Pharmaceutics (Nov 2022)

Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation

  • Dusan Ruzic,
  • Bernhard Ellinger,
  • Nemanja Djokovic,
  • Juan F. Santibanez,
  • Sheraz Gul,
  • Milan Beljkas,
  • Ana Djuric,
  • Arasu Ganesan,
  • Aleksandar Pavic,
  • Tatjana Srdic-Rajic,
  • Milos Petkovic,
  • Katarina Nikolic

DOI
https://doi.org/10.3390/pharmaceutics14122600
Journal volume & issue
Vol. 14, no. 12
p. 2600

Abstract

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Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.

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