Discovery of 1-benzhydryl-piperazine-based HDAC inhibitors with anti-breast cancer activity: Synthesis, molecular modeling, in vitro and in vivo biological evaluation

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Ruzic, Dusan, Ellinger, Bernhard, Djokovic, Nemanja, Santibanez, Juan F., Gul, Sheraz, Beljkas, Milan, Djuric, Ana, Ganesan, Arasu, Pavic, Aleksandar, Srdic-Rajic, Tatjana, Petkovic, Milos and Nikolic, Katarina (2022) Discovery of 1-benzhydryl-piperazine-based HDAC inhibitors with anti-breast cancer activity: Synthesis, molecular modeling, in vitro and in vivo biological evaluation. Pharmaceutics, 14 (12). ISSN 1999-4923

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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.

Item Type: Article
Additional Information: Data Availability Statement: The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher. Funding Information: 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.
Uncontrolled Keywords: 1-benzhydryl piperazine,anti-metastatic effect,breast cancer,drug discovery,histone deacetylases,hydroxamic acid,zebrafish xenograft model,pharmaceutical science,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/3000/3003
Faculty \ School: Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
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Depositing User: LivePure Connector
Date Deposited: 10 Jan 2025 01:00
Last Modified: 28 Jan 2025 23:47
URI: https://ueaeprints.uea.ac.uk/id/eprint/98139
DOI:

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