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

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 d...

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Autores principales: Ruzic, Dusan, Ellinger, Bernhard, Djokovic, Nemanja, Santibanez, Juan F., Gul, Sheraz, Beljkas, Milan, Djuric, Ana, Ganesan, Arasu, Pavic, Aleksandar, Srdic-Rajic, Tatjana, Petkovic, Milos, Nikolic, Katarina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9785542/
https://www.ncbi.nlm.nih.gov/pubmed/36559094
http://dx.doi.org/10.3390/pharmaceutics14122600
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author Ruzic, Dusan
Ellinger, Bernhard
Djokovic, Nemanja
Santibanez, Juan F.
Gul, Sheraz
Beljkas, Milan
Djuric, Ana
Ganesan, Arasu
Pavic, Aleksandar
Srdic-Rajic, Tatjana
Petkovic, Milos
Nikolic, Katarina
author_facet Ruzic, Dusan
Ellinger, Bernhard
Djokovic, Nemanja
Santibanez, Juan F.
Gul, Sheraz
Beljkas, Milan
Djuric, Ana
Ganesan, Arasu
Pavic, Aleksandar
Srdic-Rajic, Tatjana
Petkovic, Milos
Nikolic, Katarina
author_sort Ruzic, Dusan
collection PubMed
description 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 IC(50) 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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spelling pubmed-97855422022-12-24 Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation Ruzic, Dusan Ellinger, Bernhard Djokovic, Nemanja Santibanez, Juan F. Gul, Sheraz Beljkas, Milan Djuric, Ana Ganesan, Arasu Pavic, Aleksandar Srdic-Rajic, Tatjana Petkovic, Milos Nikolic, Katarina Pharmaceutics Article 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 IC(50) 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. MDPI 2022-11-25 /pmc/articles/PMC9785542/ /pubmed/36559094 http://dx.doi.org/10.3390/pharmaceutics14122600 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ruzic, Dusan
Ellinger, Bernhard
Djokovic, Nemanja
Santibanez, Juan F.
Gul, Sheraz
Beljkas, Milan
Djuric, Ana
Ganesan, Arasu
Pavic, Aleksandar
Srdic-Rajic, Tatjana
Petkovic, Milos
Nikolic, Katarina
Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
title Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
title_full Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
title_fullStr Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
title_full_unstemmed Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
title_short Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
title_sort discovery of 1-benzhydryl-piperazine-based hdac inhibitors with anti-breast cancer activity: synthesis, molecular modeling, in vitro and in vivo biological evaluation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9785542/
https://www.ncbi.nlm.nih.gov/pubmed/36559094
http://dx.doi.org/10.3390/pharmaceutics14122600
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