TY  - JOUR
AU  - Ćurčić, Vladimir
AU  - Olszewski, Mateusz
AU  - Maciejewska, Natalia
AU  - Višnjevac, Aleksandar
AU  - Srdić-Rajić, Tatjana
AU  - Dobričić, Vladimir
AU  - García-Sosa, Alfonso T.
AU  - Kokanov, Sanja B.
AU  - Araškov, Jovana B.
AU  - Silvestri, Romano
AU  - Schüle, Roland
AU  - Jung, Manfred
AU  - Nikolić, Milan
AU  - Filipović, Nenad R.
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5298
AB  - Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a–c), 2-quinoline (2a–c), and 8-hydroxy-2-quinolyl moiety (3a–c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition.
PB  - John Wiley and Sons Inc
T2  - Archiv der Pharmazie
T1  - Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition
VL  - 357
IS  - 2
SP  - 2300426
DO  - 10.1002/ardp.202300426
ER  - 

@article{
author = "Ćurčić, Vladimir and Olszewski, Mateusz and Maciejewska, Natalia and Višnjevac, Aleksandar and Srdić-Rajić, Tatjana and Dobričić, Vladimir and García-Sosa, Alfonso T. and Kokanov, Sanja B. and Araškov, Jovana B. and Silvestri, Romano and Schüle, Roland and Jung, Manfred and Nikolić, Milan and Filipović, Nenad R.",
year = "2024",
abstract = "Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a–c), 2-quinoline (2a–c), and 8-hydroxy-2-quinolyl moiety (3a–c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition.",
publisher = "John Wiley and Sons Inc",
journal = "Archiv der Pharmazie",
title = "Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition",
volume = "357",
number = "2",
pages = "2300426",
doi = "10.1002/ardp.202300426"
}

Ćurčić, V., Olszewski, M., Maciejewska, N., Višnjevac, A., Srdić-Rajić, T., Dobričić, V., García-Sosa, A. T., Kokanov, S. B., Araškov, J. B., Silvestri, R., Schüle, R., Jung, M., Nikolić, M.,& Filipović, N. R.. (2024). Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition. in Archiv der Pharmazie
John Wiley and Sons Inc., 357(2), 2300426.
https://doi.org/10.1002/ardp.202300426

Ćurčić V, Olszewski M, Maciejewska N, Višnjevac A, Srdić-Rajić T, Dobričić V, García-Sosa AT, Kokanov SB, Araškov JB, Silvestri R, Schüle R, Jung M, Nikolić M, Filipović NR. Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition. in Archiv der Pharmazie. 2024;357(2):2300426.
doi:10.1002/ardp.202300426 .

Ćurčić, Vladimir, Olszewski, Mateusz, Maciejewska, Natalia, Višnjevac, Aleksandar, Srdić-Rajić, Tatjana, Dobričić, Vladimir, García-Sosa, Alfonso T., Kokanov, Sanja B., Araškov, Jovana B., Silvestri, Romano, Schüle, Roland, Jung, Manfred, Nikolić, Milan, Filipović, Nenad R., "Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition" in Archiv der Pharmazie, 357, no. 2 (2024):2300426,
https://doi.org/10.1002/ardp.202300426 . .

TY  - CONF
AU  - Ružić, Dušan
AU  - Petković, Miloš
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
AU  - Pavić, Aleksandar
AU  - Ganesan, A.
AU  - Srdić Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5074
AB  - Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HDAC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations.
PB  - Serbian Association on for Cancer Research Belgrade, Serbia
C3  - Oncology
Insights
T1  - Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study
VL  - 1
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5074
ER  - 

@conference{
author = "Ružić, Dušan and Petković, Miloš and Đoković, Nemanja and Santibanez, Juan and Pavić, Aleksandar and Ganesan, A. and Srdić Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HDAC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations.",
publisher = "Serbian Association on for Cancer Research Belgrade, Serbia",
journal = "Oncology
Insights",
title = "Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study",
volume = "1",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5074"
}

Ružić, D., Petković, M., Đoković, N., Santibanez, J., Pavić, A., Ganesan, A., Srdić Rajić, T.,& Nikolić, K.. (2023). Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study. in Oncology
Insights
Serbian Association on for Cancer Research Belgrade, Serbia., 1.
https://hdl.handle.net/21.15107/rcub_farfar_5074

Ružić D, Petković M, Đoković N, Santibanez J, Pavić A, Ganesan A, Srdić Rajić T, Nikolić K. Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study. in Oncology
Insights. 2023;1.
https://hdl.handle.net/21.15107/rcub_farfar_5074 .

Ružić, Dušan, Petković, Miloš, Đoković, Nemanja, Santibanez, Juan, Pavić, Aleksandar, Ganesan, A., Srdić Rajić, Tatjana, Nikolić, Katarina, "Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study" in Oncology
Insights, 1 (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5074 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Ilić, Aleksandra
AU  - Čebzan, Alen
AU  - Radović, Branko
AU  - Ružić, Dušan
AU  - Đurić, Ana
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5001
AB  - Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
T1  - Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling
SP  - 47
EP  - 47
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5001
ER  - 

@conference{
author = "Đoković, Nemanja and Ilić, Aleksandra and Čebzan, Alen and Radović, Branko and Ružić, Dušan and Đurić, Ana and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6",
title = "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling",
pages = "47-47",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5001"
}

Đoković, N., Ilić, A., Čebzan, A., Radović, B., Ružić, D., Đurić, A., Srdić-Rajić, T.,& Nikolić, K.. (2023). Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
International Association of Physical Chemists., 47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001

Đoković N, Ilić A, Čebzan A, Radović B, Ružić D, Đurić A, Srdić-Rajić T, Nikolić K. Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6. 2023;:47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

Đoković, Nemanja, Ilić, Aleksandra, Čebzan, Alen, Radović, Branko, Ružić, Dušan, Đurić, Ana, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling" in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6 (2023):47-47,
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

TY  - JOUR
AU  - Đoković, Nemanja
AU  - Đurić, Ana
AU  - Ružić, Dušan
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4472
AB  - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.
PB  - MDPI
T2  - Pharmaceuticals
T1  - Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma
VL  - 16
IS  - 2
DO  - 10.3390/ph16020294
ER  - 

@article{
author = "Đoković, Nemanja and Đurić, Ana and Ružić, Dušan and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.",
publisher = "MDPI",
journal = "Pharmaceuticals",
title = "Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma",
volume = "16",
number = "2",
doi = "10.3390/ph16020294"
}

Đoković, N., Đurić, A., Ružić, D., Srdić-Rajić, T.,& Nikolić, K.. (2023). Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma. in Pharmaceuticals
MDPI., 16(2).
https://doi.org/10.3390/ph16020294

Đoković N, Đurić A, Ružić D, Srdić-Rajić T, Nikolić K. Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma. in Pharmaceuticals. 2023;16(2).
doi:10.3390/ph16020294 .

Đoković, Nemanja, Đurić, Ana, Ružić, Dušan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma" in Pharmaceuticals, 16, no. 2 (2023),
https://doi.org/10.3390/ph16020294 . .

TY  - GEN
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Rahnasto‐Rilla, Minna
AU  - Srdić Rajić, Tatjana
AU  - Lahtela-Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5462
AB  - Intricate structural heterogeneity of SIRT2
Initial goal: Discovery of novel scaffolds of SIRT2
inhibitors.
Experimentally confirmed conformal flexibility of SIRT2
binding site place it in the group of structures of
relatively challenging targets for modeling.
Different chemistry = Different conformational state
Scientific question: Have we discovered all states of
SIRT2?
Why deciphering of binding pocket dynamics is that
important from the aspect of structure-based drug
design?
T2  - Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022
T1  - Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5462
ER  - 

@misc{
author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto‐Rilla, Minna and Srdić Rajić, Tatjana and Lahtela-Kakkonen, Maija and Nikolić, Katarina",
year = "2022",
abstract = "Intricate structural heterogeneity of SIRT2
Initial goal: Discovery of novel scaffolds of SIRT2
inhibitors.
Experimentally confirmed conformal flexibility of SIRT2
binding site place it in the group of structures of
relatively challenging targets for modeling.
Different chemistry = Different conformational state
Scientific question: Have we discovered all states of
SIRT2?
Why deciphering of binding pocket dynamics is that
important from the aspect of structure-based drug
design?",
journal = "Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022",
title = "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5462"
}

Đoković, N., Ružić, D., Rahnasto‐Rilla, M., Srdić Rajić, T., Lahtela-Kakkonen, M.,& Nikolić, K.. (2022). Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022.
https://hdl.handle.net/21.15107/rcub_farfar_5462

Đoković N, Ružić D, Rahnasto‐Rilla M, Srdić Rajić T, Lahtela-Kakkonen M, Nikolić K. Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_5462 .

Đoković, Nemanja, Ružić, Dušan, Rahnasto‐Rilla, Minna, Srdić Rajić, Tatjana, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics" in Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022 (2022),
https://hdl.handle.net/21.15107/rcub_farfar_5462 .

