC, Dervan PB (2012) Enhancing the cellular uptake of Py-Im polyamides through next-generation aryl turns. Nucleic Acids Res 40:2345–2356.  https://doi.org/10.1093/nar/gkr970 CrossRefGoogle Scholar
  20. 20.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676.  https://doi.org/10.1016/j.cell.2006.07.024 CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Institute CurieOrsayFrance

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