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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
dc.creator | Ružić, Dušan | |
dc.creator | Ellinger, Bernhard | |
dc.creator | Đoković, Nemanja | |
dc.creator | Santibanez, Juan F. | |
dc.creator | Gul, Sheraz | |
dc.creator | Beljkaš, Milan | |
dc.creator | Đurić, Ana | |
dc.creator | Ganesan, Arasu | |
dc.creator | Pavić, Aleksandar | |
dc.creator | Srdić-Rajić, Tatjana | |
dc.creator | Petković, Miloš | |
dc.creator | Nikolić, Katarina | |
dc.date.accessioned | 2023-01-31T11:41:23Z | |
dc.date.available | 2023-01-31T11:41:23Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 1999-4923 | |
dc.identifier.uri | http://rimi.imi.bg.ac.rs/handle/123456789/1271 | |
dc.description.abstract | 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. | |
dc.publisher | Multidisciplinary Digital Publishing Institute (MDPI) | |
dc.relation | info:eu-repo/grantAgreement/MESTD/inst-2020/200161/RS// | |
dc.relation | info:eu-repo/grantAgreement/MESTD/inst-2020/200042/RS// | |
dc.relation | British Scholarship Trust Foundation for sup- port in Short term research grant at the University of East Anglia, Norwich, United Kingdom | |
dc.relation | OST-Action CM1406 “Epigenetic Chemical Biol- ogy” (EpiChemBio) | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.source | Pharmaceutics | |
dc.subject | 1-benzhydryl piperazine | |
dc.subject | anti-metastatic effect | |
dc.subject | breast cancer | |
dc.subject | drug discovery | |
dc.subject | histone deacetylases | |
dc.subject | hydroxamic acid | |
dc.subject | zebrafish xenograft model | |
dc.title | Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation | |
dc.type | article | |
dc.rights.license | BY | |
dc.citation.issue | 12 | |
dc.citation.spage | 2600 | |
dc.citation.volume | 14 | |
dc.identifier.doi | 10.3390/pharmaceutics14122600 | |
dc.identifier.fulltext | http://rimi.imi.bg.ac.rs/bitstream/id/2870/Discovery_of_1-Benzhydryl-Piperazine-Based_HDAC_Inhibitors_pub_2022.pdf | |
dc.type.version | publishedVersion |