TY  - CONF
AU  - Ostojić, Marija
AU  - Đurić, Ana
AU  - Srdić-Rajić, Tatjana
AU  - Dobričić, Vladimir
AU  - Grahovac, Jelena
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5477
AB  - Pancreatic ductal adenocarcinoma (PDAC) is the sixth leading cause of death worldwide and the fourth
in Europe with a 5-year survival rate. The common cause of treatment failure in PDAC patients is
multidrug resistance (MDR) due to the increased expression of plasma membrane efflux pumps that
limit the intracellular uptake and retention of numerous xeno- and endobiotics. As the 93.3% of
pancreatic carcinomas expressed P-glycoprotein (P-gp-MDR1/ABCB1) and 31% co-expressed multidrug
resistance protein 1 (MRP1/ABCC1) with MDR1 P-gp, the inhibition of these pumps may be the target
for novel anticancer drugs.
We used the FRED 3.2.0.2 software to predict the affinity of I1-imidazoline receptor ligand rilmenidine
within the binding site of P-gp-MDR1/ABCB1 and MRP1/ABCC1, and flow cytometry to evaluate the
effect of rilmenidine phosphate and rilmenidine fumarate on the efflux pumps in PDAC cells in vitro.
The results of the molecular docking studies indicate that rilmenidine has the binding affinity for both
P-gp-MDR1/ABCB1 and MRP1/ABCC1 efflux pumps. While, in vitro studies show that rilmenidine
fumarate has better potential to inhibit Calcein AM efflux than rilmenidine phosphate, and it did so in a
dose-dependent manner.
Our results indicate that rilmenidine has the affinity to bind to MDR efflux pumps and to inhibit their
activity. This potential of rilmenidine to overcome multidrug resistance in PDAC should be further
investigated in order to develop more effective PDAC therapy.
PB  - COST Action 17104 (STRATAGEM)
C3  - STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal
T1  - Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma
SP  - 80
EP  - 80
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5477
ER  - 

@conference{
author = "Ostojić, Marija and Đurić, Ana and Srdić-Rajić, Tatjana and Dobričić, Vladimir and Grahovac, Jelena",
year = "2022",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is the sixth leading cause of death worldwide and the fourth
in Europe with a 5-year survival rate. The common cause of treatment failure in PDAC patients is
multidrug resistance (MDR) due to the increased expression of plasma membrane efflux pumps that
limit the intracellular uptake and retention of numerous xeno- and endobiotics. As the 93.3% of
pancreatic carcinomas expressed P-glycoprotein (P-gp-MDR1/ABCB1) and 31% co-expressed multidrug
resistance protein 1 (MRP1/ABCC1) with MDR1 P-gp, the inhibition of these pumps may be the target
for novel anticancer drugs.
We used the FRED 3.2.0.2 software to predict the affinity of I1-imidazoline receptor ligand rilmenidine
within the binding site of P-gp-MDR1/ABCB1 and MRP1/ABCC1, and flow cytometry to evaluate the
effect of rilmenidine phosphate and rilmenidine fumarate on the efflux pumps in PDAC cells in vitro.
The results of the molecular docking studies indicate that rilmenidine has the binding affinity for both
P-gp-MDR1/ABCB1 and MRP1/ABCC1 efflux pumps. While, in vitro studies show that rilmenidine
fumarate has better potential to inhibit Calcein AM efflux than rilmenidine phosphate, and it did so in a
dose-dependent manner.
Our results indicate that rilmenidine has the affinity to bind to MDR efflux pumps and to inhibit their
activity. This potential of rilmenidine to overcome multidrug resistance in PDAC should be further
investigated in order to develop more effective PDAC therapy.",
publisher = "COST Action 17104 (STRATAGEM)",
journal = "STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal",
title = "Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma",
pages = "80-80",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5477"
}

Ostojić, M., Đurić, A., Srdić-Rajić, T., Dobričić, V.,& Grahovac, J.. (2022). Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma. in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal
COST Action 17104 (STRATAGEM)., 80-80.
https://hdl.handle.net/21.15107/rcub_farfar_5477

Ostojić M, Đurić A, Srdić-Rajić T, Dobričić V, Grahovac J. Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma. in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal. 2022;:80-80.
https://hdl.handle.net/21.15107/rcub_farfar_5477 .

Ostojić, Marija, Đurić, Ana, Srdić-Rajić, Tatjana, Dobričić, Vladimir, Grahovac, Jelena, "Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma" in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal (2022):80-80,
https://hdl.handle.net/21.15107/rcub_farfar_5477 .

TY  - JOUR
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Rahnasto-Rilla, Mina
AU  - Srdić-Rajić, Tatjana
AU  - Lahtela-Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4102
AB  - Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.
PB  - American Chemical Society
T2  - Journal of Chemical Information and Modeling
T1  - Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics
VL  - 62
IS  - 10
SP  - 2571
EP  - 2585
DO  - 10.1021/acs.jcim.2c00241
ER  - 

@article{
author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto-Rilla, Mina and Srdić-Rajić, Tatjana and Lahtela-Kakkonen, Maija and Nikolić, Katarina",
year = "2022",
abstract = "Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.",
publisher = "American Chemical Society",
journal = "Journal of Chemical Information and Modeling",
title = "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics",
volume = "62",
number = "10",
pages = "2571-2585",
doi = "10.1021/acs.jcim.2c00241"
}

Đoković, N., Ružić, D., Rahnasto-Rilla, M., Srdić-Rajić, T., Lahtela-Kakkonen, M.,& Nikolić, K.. (2022). Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Journal of Chemical Information and Modeling
American Chemical Society., 62(10), 2571-2585.
https://doi.org/10.1021/acs.jcim.2c00241

Đoković N, Ružić D, Rahnasto-Rilla M, Srdić-Rajić T, Lahtela-Kakkonen M, Nikolić K. Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Journal of Chemical Information and Modeling. 2022;62(10):2571-2585.
doi:10.1021/acs.jcim.2c00241 .

Đoković, Nemanja, Ružić, Dušan, Rahnasto-Rilla, Mina, Srdić-Rajić, Tatjana, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics" in Journal of Chemical Information and Modeling, 62, no. 10 (2022):2571-2585,
https://doi.org/10.1021/acs.jcim.2c00241 . .

TY  - JOUR
AU  - Ružić, Dušan
AU  - Ellinger, Bernhard
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
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  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4368
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.
PB  - 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
VL  - 14
IS  - 12
DO  - 10.3390/pharmaceutics14122600
ER  - 

@article{
author = "Ružić, Dušan and Ellinger, Bernhard and Đoković, Nemanja and Santibanez, Juan 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 = "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 = "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",
volume = "14",
number = "12",
doi = "10.3390/pharmaceutics14122600"
}

Ružić, D., Ellinger, B., Đoković, N., Santibanez, J., 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
MDPI., 14(12).
https://doi.org/10.3390/pharmaceutics14122600

Ružić D, Ellinger B, Đoković N, Santibanez J, 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).
doi:10.3390/pharmaceutics14122600 .

Ružić, Dušan, Ellinger, Bernhard, Đoković, Nemanja, Santibanez, Juan, 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),
https://doi.org/10.3390/pharmaceutics14122600 . .

TY  - JOUR
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Srdić-Rajić, Tatjana
AU  - Echeverria, Cesar
AU  - Nikolić, Katarina
AU  - Santibanez, Juan
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4025
AB  - The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.
PB  - MDPI
T2  - Pharmaceutics
T1  - Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention
VL  - 14
IS  - 1
DO  - 10.3390/pharmaceutics14010209
ER  - 

@article{
author = "Ružić, Dušan and Đoković, Nemanja and Srdić-Rajić, Tatjana and Echeverria, Cesar and Nikolić, Katarina and Santibanez, Juan",
year = "2022",
abstract = "The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention",
volume = "14",
number = "1",
doi = "10.3390/pharmaceutics14010209"
}

Ružić, D., Đoković, N., Srdić-Rajić, T., Echeverria, C., Nikolić, K.,& Santibanez, J.. (2022). Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. in Pharmaceutics
MDPI., 14(1).
https://doi.org/10.3390/pharmaceutics14010209

Ružić D, Đoković N, Srdić-Rajić T, Echeverria C, Nikolić K, Santibanez J. Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. in Pharmaceutics. 2022;14(1).
doi:10.3390/pharmaceutics14010209 .

Ružić, Dušan, Đoković, Nemanja, Srdić-Rajić, Tatjana, Echeverria, Cesar, Nikolić, Katarina, Santibanez, Juan, "Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention" in Pharmaceutics, 14, no. 1 (2022),
https://doi.org/10.3390/pharmaceutics14010209 . .

TY  - GEN
AU  - Ružić, Dušan
AU  - Ellinger, Bernhard
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
AU  - Ganesan, A.
AU  - Pavić, Aleksandar
AU  - Srdić Rajić, Tatjana
AU  - Petković, Miloš
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4951
PB  - Institute Pasteur, France
T2  - Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022
T1  - Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4951
ER  - 

@misc{
author = "Ružić, Dušan and Ellinger, Bernhard and Đoković, Nemanja and Santibanez, Juan and Ganesan, A. and Pavić, Aleksandar and Srdić Rajić, Tatjana and Petković, Miloš and Nikolić, Katarina",
year = "2022",
publisher = "Institute Pasteur, France",
journal = "Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022",
title = "Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4951"
}

Ružić, D., Ellinger, B., Đoković, N., Santibanez, J., Ganesan, A., Pavić, A., Srdić Rajić, T., Petković, M.,& Nikolić, K.. (2022). Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy. in Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022
Institute Pasteur, France..
https://hdl.handle.net/21.15107/rcub_farfar_4951

Ružić D, Ellinger B, Đoković N, Santibanez J, Ganesan A, Pavić A, Srdić Rajić T, Petković M, Nikolić K. Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy. in Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4951 .

