Biological and Medicinal Chemistry

Discovery of 1-benzhydryl piperazine-based HDAC inhibitors with anti-cancer and anti-metastatic properties against human breast cancer: synthesis, molecular modeling, in vitro and in vivo biological evaluation

Authors

  • Dusan Ruzic Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade ,
  • Milos Petkovic Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia ,
  • Nemanja Djokovic Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia ,
  • Juan Santibanez Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O’Higgins & Group for Molecular Oncology, Institute for Medical Research, University of Belgrade, Dr. Subotića 4, 11129 Belgrade, Serbia ,
  • Bernhard Ellinger Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg, Germany & Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Hamburg, Germany ,
  • Milan Beljkas Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia ,
  • Sheraz Gul Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg, Germany & Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Hamburg, Germany ,
  • Ana Djuric Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia ,
  • A. Ganesan School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ Norwich, United Kingdom ,
  • Aleksandar Pavic Institute of Molecular Genetics and Genetic Engineering, University of Belgrade ,
  • Tatjana Srdic-Rajic Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia ,
  • Katarina Nikolic Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade

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. Surprisingly, in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. 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, leading to 8b as the most promising compound. In our study, 8b is identified as the HDAC inhibitor with very potent anti-angiogenic, anti-metastatic and anti-tumor effects in zebrafish MDA-MB-231 xenograft models at low micromolar concentrations.

Version notes

Compared to the first version of preprint, two novel biological assays are added - determination of reactive oxygen species production and 3D spheres model of breast cancer.

Content

Thumbnail image of RuzicD_2022.pdf

Supplementary material

Thumbnail image of Supplementary material_DRuzic.pdf
Supporting Information
Supporting Information - experimental data