Institut za onkologiju i radiologiju Srbije / Institute for Oncology and Radiology of Serbia
Published November 25, 2022 | Version v.1
Journal article Open

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

Authors/Creators

  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
  • 2. Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 22525 Hamburg, Germany3Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), 22525 Hamburg, Germany
  • 3. Group for Molecular Oncology, Institute for Medical Research, University of Belgrade, Dr. Suboti ́ca 4,11129 Belgrade, Serbia; Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O'Higgins, Santiago 8370993, Chile
  • 4. Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 22525 Hamburg, Germany ; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), 22525 Hamburg, Germany
  • 5. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14,11000 Belgrade, Serbia
  • 6. School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
  • 7. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a,11000 Belgrade, Serbia
  • 8. Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450,11221 Belgrade, Serbia

Description

Abstract

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.

Notes

This research was funded by the Ministry of Education, Science and Technological Development, Republic of Serbia through Grant Agreement with University of Belgrade-Faculty of Pharmacy No: 451-03-68/2022-14/200161. Numerical simulations were ran on the PARADOX-IV supercomputing facility at the Scientific Computing Laboratory, National Center of Excellence for the Study of Complex Systems, Institute of Physics Belgrade, supported in part by the Ministry of Education, Science, and the Technological Development of the Republic of Serbia under project no. ON171017.

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Related works

Is derived from
https://www.mdpi.com/journal/pharmaceutics (URL)
Is described by
36559094 (PMID)
Is identical to
PMC9785542 (pmcid)
Is source of
1999-4923 (ISSN)