Ružić, Dušan, Ellinger, Bernhard, Đoković, Nemanja, Santibanez, Juan, Ganesan, A., Pavić, Aleksandar, Srdić Rajić, Tatjana, Petković, Miloš, Nikolić, Katarina, "Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy" in Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022 (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4951 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Gul, Sheraz
AU  - Lahtela‐Kakkonen, Maija
AU  - Ganesan, A.
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4763
PB  - European Federation for Medicinal Chemistry and Chemical Biology (EFMC)
PB  - Société de Chimie Thérapeutique (SCT)
C3  - EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
T1  - Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6
SP  - 141
EP  - 141
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4763
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Gul, Sheraz and Lahtela‐Kakkonen, Maija and Ganesan, A. and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2022",
publisher = "European Federation for Medicinal Chemistry and Chemical Biology (EFMC), Société de Chimie Thérapeutique (SCT)",
journal = "EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts",
title = "Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6",
pages = "141-141",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4763"
}

Ružić, D., Đoković, N., Petković, M., Gul, S., Lahtela‐Kakkonen, M., Ganesan, A., Srdić-Rajić, T.,& Nikolić, K.. (2022). Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6. in EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
European Federation for Medicinal Chemistry and Chemical Biology (EFMC)., 141-141.
https://hdl.handle.net/21.15107/rcub_farfar_4763

Ružić D, Đoković N, Petković M, Gul S, Lahtela‐Kakkonen M, Ganesan A, Srdić-Rajić T, Nikolić K. Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6. in EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts. 2022;:141-141.
https://hdl.handle.net/21.15107/rcub_farfar_4763 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Gul, Sheraz, Lahtela‐Kakkonen, Maija, Ganesan, A., Srdić-Rajić, Tatjana, Nikolić, Katarina, "Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6" in EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts (2022):141-141,
https://hdl.handle.net/21.15107/rcub_farfar_4763 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4737
AB  - Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as
a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC
inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity
and selectivity are defined as: surface recognition group (CAP group), aliphatic or
aromatic linker and zinc-binding group (ZBG).
Herein, we describe a comprehensive protocol for the computational fragment search of
novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase
6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl
piperazine was employed to synthesize novel HDAC inhibitors with small structural
perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified
two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as
two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker
chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based
molecular modelling.

References
1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas,
The Oncologist, 2021, 26(3), 184 e366.
2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5),
1800083.

Acknowledgments
The authors acknowledge a Ministry of Education, Science and Technological
Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022-
14/200161).
PB  - Serbian Chemical Society and Serbian Young Chemists’ Club
C3  - 8th Conference of the Young Chemists of Serbia, Book of Abstracts
T1  - Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors
SP  - 15
EP  - 15
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4737
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2022",
abstract = "Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as
a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC
inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity
and selectivity are defined as: surface recognition group (CAP group), aliphatic or
aromatic linker and zinc-binding group (ZBG).
Herein, we describe a comprehensive protocol for the computational fragment search of
novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase
6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl
piperazine was employed to synthesize novel HDAC inhibitors with small structural
perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified
two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as
two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker
chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based
molecular modelling.

References
1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas,
The Oncologist, 2021, 26(3), 184 e366.
2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5),
1800083.

Acknowledgments
The authors acknowledge a Ministry of Education, Science and Technological
Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022-
14/200161).",
publisher = "Serbian Chemical Society and Serbian Young Chemists’ Club",
journal = "8th Conference of the Young Chemists of Serbia, Book of Abstracts",
title = "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors",
pages = "15-15",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4737"
}

Ružić, D., Đoković, N., Srdić-Rajić, T.,& Nikolić, K.. (2022). Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in 8th Conference of the Young Chemists of Serbia, Book of Abstracts
Serbian Chemical Society and Serbian Young Chemists’ Club., 15-15.
https://hdl.handle.net/21.15107/rcub_farfar_4737

Ružić D, Đoković N, Srdić-Rajić T, Nikolić K. Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in 8th Conference of the Young Chemists of Serbia, Book of Abstracts. 2022;:15-15.
https://hdl.handle.net/21.15107/rcub_farfar_4737 .

Ružić, Dušan, Đoković, Nemanja, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors" in 8th Conference of the Young Chemists of Serbia, Book of Abstracts (2022):15-15,
https://hdl.handle.net/21.15107/rcub_farfar_4737 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Rahnasto‐Rilla, Minna
AU  - Srdić-Rajić, Tatjana
AU  - Lahtela‐Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4523
AB  - Inhibitors of sirtuin 2 (SIRT2i) represent a promising group of novel therapeutics in
treatment of the age-related disorders, including carcinomas, neurodegenerative diseases,
metabolic syndrome etc. (1). Despite the promising preclinical results, none of the known
SIRT2i reached clinical trials. One of the main obstacles in the structure-based drug design of
novel SIRT2i represents intricate conformational dynamics of sirtuin 2 (SIRT2) binding
pocket (2). In order to facilitate the discovery of novel SIRT2i, we have developed the
protocol for enhanced sampling of the binding pocket dynamics and validated it by
integration into structure-based virtual screening (SBVS) pipeline for discovery of novel
SIRT2i. Developed protocol relies on well-tempered metadynamics simulations using the set
of pocket-related collective variables derived from time-lagged independent component
analysis (tICA). Our protocol outperformed classical molecular dynamics in search for
alternative conformational states of the binding pocket. Additionally, the protocol was able
to reveal the existence of cryptic subpocket inside SIRT2 binding pocket. To validate our
findings, the protocol was implemented into SBVS which resulted in significant expansion of
SIRT2i chemical space. To further probe the potential of expanded chemical space in
discovery of chemically novel groups of SIRT2i, a few virtual hit molecules were selected and
tested in vitro. Compound NDJ18 was shown to be potent and selective SIRT2i with
anticancer activity on triple-negative breast cancer cell line MDA-MB-231. Experimental
validation supported future generalization of the protocol by application on wider scope of
challenging protein targets.
AB  - Inhibitori sirtuina 2 (SIRT2i) predstavljaju obećavajuću grupu novih terapeutika u
terapiji poremećaja povezanih sa starenjem, poput malignih oboljenja, neurodegenerativnih
oboljenja, metaboličkog sindroma itd. (1). Uprkos obećavajućim rezultatima prekliničkih
ispitivanja, nijedan SIRT2i nije došao do kliničkih studija. Jedna od glavnih prepreka u
strukturno-zavisnom dizajnu novih SIRT2i predstavlja kompleksna konformaciona dinamika
vezivnog mesta sirtuina 2 (SIRT2) (2). U cilju povećanja efikasnosti racionalnog dizajna
novih SIRT2i, razvijen je protokol za poboljšano uzorkovanje konformacione dinamike
vezivnog mesta SIRT2 koji se zasniva na metadinamičkim simulacijama uz set kolektivnih
varijabli izvedenih iz analize nezavisnih komponenti vremenskih zaostataka dinamike
vezivnog mesta (tICA). Razvijeni protokol nadmašio je klasičnu molekulsku dinamiku u
efikasnosti pretrage alternativnih konformacionih stanja vezivnog mesta. Dodatno,
primenom razvijenog protokola otkriveno je postojanje skrivenog džepa unutar vezivnog
mesta SIRT2. U cilju validacije, protokol je implementiran u strukturno-zavisni virtuelni
skrining SIRT2i što je rezultovalo u značajnoj ekspanziji postojećeg hemijskog prostora
SIRT2i. U daljem testiranju potencijala proširenog hemijskog prostora u otkriću potpuno
novih hemijskih skeleta SIRT2i, nekoliko najbolje rangiranih molekula je selektovano i
evaluirano in vitro. Jedinjenje NDJ18 se pokazalo kao potentan i selektivan novi SIRT2i.
Testiranjima na trostruko-negativnoj ćelijskoj liniji kancera dojke MDA-MB-231 utvrđen je
značajan antikancerski potencijal navedenog jedinjenja. Eksperimentalnom validacijom
podržan je dalji razvoj i generalizacija protokola kroz primenu na širem spektru proteinskih
targeta izazovnih sa aspekta tehnika racionalnog dizajna lekova.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign
T1  - Novi protokol za poboljšano uzorkovanje dinamike vezivnih mesta i njegova integracija u virtuelni skrining inhibitora sirtuina 2
VL  - 72
IS  - 4 suplement
SP  - S241
EP  - S242
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4523
ER  - 

@conference{
author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto‐Rilla, Minna and Srdić-Rajić, Tatjana and Lahtela‐Kakkonen, Maija and Nikolić, Katarina",
year = "2022",
abstract = "Inhibitors of sirtuin 2 (SIRT2i) represent a promising group of novel therapeutics in
treatment of the age-related disorders, including carcinomas, neurodegenerative diseases,
metabolic syndrome etc. (1). Despite the promising preclinical results, none of the known
SIRT2i reached clinical trials. One of the main obstacles in the structure-based drug design of
novel SIRT2i represents intricate conformational dynamics of sirtuin 2 (SIRT2) binding
pocket (2). In order to facilitate the discovery of novel SIRT2i, we have developed the
protocol for enhanced sampling of the binding pocket dynamics and validated it by
integration into structure-based virtual screening (SBVS) pipeline for discovery of novel
SIRT2i. Developed protocol relies on well-tempered metadynamics simulations using the set
of pocket-related collective variables derived from time-lagged independent component
analysis (tICA). Our protocol outperformed classical molecular dynamics in search for
alternative conformational states of the binding pocket. Additionally, the protocol was able
to reveal the existence of cryptic subpocket inside SIRT2 binding pocket. To validate our
findings, the protocol was implemented into SBVS which resulted in significant expansion of
SIRT2i chemical space. To further probe the potential of expanded chemical space in
discovery of chemically novel groups of SIRT2i, a few virtual hit molecules were selected and
tested in vitro. Compound NDJ18 was shown to be potent and selective SIRT2i with
anticancer activity on triple-negative breast cancer cell line MDA-MB-231. Experimental
validation supported future generalization of the protocol by application on wider scope of
challenging protein targets., Inhibitori sirtuina 2 (SIRT2i) predstavljaju obećavajuću grupu novih terapeutika u
terapiji poremećaja povezanih sa starenjem, poput malignih oboljenja, neurodegenerativnih
oboljenja, metaboličkog sindroma itd. (1). Uprkos obećavajućim rezultatima prekliničkih
ispitivanja, nijedan SIRT2i nije došao do kliničkih studija. Jedna od glavnih prepreka u
strukturno-zavisnom dizajnu novih SIRT2i predstavlja kompleksna konformaciona dinamika
vezivnog mesta sirtuina 2 (SIRT2) (2). U cilju povećanja efikasnosti racionalnog dizajna
novih SIRT2i, razvijen je protokol za poboljšano uzorkovanje konformacione dinamike
vezivnog mesta SIRT2 koji se zasniva na metadinamičkim simulacijama uz set kolektivnih
varijabli izvedenih iz analize nezavisnih komponenti vremenskih zaostataka dinamike
vezivnog mesta (tICA). Razvijeni protokol nadmašio je klasičnu molekulsku dinamiku u
efikasnosti pretrage alternativnih konformacionih stanja vezivnog mesta. Dodatno,
primenom razvijenog protokola otkriveno je postojanje skrivenog džepa unutar vezivnog
mesta SIRT2. U cilju validacije, protokol je implementiran u strukturno-zavisni virtuelni
skrining SIRT2i što je rezultovalo u značajnoj ekspanziji postojećeg hemijskog prostora
SIRT2i. U daljem testiranju potencijala proširenog hemijskog prostora u otkriću potpuno
novih hemijskih skeleta SIRT2i, nekoliko najbolje rangiranih molekula je selektovano i
evaluirano in vitro. Jedinjenje NDJ18 se pokazalo kao potentan i selektivan novi SIRT2i.
Testiranjima na trostruko-negativnoj ćelijskoj liniji kancera dojke MDA-MB-231 utvrđen je
značajan antikancerski potencijal navedenog jedinjenja. Eksperimentalnom validacijom
podržan je dalji razvoj i generalizacija protokola kroz primenu na širem spektru proteinskih
targeta izazovnih sa aspekta tehnika racionalnog dizajna lekova.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign, Novi protokol za poboljšano uzorkovanje dinamike vezivnih mesta i njegova integracija u virtuelni skrining inhibitora sirtuina 2",
volume = "72",
number = "4 suplement",
pages = "S241-S242",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4523"
}

