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A DNA Methyltransferase Modulator Inspired by Peyssonenyne Natural Product Structures

Authors

  • Dr. Patricia García-Domínguez,

    1. Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo (Spain)
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  • Mélanie Weiss,

    1. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg (France)
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  • Ilaria Lepore,

    1. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. de Crecchio 7, 80138 Napoli (Italy)
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  • Prof. Dr. Rosana Álvarez,

    1. Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo (Spain)
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  • Prof. Dr. Lucia Altucci,

    Corresponding author
    1. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. de Crecchio 7, 80138 Napoli (Italy)
    2. CNR-IGB, via P. Castellino, 80100 Napoli (Italy)
    • Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. de Crecchio 7, 80138 Napoli (Italy)
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  • Prof. Dr. Hinrich Gronemeyer,

    Corresponding author
    1. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg (France)
    • Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg (France)
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  • Prof. Dr. Ángel R. de Lera

    Corresponding author
    1. Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo (Spain)
    • Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo (Spain)
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Abstract

A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5-azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8, but not by the DNMT inhibitor SGI-1027.

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