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
Affiliations
Dusan Ruzic
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Bernhard Ellinger
Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 22525 Hamburg, Germany
Nemanja Djokovic
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Juan F. Santibanez
Group for Molecular Oncology, Institute for Medical Research, University of Belgrade, Dr. Subotića 4, 11129 Belgrade, Serbia
Sheraz Gul
Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 22525 Hamburg, Germany
Milan Beljkas
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Ana Djuric
Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
Arasu Ganesan
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
Aleksandar Pavic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia
Tatjana Srdic-Rajic
Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
Milos Petkovic
Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Katarina Nikolic
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
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.