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Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity

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Abstract

Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound 6i, displayed submicromolar tumor cell-inhibitory potential (IC50: 0.21–0.67 μM) against all five cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.

Graphical abstract: Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity

  • This article is part of the themed collection: New Talent
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Publication details

The article was received on 10 Sep 2018, accepted on 18 Oct 2018 and first published on 23 Oct 2018


Article type: Research Article
DOI: 10.1039/C8MD00454D
Citation: Med. Chem. Commun., 2018, Advance Article
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    Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity

    N. Reßing, V. Marquardt, C. G. W. Gertzen, A. Schöler, A. Schramm, T. Kurz, H. Gohlke, A. Aigner, M. Remke and F. K. Hansen, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C8MD00454D

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