tert-Butylcarbamate-Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells

Authors

  • Dr. Sergio Valente,

    1. Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy)
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  • Dr. Daniela Trisciuoglio,

    1. Regina Elena National Cancer Institute, Laboratorio di Chemioterapia Sperimentale Preclinica, Via delle Messi d'Oro 156, 00158 Roma (Italy)
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    • These authors contributed equally to this work.

  • Dr. Maria Tardugno,

    1. Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy)
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    • These authors contributed equally to this work.

  • Dr. Rosaria Benedetti,

    1. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli vico L. De Crecchio 7, 80138 Napoli (Italy)
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  • Dr. Donatella Labella,

    1. Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy)
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  • Prof. Daniela Secci,

    1. Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy)
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  • Dr. Ciro Mercurio,

    1. Genextra Group, DAC s.r.l., Via Adamello 16, 20139 Milano (Italy)
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  • Dr. Roberto Boggio,

    1. Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milano (Italy)
    2. Present address: Nerviano Medical Sciences, Via Pasteur 10, 20014 Nerviano (Italy)
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  • Dr. Stefano Tomassi,

    1. Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli (Italy)
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  • Dr. Salvatore Di Maro,

    1. Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli (Italy)
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  • Prof. Ettore Novellino,

    1. Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli (Italy)
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  • Prof. Lucia Altucci,

    Corresponding author
    1. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli vico L. De Crecchio 7, 80138 Napoli (Italy)
    2. IGB-CNR, Via P. Castellino Napoli (Italy)
    • Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli vico L. De Crecchio 7, 80138 Napoli (Italy)
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  • Dr. Donatella Del Bufalo,

    Corresponding author
    1. Regina Elena National Cancer Institute, Laboratorio di Chemioterapia Sperimentale Preclinica, Via delle Messi d'Oro 156, 00158 Roma (Italy)
    • Regina Elena National Cancer Institute, Laboratorio di Chemioterapia Sperimentale Preclinica, Via delle Messi d'Oro 156, 00158 Roma (Italy)
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  • Prof. Antonello Mai,

    Corresponding author
    1. Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy)
    • Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy)
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  • Dr. Sandro Cosconati

    Corresponding author
    1. DiSTABiF, Seconda Università di Napoli, Via G. Vivaldi 43, 81100 Caserta (Italy)
    • DiSTABiF, Seconda Università di Napoli, Via G. Vivaldi 43, 81100 Caserta (Italy)
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Abstract

Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2′-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %.

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