Đoković, N., Ružić, D., Rahnasto‐Rilla, M., Srdić-Rajić, T., Lahtela‐Kakkonen, M.,& Nikolić, K.. (2022). Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S241-S242.
https://hdl.handle.net/21.15107/rcub_farfar_4523

Đoković N, Ružić D, Rahnasto‐Rilla M, Srdić-Rajić T, Lahtela‐Kakkonen M, Nikolić K. Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign. in Arhiv za farmaciju. 2022;72(4 suplement):S241-S242.
https://hdl.handle.net/21.15107/rcub_farfar_4523 .

Đoković, Nemanja, Ružić, Dušan, Rahnasto‐Rilla, Minna, Srdić-Rajić, Tatjana, Lahtela‐Kakkonen, Maija, Nikolić, Katarina, "Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S241-S242,
https://hdl.handle.net/21.15107/rcub_farfar_4523 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Corentin, Bon
AU  - Petković, Miloš
AU  - Ellinger, Bertrand
AU  - Gul, Sheraz
AU  - Santibanez, Juan
AU  - Lahtela-Kakkonen, Maija
AU  - Halby, Ludovic
AU  - Ganesan, A.
AU  - Srdić Rajić, Tatjana
AU  - Arimondo, Paola
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4938
C3  - e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021
T1  - Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4938
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Corentin, Bon and Petković, Miloš and Ellinger, Bertrand and Gul, Sheraz and Santibanez, Juan and Lahtela-Kakkonen, Maija and Halby, Ludovic and Ganesan, A. and Srdić Rajić, Tatjana and Arimondo, Paola and Nikolić, Katarina",
year = "2021",
journal = "e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021",
title = "Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4938"
}

Ružić, D., Đoković, N., Corentin, B., Petković, M., Ellinger, B., Gul, S., Santibanez, J., Lahtela-Kakkonen, M., Halby, L., Ganesan, A., Srdić Rajić, T., Arimondo, P.,& Nikolić, K.. (2021). Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors. in e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021.
https://hdl.handle.net/21.15107/rcub_farfar_4938

Ružić D, Đoković N, Corentin B, Petković M, Ellinger B, Gul S, Santibanez J, Lahtela-Kakkonen M, Halby L, Ganesan A, Srdić Rajić T, Arimondo P, Nikolić K. Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors. in e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_4938 .

Ružić, Dušan, Đoković, Nemanja, Corentin, Bon, Petković, Miloš, Ellinger, Bertrand, Gul, Sheraz, Santibanez, Juan, Lahtela-Kakkonen, Maija, Halby, Ludovic, Ganesan, A., Srdić Rajić, Tatjana, Arimondo, Paola, Nikolić, Katarina, "Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors" in e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021 (2021),
https://hdl.handle.net/21.15107/rcub_farfar_4938 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Petković, Miloš
AU  - Gul, Sheraz
AU  - Santibanez, Juan
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4942
PB  - European Association for Cancer Research
C3  - EACR 2021 Congress, Innovative Cancer Science: Better Outcomes Through Research, Virtual Congress, 9 – 12 June, 2021.
T1  - Novel 1-benzhydryl piperazine derivative inhibits the migration and invasiveness of breast cancer cells: Synthesis, molecular modelling and biological characterization
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4942
ER  - 

@conference{
author = "Ružić, Dušan and Petković, Miloš and Gul, Sheraz and Santibanez, Juan and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2021",
publisher = "European Association for Cancer Research",
journal = "EACR 2021 Congress, Innovative Cancer Science: Better Outcomes Through Research, Virtual Congress, 9 – 12 June, 2021.",
title = "Novel 1-benzhydryl piperazine derivative inhibits the migration and invasiveness of breast cancer cells: Synthesis, molecular modelling and biological characterization",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4942"
}

Ružić, D., Petković, M., Gul, S., Santibanez, J., Srdić-Rajić, T.,& Nikolić, K.. (2021). Novel 1-benzhydryl piperazine derivative inhibits the migration and invasiveness of breast cancer cells: Synthesis, molecular modelling and biological characterization. in EACR 2021 Congress, Innovative Cancer Science: Better Outcomes Through Research, Virtual Congress, 9 – 12 June, 2021.
European Association for Cancer Research..
https://hdl.handle.net/21.15107/rcub_farfar_4942

Ružić D, Petković M, Gul S, Santibanez J, Srdić-Rajić T, Nikolić K. Novel 1-benzhydryl piperazine derivative inhibits the migration and invasiveness of breast cancer cells: Synthesis, molecular modelling and biological characterization. in EACR 2021 Congress, Innovative Cancer Science: Better Outcomes Through Research, Virtual Congress, 9 – 12 June, 2021.. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_4942 .

Ružić, Dušan, Petković, Miloš, Gul, Sheraz, Santibanez, Juan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Novel 1-benzhydryl piperazine derivative inhibits the migration and invasiveness of breast cancer cells: Synthesis, molecular modelling and biological characterization" in EACR 2021 Congress, Innovative Cancer Science: Better Outcomes Through Research, Virtual Congress, 9 – 12 June, 2021. (2021),
https://hdl.handle.net/21.15107/rcub_farfar_4942 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Petković, Miloš
AU  - Ellinger, Bernhard
AU  - Gul, Sheraz
AU  - Santibanez, Juan
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4890
AB  - Human epigenetic metalloenzymes that modulate the acetylation status of histones, alter cancer cell morphology
and cell survival are histone deacetylases (HDACs). Of particular importance, histone deacetylase 6 is studied as
a cytoplasmic isoform implicated in the microtubule dynamics in cancer 1. Still, more efforts need to be
undertaken to make these inhibitors reach to global oncology market 2. In this study, we probed the 1-benzhydryl
piperazine as the capping (CAP) group to selectively target the HDAC6 isoform and alter the migration and
invasiveness of the breast cancer cell lines. Nine different 1-benzhydryl piperazine derivatives were synthesized
and the structure-activity relationship study was postulated with combined ligand-based (3D-QSAR) and
structure-based (molecular docking) in silico approaches 3,4. We performed wound healing, matrigel invasion
and transwell migration assays to search for the inhibitor that shows antimigratory and antiinvasive properties of
the breast cancer cell lines (MDA-MB-231 and MCF-7). Most of the synthesized compounds induce apoptosis in
excellent non-cytotoxic, antimigratory and antiinvasive profile in breast cancer cell lines, which is in agreement
with the proposed cellular roles of HDAC6 in cancer. The work presented in this study integrates in silico modelling, synthesis and in vitro biological profiling to
discover selective HDAC6 inhibitor. Identification of potent HDAC6 inhibitor that alters migration and
invasiveness of breast cancer cell lines opens up new horizons to treat metastatic diseases.
PB  - EFMC-ISMC
C3  - EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
T1  - Synthesis, molecular modelling and biological characterization of novel antimigratory and antiinvasive 1-benzhydryl piperazine derivatives
SP  - 372
EP  - 372
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4890
ER  - 

@conference{
author = "Ružić, Dušan and Petković, Miloš and Ellinger, Bernhard and Gul, Sheraz and Santibanez, Juan and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2021",
abstract = "Human epigenetic metalloenzymes that modulate the acetylation status of histones, alter cancer cell morphology
and cell survival are histone deacetylases (HDACs). Of particular importance, histone deacetylase 6 is studied as
a cytoplasmic isoform implicated in the microtubule dynamics in cancer 1. Still, more efforts need to be
undertaken to make these inhibitors reach to global oncology market 2. In this study, we probed the 1-benzhydryl
piperazine as the capping (CAP) group to selectively target the HDAC6 isoform and alter the migration and
invasiveness of the breast cancer cell lines. Nine different 1-benzhydryl piperazine derivatives were synthesized
and the structure-activity relationship study was postulated with combined ligand-based (3D-QSAR) and
structure-based (molecular docking) in silico approaches 3,4. We performed wound healing, matrigel invasion
and transwell migration assays to search for the inhibitor that shows antimigratory and antiinvasive properties of
the breast cancer cell lines (MDA-MB-231 and MCF-7). Most of the synthesized compounds induce apoptosis in
excellent non-cytotoxic, antimigratory and antiinvasive profile in breast cancer cell lines, which is in agreement
with the proposed cellular roles of HDAC6 in cancer. The work presented in this study integrates in silico modelling, synthesis and in vitro biological profiling to
discover selective HDAC6 inhibitor. Identification of potent HDAC6 inhibitor that alters migration and
invasiveness of breast cancer cell lines opens up new horizons to treat metastatic diseases.",
publisher = "EFMC-ISMC",
journal = "EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts",
title = "Synthesis, molecular modelling and biological characterization of novel antimigratory and antiinvasive 1-benzhydryl piperazine derivatives",
pages = "372-372",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4890"
}

