Alkoxyurea-based histone deacetylase inhibitors increase cisplatin potency in chemoresistant cancer cell lines - Archive ouverte HAL Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2017

Alkoxyurea-based histone deacetylase inhibitors increase cisplatin potency in chemoresistant cancer cell lines

Katharina Stenzel
  • Function : Author
Alexandra Hamacher
  • Function : Author
Finn Hansen
  • Function : Author
Christoph Gertzen
  • Function : Author
Johanna Senger
  • Function : Author
Viktoria Marquardt
  • Function : Author
Linda Marek
  • Function : Author
Marc Remke
  • Function : Author
Manfred Jung
  • Function : Author
Holger Gohlke
  • Function : Author
Matthias Kassack
  • Function : Author
Thomas Kurz
  • Function : Author

Abstract

The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC50 values in the low muM and sub-muM range. 1g-i revealed low nM IC50 values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.
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Dates and versions

hal-03691179 , version 1 (08-06-2022)

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Katharina Stenzel, Alexandra Hamacher, Finn Hansen, Christoph Gertzen, Johanna Senger, et al.. Alkoxyurea-based histone deacetylase inhibitors increase cisplatin potency in chemoresistant cancer cell lines. Journal of Medicinal Chemistry, 2017, 60 (13), pp.5334-5348. ⟨10.1021/acs.jmedchem.6b01538⟩. ⟨hal-03691179⟩
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