Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups - Archive ouverte HAL Access content directly
Journal Articles Journal of Medical Chemistry Year : 2017

Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups

Viktoria Krieger
  • Function : Author
Alexandra Hamacher
  • Function : Author
Christoph Gertzen
  • Function : Author
Johanna Senger
  • Function : Author
Martijn Zwinderman
  • Function : Author
Frank Dekker
  • Function : Author
Thomas Kurz
  • Function : Author
Manfred Jung
  • Function : Author
Holger Gohlke
  • Function : Author
Matthias Kassack
  • Function : Author
Finn Hansen
  • Function : Author

Abstract

In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy activity in the cellular HDAC assays, four compounds were further screened for their inhibitory activity against recombinant HDAC1-3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1-3 as well as significant inhibition of HDAC6 with IC50 values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head-neck cancer cell line Cal27CisR by almost 7-fold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.

Dates and versions

hal-03682266 , version 1 (30-05-2022)

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Viktoria Krieger, Alexandra Hamacher, Christoph Gertzen, Johanna Senger, Martijn Zwinderman, et al.. Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups. Journal of Medical Chemistry, 2017, 60 (13), pp.5493-5506. ⟨10.1021/acs.jmedchem.7b00197⟩. ⟨hal-03682266⟩
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