Ružić, D., Petković, M., Ellinger, B., Gul, S., Santibanez, J., Srdić-Rajić, T.,& Nikolić, K.. (2021). Synthesis, molecular modelling and biological characterization of novel antimigratory and antiinvasive 1-benzhydryl piperazine derivatives. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
EFMC-ISMC., 372-372.
https://hdl.handle.net/21.15107/rcub_farfar_4890

Ružić D, Petković M, Ellinger B, Gul S, Santibanez J, Srdić-Rajić T, Nikolić K. Synthesis, molecular modelling and biological characterization of novel antimigratory and antiinvasive 1-benzhydryl piperazine derivatives. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts. 2021;:372-372.
https://hdl.handle.net/21.15107/rcub_farfar_4890 .

Ružić, Dušan, Petković, Miloš, Ellinger, Bernhard, Gul, Sheraz, Santibanez, Juan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Synthesis, molecular modelling and biological characterization of novel antimigratory and antiinvasive 1-benzhydryl piperazine derivatives" in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts (2021):372-372,
https://hdl.handle.net/21.15107/rcub_farfar_4890 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Gul, Sheraz
AU  - Lahtela‐Kakkonen, Maija
AU  - Ganesan, A.
AU  - Santibanez, Juan
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4889
AB  - Histone deacetylases (HDACs) are epigenetic enzymes involved in regulation of histone posttranslational
modifications and gene expression. Since changed function of HDACs is involved in pathogenesis of cancer 1-3,
the HDAC inhibitors are extensive examined as promising anticancer agents. In our in silico study we have
combined structure-based, ligand-based, and fragment-based methodologies to design selective inhibitors against
cytoplasmic isoforms of HDAC, such as histone deacetylase 6 inhibitors (HDAC6) and SIRT2. The drug design
study has defined several promising selective HDAC6 and SIRT2 inhibitors for further synthesis and in vitro
testing. Based on the in vitro activities of the novel compounds in a panel of biochemical HDAC assays as well
as various cell-based assays were selected the most promising candidates for further investigation.
PB  - EFMC-ISMC
C3  - EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
T1  - Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors
SP  - 360
EP  - 360
EP  - 
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4889
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Gul, Sheraz and Lahtela‐Kakkonen, Maija and Ganesan, A. and Santibanez, Juan and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2021",
abstract = "Histone deacetylases (HDACs) are epigenetic enzymes involved in regulation of histone posttranslational
modifications and gene expression. Since changed function of HDACs is involved in pathogenesis of cancer 1-3,
the HDAC inhibitors are extensive examined as promising anticancer agents. In our in silico study we have
combined structure-based, ligand-based, and fragment-based methodologies to design selective inhibitors against
cytoplasmic isoforms of HDAC, such as histone deacetylase 6 inhibitors (HDAC6) and SIRT2. The drug design
study has defined several promising selective HDAC6 and SIRT2 inhibitors for further synthesis and in vitro
testing. Based on the in vitro activities of the novel compounds in a panel of biochemical HDAC assays as well
as various cell-based assays were selected the most promising candidates for further investigation.",
publisher = "EFMC-ISMC",
journal = "EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts",
title = "Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors",
pages = "360-360-",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4889"
}

Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela‐Kakkonen, M., Ganesan, A., Santibanez, J., Srdić-Rajić, T.,& Nikolić, K.. (2021). Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
EFMC-ISMC., 360-360.
https://hdl.handle.net/21.15107/rcub_farfar_4889

Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela‐Kakkonen M, Ganesan A, Santibanez J, Srdić-Rajić T, Nikolić K. Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts. 2021;:360-360.
https://hdl.handle.net/21.15107/rcub_farfar_4889 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela‐Kakkonen, Maija, Ganesan, A., Santibanez, Juan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors" in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts (2021):360-360,
https://hdl.handle.net/21.15107/rcub_farfar_4889 .

TY  - CONF
AU  - Nikolić, Katarina
AU  - Ružić, Dušan
AU  - Beljkaš, Milan
AU  - Petković, Miloš
AU  - Gul, Sheraz
AU  - Santibanez, Juan
AU  - Srdić Rajić, Tatjana
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4928
AB  - Academia and industry make an extensive effort to discover selective histone deacetylase 6 inhibitors (HDAC6i) which could be delivered to the patients. These attempts are partially obscured by inconsistency in preclinical data regarding the cellular and biochemical changes upon treatment of solid tumours with HDAC6i. In this study, we present computational design, synthesis of three novel HDAC6 inhibitors along with their in vitro pharmacological profile against zinc-dependent HDACs. The in vitro anticancer effects of the synthesized compounds were examined on four types of cancer cell lines, human breast cancer cell lines (MDA-MB-231 and MCF-7) as well as human melanoma cells (A-375 and 518A2). It was found that the synthesized compounds induce apoptosis in high concentrations (IC50 >30 μM) nonetheless, the observed morphological changes of studied cell lines during cell viability assay prompted us to examine their antimetastatic properties. Novel compound MBDR-4 significantly reduces migration and invasiveness of the MDA-MB-231 and A375 cancer cell lines at subapoptotic concentration (5 μM), which open new avenues for redirecting drug development of selective HDAC6 inhibitors as adjuvant chemotherapeutics, with antimetastatic effects.
AB  - Истраживачи тренутно улажу велике напоре у испитивање селективних
инхибитора хистон деацетилазе 6 (HDAC6i) 1,2 који би могли да нађу клиничку
примену 3 . Ова истраживања су делимично отежана услед неконзистентних
преклиничких резултата о ћелијским и биохемијским променама након
третмана солидних тумора HDAC6i(4,5). Наша студија обухвата компјутерски дизајн и синтезу три нова HDAC6
инхибитора, заједно са in vitro ензимским испитивањем активности на
сродним изоформама HDAC ензимима. Антинеопластичан ефекат синтетисаних једињења је испитан in vitro на четири типа ћелија карцинома,
хуманим ћелијама карцинома дојке (MDA-MB-231 и MCF-7) и хуманим ћелијама меланома (A-375 и 518A2). Утврђено је да синтетисана једињења
индукују апоптозу при високим концентрацијама (IC 50 >30 μM). Истовремено је уочено да ова једињења доводе и до морфолошких промена на третираним ћелијама током извођења теста виабилности што нас је усмерило ка испитивању њихових антиметастатских особина. Једињење MBDR-4
снажно инхибира миграцију и инвазивност MDA-MB-231 и A375 ћелија канцера на субапоптотској концентрацији (5 μM), што отвара нове могућности
за истраживање селективних HDAC6 инхибитора као адјувантних хемотерапеутика са антиметастатским ефектом.
PB  - Serbian Medical Society Oncology Section
C3  - 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia
T1  - Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?
T1  - Постоји ли граница између цитотоксичног и
антиметастатског ефекта селективних инхибитора
хистон деацетилазе 6 код солидних тумора?
SP  - 264
EP  - 266
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4928
ER  - 

@conference{
author = "Nikolić, Katarina and Ružić, Dušan and Beljkaš, Milan and Petković, Miloš and Gul, Sheraz and Santibanez, Juan and Srdić Rajić, Tatjana",
year = "2019",
abstract = "Academia and industry make an extensive effort to discover selective histone deacetylase 6 inhibitors (HDAC6i) which could be delivered to the patients. These attempts are partially obscured by inconsistency in preclinical data regarding the cellular and biochemical changes upon treatment of solid tumours with HDAC6i. In this study, we present computational design, synthesis of three novel HDAC6 inhibitors along with their in vitro pharmacological profile against zinc-dependent HDACs. The in vitro anticancer effects of the synthesized compounds were examined on four types of cancer cell lines, human breast cancer cell lines (MDA-MB-231 and MCF-7) as well as human melanoma cells (A-375 and 518A2). It was found that the synthesized compounds induce apoptosis in high concentrations (IC50 >30 μM) nonetheless, the observed morphological changes of studied cell lines during cell viability assay prompted us to examine their antimetastatic properties. Novel compound MBDR-4 significantly reduces migration and invasiveness of the MDA-MB-231 and A375 cancer cell lines at subapoptotic concentration (5 μM), which open new avenues for redirecting drug development of selective HDAC6 inhibitors as adjuvant chemotherapeutics, with antimetastatic effects., Истраживачи тренутно улажу велике напоре у испитивање селективних
инхибитора хистон деацетилазе 6 (HDAC6i) 1,2 који би могли да нађу клиничку
примену 3 . Ова истраживања су делимично отежана услед неконзистентних
преклиничких резултата о ћелијским и биохемијским променама након
третмана солидних тумора HDAC6i(4,5). Наша студија обухвата компјутерски дизајн и синтезу три нова HDAC6
инхибитора, заједно са in vitro ензимским испитивањем активности на
сродним изоформама HDAC ензимима. Антинеопластичан ефекат синтетисаних једињења је испитан in vitro на четири типа ћелија карцинома,
хуманим ћелијама карцинома дојке (MDA-MB-231 и MCF-7) и хуманим ћелијама меланома (A-375 и 518A2). Утврђено је да синтетисана једињења
индукују апоптозу при високим концентрацијама (IC 50 >30 μM). Истовремено је уочено да ова једињења доводе и до морфолошких промена на третираним ћелијама током извођења теста виабилности што нас је усмерило ка испитивању њихових антиметастатских особина. Једињење MBDR-4
снажно инхибира миграцију и инвазивност MDA-MB-231 и A375 ћелија канцера на субапоптотској концентрацији (5 μM), што отвара нове могућности
за истраживање селективних HDAC6 инхибитора као адјувантних хемотерапеутика са антиметастатским ефектом.",
publisher = "Serbian Medical Society Oncology Section",
journal = "56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia",
title = "Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?, Постоји ли граница између цитотоксичног и
антиметастатског ефекта селективних инхибитора
хистон деацетилазе 6 код солидних тумора?",
pages = "264-266",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4928"
}

Nikolić, K., Ružić, D., Beljkaš, M., Petković, M., Gul, S., Santibanez, J.,& Srdić Rajić, T.. (2019). Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?. in 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia
Serbian Medical Society Oncology Section., 264-266.
https://hdl.handle.net/21.15107/rcub_farfar_4928

Nikolić K, Ružić D, Beljkaš M, Petković M, Gul S, Santibanez J, Srdić Rajić T. Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?. in 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia. 2019;:264-266.
https://hdl.handle.net/21.15107/rcub_farfar_4928 .

