Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
Autori
Ruzic, DusanEllinger, Bernhard
Djokovic, Nemanja
Santibanez, Juan F.
Gul, Sheraz
Beljkas, Milan
Djuric, Ana
Ganesan, Arasu
Pavić, Aleksandar
Srdic-Rajic, Tatjana
Petkovic, Milos
Nikolic, Katarina
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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 inhi...bitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.
Ključne reči:
1-benzhydryl piperazine / anti-metastatic effect / breast cancer / drug discovery / histone deacetylases / hydroxamic acid / zebrafish xenograft modelIzvor:
Pharmaceutics, 2022, 14, 12, 2600-Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200042 (Univerzitet u Beogradu, Institut za molekularnu genetiku i genetičko inženjerstvo) (RS-MESTD-inst-2020-200042)
Institucija/grupa
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Ruzic, Dusan AU - Ellinger, Bernhard AU - Djokovic, Nemanja AU - Santibanez, Juan F. AU - Gul, Sheraz AU - Beljkas, Milan AU - Djuric, Ana AU - Ganesan, Arasu AU - Pavić, Aleksandar AU - Srdic-Rajic, Tatjana AU - Petkovic, Milos AU - Nikolic, Katarina PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1662 AB - 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. T2 - Pharmaceutics 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 = "Ruzic, Dusan and Ellinger, Bernhard and Djokovic, Nemanja and Santibanez, Juan F. and Gul, Sheraz and Beljkas, Milan and Djuric, Ana and Ganesan, Arasu and Pavić, Aleksandar and Srdic-Rajic, Tatjana and Petkovic, Milos and Nikolic, Katarina", year = "2022", 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.", journal = "Pharmaceutics, 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" }
Ruzic, D., Ellinger, B., Djokovic, N., Santibanez, J. F., Gul, S., Beljkas, M., Djuric, A., Ganesan, A., Pavić, A., Srdic-Rajic, T., Petkovic, M.,& Nikolic, 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, 14(12), 2600. https://doi.org/10.3390/pharmaceutics14122600
Ruzic D, Ellinger B, Djokovic N, Santibanez JF, Gul S, Beljkas M, Djuric A, Ganesan A, Pavić A, Srdic-Rajic T, Petkovic M, Nikolic 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 .
Ruzic, Dusan, Ellinger, Bernhard, Djokovic, Nemanja, Santibanez, Juan F., Gul, Sheraz, Beljkas, Milan, Djuric, Ana, Ganesan, Arasu, Pavić, 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" in Pharmaceutics, 14, no. 12 (2022):2600, https://doi.org/10.3390/pharmaceutics14122600 . .