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Phenylpyrrole-based HDAC inhibitors: synthesis, molecular modeling and biological studies

    Margherita Brindisi

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    ,
    Caterina Cavella

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    ,
    Simone Brogi

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    ,
    Angela Nebbioso

    Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy

    Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy

    ,
    Johanna Senger

    Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany

    ,
    Samuele Maramai

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    ,
    Alfonso Ciotta

    Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy

    Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy

    ,
    Concetta Iside

    Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy

    Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy

    ,
    Stefania Butini

    *Author for correspondence:

    E-mail Address: butini3@unisi.it

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    ,
    Stefania Lamponi

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    ,
    Ettore Novellino

    Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy

    ,
    Lucia Altucci

    Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy

    Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy

    ,
    Manfred Jung

    Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany

    ,
    Giuseppe Campiani

    **Author for correspondence:

    E-mail Address: campiani@unisi.it

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    &
    Sandra Gemma

    European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy

    Published Online:https://doi.org/10.4155/fmc-2016-0068

    Aim: Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in the initiation and progression of cancer. Currently, three hydroxamate-containing HDAC pan-inhibitors have been approved as antitumor agents. Results: We herein present the development of a series of novel phenylpyrrole-based derivatives stemmed from combined computational and medicinal chemistry efforts to rationally modulate HDAC1/6 isoform selectivity. In vitro activity on HDAC1 and HDAC6 isoforms and the effects of selected analogs on histone H3 and α-tubulin acetylation levels were determined. Cell-based data evidenced, for selected compounds, a promising antitumor potential and low toxicity on normal cells. Conclusion: The newly developed compounds represent a valuable starting point for the development of novel anticancer agents.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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