Nikolić, Katarina, Ružić, Dušan, Beljkaš, Milan, Petković, Miloš, Gul, Sheraz, Santibanez, Juan, Srdić Rajić, Tatjana, "Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?" in 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia (2019):264-266,
https://hdl.handle.net/21.15107/rcub_farfar_4928 .

TY  - CONF
AU  - Gagić, Žarko
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4877
AB  - U velikom broju studija pokazana je antitumorska aktivnost prirodnih izomera
vitamina E, a naročito njihovih polusintetskih derivata. Cilj ove studije je bio ispitivanje
citotoksične aktivnosti estara α‐tokoferola sa aminokiselinama lizinom, prolinom,
glutaminom, asparaginom i estara γ‐tokotrienola sa lizinom, prolinom i glutaminom na
MCF7 i MDA‐MB 231 ćelijskim linijama tumora dojke i A549 ćelijskoj liniji tumora
pluća. Sve ćelijske linije tretirane su koncentracijama ispitivanih jedinjenja u opsegu
0,62‐50 μM u toku 48 sati. Preživljavanje ćelija nakon tretmana ispitivanim
jedinjenjima je određeno MTT‐testom. Najveći uticaj na preživljavanje malignih ćelija
su imali α‐tokoferil lizin, α‐tokoferil asparagin u formi nitrila i γ‐tokotrienil lizin. α‐
Tokoferil lizin je ispoljio snažnu antitumorsku aktivnost na A549 (IC50=10,6 μM) i MCF7
(IC50=8,6 μM) ćelijama, dok je γ‐tokotrienil lizin je jedini od ispitivanih jedinjenja koji je
ispoljio aktivnost na sve tri maligne ćelijske linije, sa IC50 vrednostima 20,6 μM (MCF7),
28,6 μM (MDA‐MB‐231) i 19 μM (A549). Asparaginski estar α‐tokoferola u formi nitrila
je je doveo do snažne inhibicije preživljavanja MDA‐MB‐231 ćelija (IC50=9,2 μM) koje se
odlikuju višestrukom rezistencijom na lekove koji se koriste u terapiji tumora dojke.
Ispitivana jedinjenja nisu ispoljila toksičnost ka MRC‐5 zdravoj ćelijskoj liniji fetalnih
fibroblasta pluća.
Zahvaljujući pokazanoj in vitro citotoksičnoj aktivnosti i selektivnosti za maligne
ćelije, aminokiselinski estri α‐tokoferola i γ‐tokotrienola predstavljaju dobre kandidate
za buduća in vivo ispitivanja.
AB  - In recent studies, the antitumor activity of vitamin E derivatives has been
demonstrated. The aim of this study was to investigate the cytotoxic activity of α‐
tocopherol esters with amino acids lysine, proline, glutamine, asparagine and γ‐
tocotrienol esters with lysine, proline and glutamine on MCF7 and MDA‐MB 231 breast
cancer cell lines and A549 lung cancer cell line. All cell lines were treated with
concentrations of the test compounds in the range of 0.62‐50 μM for 48 hours. Cell
survival after treatment with the investigated compounds was determined by MTT test.
The greatest influence on the survival of malignant cells was observed with α‐
tocopheryl lysine, α‐tocopheryl asparagine in the form of nitrile and γ‐tocotrienyl
lysine. α‐Tocopheryl lysine exhibited strong cytotoxic activity on A549 (IC50 = 10.6 μM)
and MCF7 (IC50 = 8.6 μM) cells, while γ‐tocotrienyl lysine is the only compound that
exhibited activity on all three cancer cell lines, with IC50 values of 20.6 μM (MCF7),
28.6μM (MDA‐MB‐231) and 19 μM (A549). The α‐tocopheryl asparagine nitrile led to a
strong inhibition of the survival of MDA‐MB‐231 cells (IC50 =9.2 μM) that are
characterized by multiple resistance to drugs used for treatment of breast cancer. All
investigated compounds did not exhibit toxicity to normal MRC‐5 cell line of the fetal
fibroblasts of the lungs.
Based on the shown in vitro cytotoxic activity and selectivity for tumor cells, α‐
tocopherol and γ‐tocotrienol amino acid esters represent promising candidates for
future in vivo studies.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Ispitivanje citotoksične aktivnosti aminokiselinskih estara vitamina E na ćelijama tumora dojke i pluća
T1  - Cytotoxic activity of amino acid esters of vitamin E against breast and lung cancer cell lines
VL  - 68
IS  - 3
SP  - 391
EP  - 392
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4877
ER  - 

@conference{
author = "Gagić, Žarko and Srdić-Rajić, Tatjana and Nikolić, Katarina and Agbaba, Danica",
year = "2018",
abstract = "U velikom broju studija pokazana je antitumorska aktivnost prirodnih izomera
vitamina E, a naročito njihovih polusintetskih derivata. Cilj ove studije je bio ispitivanje
citotoksične aktivnosti estara α‐tokoferola sa aminokiselinama lizinom, prolinom,
glutaminom, asparaginom i estara γ‐tokotrienola sa lizinom, prolinom i glutaminom na
MCF7 i MDA‐MB 231 ćelijskim linijama tumora dojke i A549 ćelijskoj liniji tumora
pluća. Sve ćelijske linije tretirane su koncentracijama ispitivanih jedinjenja u opsegu
0,62‐50 μM u toku 48 sati. Preživljavanje ćelija nakon tretmana ispitivanim
jedinjenjima je određeno MTT‐testom. Najveći uticaj na preživljavanje malignih ćelija
su imali α‐tokoferil lizin, α‐tokoferil asparagin u formi nitrila i γ‐tokotrienil lizin. α‐
Tokoferil lizin je ispoljio snažnu antitumorsku aktivnost na A549 (IC50=10,6 μM) i MCF7
(IC50=8,6 μM) ćelijama, dok je γ‐tokotrienil lizin je jedini od ispitivanih jedinjenja koji je
ispoljio aktivnost na sve tri maligne ćelijske linije, sa IC50 vrednostima 20,6 μM (MCF7),
28,6 μM (MDA‐MB‐231) i 19 μM (A549). Asparaginski estar α‐tokoferola u formi nitrila
je je doveo do snažne inhibicije preživljavanja MDA‐MB‐231 ćelija (IC50=9,2 μM) koje se
odlikuju višestrukom rezistencijom na lekove koji se koriste u terapiji tumora dojke.
Ispitivana jedinjenja nisu ispoljila toksičnost ka MRC‐5 zdravoj ćelijskoj liniji fetalnih
fibroblasta pluća.
Zahvaljujući pokazanoj in vitro citotoksičnoj aktivnosti i selektivnosti za maligne
ćelije, aminokiselinski estri α‐tokoferola i γ‐tokotrienola predstavljaju dobre kandidate
za buduća in vivo ispitivanja., In recent studies, the antitumor activity of vitamin E derivatives has been
demonstrated. The aim of this study was to investigate the cytotoxic activity of α‐
tocopherol esters with amino acids lysine, proline, glutamine, asparagine and γ‐
tocotrienol esters with lysine, proline and glutamine on MCF7 and MDA‐MB 231 breast
cancer cell lines and A549 lung cancer cell line. All cell lines were treated with
concentrations of the test compounds in the range of 0.62‐50 μM for 48 hours. Cell
survival after treatment with the investigated compounds was determined by MTT test.
The greatest influence on the survival of malignant cells was observed with α‐
tocopheryl lysine, α‐tocopheryl asparagine in the form of nitrile and γ‐tocotrienyl
lysine. α‐Tocopheryl lysine exhibited strong cytotoxic activity on A549 (IC50 = 10.6 μM)
and MCF7 (IC50 = 8.6 μM) cells, while γ‐tocotrienyl lysine is the only compound that
exhibited activity on all three cancer cell lines, with IC50 values of 20.6 μM (MCF7),
28.6μM (MDA‐MB‐231) and 19 μM (A549). The α‐tocopheryl asparagine nitrile led to a
strong inhibition of the survival of MDA‐MB‐231 cells (IC50 =9.2 μM) that are
characterized by multiple resistance to drugs used for treatment of breast cancer. All
investigated compounds did not exhibit toxicity to normal MRC‐5 cell line of the fetal
fibroblasts of the lungs.
Based on the shown in vitro cytotoxic activity and selectivity for tumor cells, α‐
tocopherol and γ‐tocotrienol amino acid esters represent promising candidates for
future in vivo studies.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Ispitivanje citotoksične aktivnosti aminokiselinskih estara vitamina E na ćelijama tumora dojke i pluća, Cytotoxic activity of amino acid esters of vitamin E against breast and lung cancer cell lines",
volume = "68",
number = "3",
pages = "391-392",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4877"
}

Gagić, Ž., Srdić-Rajić, T., Nikolić, K.,& Agbaba, D.. (2018). Ispitivanje citotoksične aktivnosti aminokiselinskih estara vitamina E na ćelijama tumora dojke i pluća. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 68(3), 391-392.
https://hdl.handle.net/21.15107/rcub_farfar_4877

Gagić Ž, Srdić-Rajić T, Nikolić K, Agbaba D. Ispitivanje citotoksične aktivnosti aminokiselinskih estara vitamina E na ćelijama tumora dojke i pluća. in Arhiv za farmaciju. 2018;68(3):391-392.
https://hdl.handle.net/21.15107/rcub_farfar_4877 .

