Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
Аутори
Ružić, DušanEllinger, Bernhard
Đoković, Nemanja
Santibanez, Juan F.
Gul, Sheraz
Beljkaš, Milan
Đurić, Ana
Ganesan, Arasu
Pavić, Aleksandar
Srdić-Rajić, Tatjana
Petković, Miloš
Nikolić, Katarina
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
1-benzhydryl piperazine / anti-metastatic effect / breast cancer / drug discovery / histone deacetylases / hydroxamic acid / zebrafish xenograft modelИзвор:
Pharmaceutics, 2022, 14, 12, 2600-Издавач:
- Multidisciplinary Digital Publishing Institute (MDPI)
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
- British Scholarship Trust Foundation for sup- port in Short term research grant at the University of East Anglia, Norwich, United Kingdom
- OST-Action CM1406 “Epigenetic Chemical Biol- ogy” (EpiChemBio)
Институција/група
Institut za medicinska istraživanjaTY - JOUR AU - Ružić, Dušan AU - Ellinger, Bernhard AU - Đoković, Nemanja AU - Santibanez, Juan F. AU - Gul, Sheraz AU - Beljkaš, Milan AU - Đurić, Ana AU - Ganesan, Arasu AU - Pavić, Aleksandar AU - Srdić-Rajić, Tatjana AU - Petković, Miloš AU - Nikolić, Katarina PY - 2022 UR - http://rimi.imi.bg.ac.rs/handle/123456789/1271 AB - 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. PB - Multidisciplinary Digital Publishing Institute (MDPI) T2 - Pharmaceutics T1 - Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation IS - 12 SP - 2600 VL - 14 DO - 10.3390/pharmaceutics14122600 ER -
@article{ author = "Ružić, Dušan and Ellinger, Bernhard and Đoković, Nemanja and Santibanez, Juan F. and Gul, Sheraz and Beljkaš, Milan and Đurić, Ana and Ganesan, Arasu and Pavić, Aleksandar and Srdić-Rajić, Tatjana and Petković, Miloš and Nikolić, Katarina", year = "2022", 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.", publisher = "Multidisciplinary Digital Publishing Institute (MDPI)", journal = "Pharmaceutics", title = "Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation", number = "12", pages = "2600", volume = "14", doi = "10.3390/pharmaceutics14122600" }
Ružić, D., Ellinger, B., Đoković, N., Santibanez, J. F., Gul, S., Beljkaš, M., Đurić, A., Ganesan, A., Pavić, A., Srdić-Rajić, T., Petković, M.,& Nikolić, K.. (2022). Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. in Pharmaceutics Multidisciplinary Digital Publishing Institute (MDPI)., 14(12), 2600. https://doi.org/10.3390/pharmaceutics14122600
Ružić D, Ellinger B, Đoković N, Santibanez JF, Gul S, Beljkaš M, Đurić A, Ganesan A, Pavić A, Srdić-Rajić T, Petković M, Nikolić K. Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. in Pharmaceutics. 2022;14(12):2600. doi:10.3390/pharmaceutics14122600 .
Ružić, Dušan, Ellinger, Bernhard, Đoković, Nemanja, Santibanez, Juan F., Gul, Sheraz, Beljkaš, Milan, Đurić, Ana, Ganesan, Arasu, Pavić, Aleksandar, Srdić-Rajić, Tatjana, Petković, Miloš, Nikolić, Katarina, "Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation" in Pharmaceutics, 14, no. 12 (2022):2600, https://doi.org/10.3390/pharmaceutics14122600 . .