2. Academic Validation
  3. Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells

Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells

  • Arch Pharm (Weinheim). 2023 Nov 6:e2300536. doi: 10.1002/ardp.202300536.
Mohamed Abdelsalam 1 2,  Mariia Zmyslia 3,  Karin Schmidtkunz 4,  Anita Vecchio 1,  Sebastian Hilscher 5,  Hany S Ibrahim 1 6,  Mike Schutkowski 5,  Manfred Jung 4 7,  Claudia Jessen-Trefzer 3,  Wolfgang Sippl 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
  • 3 Institute of Organic Chemistry, University of Freiburg, Freiburg i. Br., Germany.
  • 4 Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg i. Br., Germany.
  • 5 Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
  • 7 CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg i. Br., Germany.
PMID: 37932028 DOI: 10.1002/ardp.202300536
Abstract

Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI50 = 77 nM) and exhibited moderate selectivity. Moreover, activation of prodrug 6 by NTR was confirmed by liquid chromatography-mass spectrometry analysis, which showed the release of the parent inhibitor after incubation with Escherichia coli NTR. Thus, compound 6 can be considered a novel prodrug selective for class I HDACs, which could be used as a good starting point for increasing selectivity and for further optimization.

Keywords

HDACs; epigenetics; hypoxia; nitroreductases; prodrugs.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157152
    HDAC 抑制剂
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