Gagić, Žarko, Srdić-Rajić, Tatjana, Nikolić, Katarina, Agbaba, Danica, "Ispitivanje citotoksične aktivnosti aminokiselinskih estara vitamina E na ćelijama tumora dojke i pluća" in Arhiv za farmaciju, 68, no. 3 (2018):391-392,
https://hdl.handle.net/21.15107/rcub_farfar_4877 .

TY  - JOUR
AU  - Gagić, Žarko
AU  - Ivković, Branka
AU  - Srdić-Rajić, Tatjana
AU  - Vučićević, Jelica
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2532
AB  - Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain alpha-tocopherol and gamma-tocotrienol derivatives used as the lead compounds in this study, antitumor activities against various cancer cell types have been reported. In the course of the last decade, structural analogs of VE (esters, ethers and amides) with an enhanced antiproliferative and proapoptotic activity against various cancer cells were synthesized. Within the framework of this study, seven amino acid esters of alpha-tocopherol (4a-d) and gamma-tocotrienol (6a-c) were prepared using the EDC/DMAP reaction conditions and their ability to inhibit proliferation of the MCF-7 and MDA-MB-231 breast cancer cells and the A549 lung cancer cells was evaluated. Compound 6a showed an activity against all three cell lines (IC50: 20.6 mu M, 28.6 mu M and 19 mu M for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50 = 8.6 mu M) and A549 cells (IC50 = 8.6 mu M). Ester 4d exerted strong antiproliferative activity against the estrogenunresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2 mu M. Compared with the strong activity of compounds 4a, 4d and 6a, commercial alpha-tocopheryl succinate and gamma-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50 mu M. Investigation of the cell cycle phase distribution and the cell death induction confirmed an apoptosis of the MDA-MB-231 cells treated with 4d, as well as a synergistic effect of 4d with the known anticancer drug doxorubicin. This result suggests a possibility of a combined therapy of breast cancer in order to improve the therapeutic response and to lower the toxicity associated with a high dose of doxorubicin. The stability study of 4d in human plasma showed that ca. 83% initial concentration of this compound remains in plasma in the course of six hours incubation. The ligand based virtual screening of the ChEMBL database identified new compounds with a potential antiproliferative activity on MCF-7 and on multi-drug resistant MDA-MB 231 breast cancer cells.
PB  - Elsevier Science BV, Amsterdam
T2  - European Journal of Pharmaceutical Sciences
T1  - Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs
VL  - 88
SP  - 59
EP  - 69
DO  - 10.1016/j.ejps.2016.04.008
ER  - 

@article{
author = "Gagić, Žarko and Ivković, Branka and Srdić-Rajić, Tatjana and Vučićević, Jelica and Nikolić, Katarina and Agbaba, Danica",
year = "2016",
abstract = "Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain alpha-tocopherol and gamma-tocotrienol derivatives used as the lead compounds in this study, antitumor activities against various cancer cell types have been reported. In the course of the last decade, structural analogs of VE (esters, ethers and amides) with an enhanced antiproliferative and proapoptotic activity against various cancer cells were synthesized. Within the framework of this study, seven amino acid esters of alpha-tocopherol (4a-d) and gamma-tocotrienol (6a-c) were prepared using the EDC/DMAP reaction conditions and their ability to inhibit proliferation of the MCF-7 and MDA-MB-231 breast cancer cells and the A549 lung cancer cells was evaluated. Compound 6a showed an activity against all three cell lines (IC50: 20.6 mu M, 28.6 mu M and 19 mu M for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50 = 8.6 mu M) and A549 cells (IC50 = 8.6 mu M). Ester 4d exerted strong antiproliferative activity against the estrogenunresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2 mu M. Compared with the strong activity of compounds 4a, 4d and 6a, commercial alpha-tocopheryl succinate and gamma-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50 mu M. Investigation of the cell cycle phase distribution and the cell death induction confirmed an apoptosis of the MDA-MB-231 cells treated with 4d, as well as a synergistic effect of 4d with the known anticancer drug doxorubicin. This result suggests a possibility of a combined therapy of breast cancer in order to improve the therapeutic response and to lower the toxicity associated with a high dose of doxorubicin. The stability study of 4d in human plasma showed that ca. 83% initial concentration of this compound remains in plasma in the course of six hours incubation. The ligand based virtual screening of the ChEMBL database identified new compounds with a potential antiproliferative activity on MCF-7 and on multi-drug resistant MDA-MB 231 breast cancer cells.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Journal of Pharmaceutical Sciences",
title = "Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs",
volume = "88",
pages = "59-69",
doi = "10.1016/j.ejps.2016.04.008"
}

Gagić, Ž., Ivković, B., Srdić-Rajić, T., Vučićević, J., Nikolić, K.,& Agbaba, D.. (2016). Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs. in European Journal of Pharmaceutical Sciences
Elsevier Science BV, Amsterdam., 88, 59-69.
https://doi.org/10.1016/j.ejps.2016.04.008

Gagić Ž, Ivković B, Srdić-Rajić T, Vučićević J, Nikolić K, Agbaba D. Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs. in European Journal of Pharmaceutical Sciences. 2016;88:59-69.
doi:10.1016/j.ejps.2016.04.008 .

Gagić, Žarko, Ivković, Branka, Srdić-Rajić, Tatjana, Vučićević, Jelica, Nikolić, Katarina, Agbaba, Danica, "Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs" in European Journal of Pharmaceutical Sciences, 88 (2016):59-69,
https://doi.org/10.1016/j.ejps.2016.04.008 . .

TY  - JOUR
AU  - Konić-Ristić, Aleksandra
AU  - Stanojković, Tatjana
AU  - Srdić-Rajić, Tatjana
AU  - Dilber, Sanda
AU  - Đorđević, Brižita
AU  - Stanković, Ivan
AU  - Juranić, Zorica
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2671
AB  - Background/Aim. Numerous epidemiological studies have shown beneficial effects of cruciferous vegetables consumption in cancer chemoprevention. Biologically active compounds of different Brassicaceae species with antitumor potential are isothiocyanates, present in the form of their precursors - glucosinolates. The aim of this study was to determine the selectivity of antiproliferative action of dietary isothiocyanates for malignant versus normal cells. Methods. Antiproliferative activity of three isothiocyanates abundant in human diet: sulforaphane, benzyl isothiocyanate (BITC) and phenylethyl isothiocyanate, on human cervix carcinoma cell line - HeLa, melanoma cell line - Fem-x, and colon cancer cell line - LS 174, and on peripheral blood mononuclear cells (PBMC), with or without mitogen, were determined by MTT colorimetric assay 72 h after their continuous action. Results. All investigated isothiocyanates inhibited the proliferation of HeLa, Fem-x and LS 174 cells. On all cell lines treated, BITC was the most potent inhibitor of cell proliferation with half-maximum inhibitory concentration (IC50) values of 5.04 mmoL m-3 on HeLa cells, 2.76 mmol m-3 on Fem-x, and 14.30 mmol m-3 on LS 174 cells. Antiproliferative effects on human PBMC were with higher IC50 than on malignant cells. Indexes of selectivity, calculated as a ratio between IC50 values obtained on PBMC and malignant cells, were between 1.12 and 16.57, with the highest values obtained for the action of BITC on melanoma Fem-x cells. Conclusion. Based on its antiproliferative effects on malignant cells, as well as the selectivity of the action to malignant vs normal cells, benzyl isothiocyanate can be considered as a promising candidate in cancer chemoprevention. In general, the safety of investigated compounds, in addition to their antitumor potential, should be considered as an important criterion in cancer chemoprevention. Screening of selectivity is a plausible approach to the evaluation of safety of both natural isothiocyanates and synthesised analogues of these bioactive compounds.
AB  - Uvod/Cilj. Brojne epidemiološke studije pokazale su povoljne efekte konzumiranja povrća iz familije kupusnjača (Brassicaceae) u hemioprevenciji karcinoma. Osnovni biološki aktivni sastojci ovog povrća su izotiocijanati, prisutni u obliku prekursora - glukozinolata. Cilj ovog rada bio je određivanje selektivnosti antiproliferativnog delovanja dijetetskih izotiocijanata na maligne ćelije u odnosu na normalne ćelije. Metode. Antiproliferativna aktivnost tri izotiocijanata zastupljena u ljudskoj ishrani: sulforafana (SFN), benzil-izotiocijanata (BITC) i feniletil-izotiocijanata (FEITC) na humane maligne ćelijske linije, HeLa, ćelijsku liniju karcinoma grlića materice, Fem-x, ćelijsku liniju melanoma, i LS 174, ćelijsku liniju karcinoma kolona, kao i na mononuklearne ćelije periferne krvi (MNĆPK), sa ili bez delovanja mitogena, određivana je MTT kalorimetrijskim testom, 72 h nakon kontinuiranog delovanja agenasa. Rezultati. Svi ispitivani izotiocijanati inhibirali su proliferaciju HeLa, Fem-x i LS 174 ćelija. Na svim ćelijskim linijama BITC je pokazao najizraženije delovanje sa vrednostima polumaksimalne inhibitorne koncentracije (IC50) od 5.04 mmol m-3 na HeLa ćelijama, 2,76 mmoL m-3 na Fem-x i 14,30 mmol m-3 na LS 174 ćelijama. Svi ispitivani izotiocijanati pokazali su citotoksično delovanje na MNĆPK, ali sa višim IC50 vrednostima u odnosu na maligne ćelije. Indeksi selektivnosti antitumorkog delovanja, izraženi kao odnos IC50 vrednosti dobijenih na MNĆPK i malignim ćelijama, bili su između 1,12 i 16,57, sa najvišom vrednosti pri delovanju BITC na Fem-x ćelije. Zaključak. Na osnovu antiproliferativne aktivnosti na maligne ćelije i selektivnosti antiproliferativnog delovanja na maligne u odnosu na normalne ćelije, benzil izotiocijanat se ističe kao perspektivni agens u hemioprevenciji karcinoma. Generalno, pored antitumorskog delovanja, bezbednost primene ovih jedinjenja treba da predstavlja važan kriterijum u izboru odgovarajućih izotiocijanata za primenu u primarnoj, sekundarnoj i tercijarnoj hemioprevenciji kancera. Ispitivanje selektivnosti predstavlja pogodan pristup oceni bezbednosti i prirodnih izotiocijanata i sintetskih analoga.
PB  - Vojnomedicinska akademija - Institut za naučne informacije, Beograd
T2  - Vojnosanitetski pregled
T1  - In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells
T1  - In vitro ispitivanje selektivnosti antiproliferativnog dejstva dijetetskih izotiocijanata na tumorske u odnosu na normalne humane ćelije
VL  - 73
IS  - 7
SP  - 636
EP  - 642
DO  - 10.2298/VSP141103066K
ER  - 

@article{
author = "Konić-Ristić, Aleksandra and Stanojković, Tatjana and Srdić-Rajić, Tatjana and Dilber, Sanda and Đorđević, Brižita and Stanković, Ivan and Juranić, Zorica",
year = "2016",
abstract = "Background/Aim. Numerous epidemiological studies have shown beneficial effects of cruciferous vegetables consumption in cancer chemoprevention. Biologically active compounds of different Brassicaceae species with antitumor potential are isothiocyanates, present in the form of their precursors - glucosinolates. The aim of this study was to determine the selectivity of antiproliferative action of dietary isothiocyanates for malignant versus normal cells. Methods. Antiproliferative activity of three isothiocyanates abundant in human diet: sulforaphane, benzyl isothiocyanate (BITC) and phenylethyl isothiocyanate, on human cervix carcinoma cell line - HeLa, melanoma cell line - Fem-x, and colon cancer cell line - LS 174, and on peripheral blood mononuclear cells (PBMC), with or without mitogen, were determined by MTT colorimetric assay 72 h after their continuous action. Results. All investigated isothiocyanates inhibited the proliferation of HeLa, Fem-x and LS 174 cells. On all cell lines treated, BITC was the most potent inhibitor of cell proliferation with half-maximum inhibitory concentration (IC50) values of 5.04 mmoL m-3 on HeLa cells, 2.76 mmol m-3 on Fem-x, and 14.30 mmol m-3 on LS 174 cells. Antiproliferative effects on human PBMC were with higher IC50 than on malignant cells. Indexes of selectivity, calculated as a ratio between IC50 values obtained on PBMC and malignant cells, were between 1.12 and 16.57, with the highest values obtained for the action of BITC on melanoma Fem-x cells. Conclusion. Based on its antiproliferative effects on malignant cells, as well as the selectivity of the action to malignant vs normal cells, benzyl isothiocyanate can be considered as a promising candidate in cancer chemoprevention. In general, the safety of investigated compounds, in addition to their antitumor potential, should be considered as an important criterion in cancer chemoprevention. Screening of selectivity is a plausible approach to the evaluation of safety of both natural isothiocyanates and synthesised analogues of these bioactive compounds., Uvod/Cilj. Brojne epidemiološke studije pokazale su povoljne efekte konzumiranja povrća iz familije kupusnjača (Brassicaceae) u hemioprevenciji karcinoma. Osnovni biološki aktivni sastojci ovog povrća su izotiocijanati, prisutni u obliku prekursora - glukozinolata. Cilj ovog rada bio je određivanje selektivnosti antiproliferativnog delovanja dijetetskih izotiocijanata na maligne ćelije u odnosu na normalne ćelije. Metode. Antiproliferativna aktivnost tri izotiocijanata zastupljena u ljudskoj ishrani: sulforafana (SFN), benzil-izotiocijanata (BITC) i feniletil-izotiocijanata (FEITC) na humane maligne ćelijske linije, HeLa, ćelijsku liniju karcinoma grlića materice, Fem-x, ćelijsku liniju melanoma, i LS 174, ćelijsku liniju karcinoma kolona, kao i na mononuklearne ćelije periferne krvi (MNĆPK), sa ili bez delovanja mitogena, određivana je MTT kalorimetrijskim testom, 72 h nakon kontinuiranog delovanja agenasa. Rezultati. Svi ispitivani izotiocijanati inhibirali su proliferaciju HeLa, Fem-x i LS 174 ćelija. Na svim ćelijskim linijama BITC je pokazao najizraženije delovanje sa vrednostima polumaksimalne inhibitorne koncentracije (IC50) od 5.04 mmol m-3 na HeLa ćelijama, 2,76 mmoL m-3 na Fem-x i 14,30 mmol m-3 na LS 174 ćelijama. Svi ispitivani izotiocijanati pokazali su citotoksično delovanje na MNĆPK, ali sa višim IC50 vrednostima u odnosu na maligne ćelije. Indeksi selektivnosti antitumorkog delovanja, izraženi kao odnos IC50 vrednosti dobijenih na MNĆPK i malignim ćelijama, bili su između 1,12 i 16,57, sa najvišom vrednosti pri delovanju BITC na Fem-x ćelije. Zaključak. Na osnovu antiproliferativne aktivnosti na maligne ćelije i selektivnosti antiproliferativnog delovanja na maligne u odnosu na normalne ćelije, benzil izotiocijanat se ističe kao perspektivni agens u hemioprevenciji karcinoma. Generalno, pored antitumorskog delovanja, bezbednost primene ovih jedinjenja treba da predstavlja važan kriterijum u izboru odgovarajućih izotiocijanata za primenu u primarnoj, sekundarnoj i tercijarnoj hemioprevenciji kancera. Ispitivanje selektivnosti predstavlja pogodan pristup oceni bezbednosti i prirodnih izotiocijanata i sintetskih analoga.",
publisher = "Vojnomedicinska akademija - Institut za naučne informacije, Beograd",
journal = "Vojnosanitetski pregled",
title = "In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells, In vitro ispitivanje selektivnosti antiproliferativnog dejstva dijetetskih izotiocijanata na tumorske u odnosu na normalne humane ćelije",
volume = "73",
number = "7",
pages = "636-642",
doi = "10.2298/VSP141103066K"
}

Konić-Ristić, A., Stanojković, T., Srdić-Rajić, T., Dilber, S., Đorđević, B., Stanković, I.,& Juranić, Z.. (2016). In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells. in Vojnosanitetski pregled
Vojnomedicinska akademija - Institut za naučne informacije, Beograd., 73(7), 636-642.
https://doi.org/10.2298/VSP141103066K

Konić-Ristić A, Stanojković T, Srdić-Rajić T, Dilber S, Đorđević B, Stanković I, Juranić Z. In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells. in Vojnosanitetski pregled. 2016;73(7):636-642.
doi:10.2298/VSP141103066K .

Konić-Ristić, Aleksandra, Stanojković, Tatjana, Srdić-Rajić, Tatjana, Dilber, Sanda, Đorđević, Brižita, Stanković, Ivan, Juranić, Zorica, "In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells" in Vojnosanitetski pregled, 73, no. 7 (2016):636-642,
https://doi.org/10.2298/VSP141103066K . .

TY  - JOUR
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
AU  - Cavić, Milena
AU  - Đokić, Ivana
AU  - Gemović, Branislava
AU  - Perović, Vladimir
AU  - Veljković, Nevena
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2578
AB  - Imidazoline I1 receptor signaling is associated with pathways that regulate cell viability leading to varied cell-type specific phenotypes. We demonstrated that the antihypertensive drug rilmenidine, a selective imidazoline I1 receptor agonist, modulates proliferation and stimulates the proapoptotic protein Bax thus inducing the perturbation of the mitochondrial pathway and apoptosis in human leukemic K562 cells. Rilmenidine acts through a mechanism which involves deactivation of Ras/MAP kinases ERK, p38 and JNK. Moreover, rilmenidine renders K562 cells, which are particularly resistant to chemotherapeutic agents, susceptible to the DNA damaging drug doxorubicin. The rilmenidine co-treatment with doxorubicin reverses G2/M arrest and triggers apoptotic response to DNA damage. Our data offer new insights into the pathways associated with imidazoline I1 receptor activation in K562 cells suggesting rilmenidine as a valuable tool to deepen our understanding of imidazoline I1 receptor signaling in hematologic malignancies and to search for medicinally active agents.
PB  - Elsevier Science BV, Amsterdam
T2  - European Journal of Pharmaceutical Sciences
T1  - Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells
VL  - 81
SP  - 172
EP  - 180
DO  - 10.1016/j.ejps.2015.10.017
ER  - 

@article{
author = "Srdić-Rajić, Tatjana and Nikolić, Katarina and Cavić, Milena and Đokić, Ivana and Gemović, Branislava and Perović, Vladimir and Veljković, Nevena",
year = "2016",
abstract = "Imidazoline I1 receptor signaling is associated with pathways that regulate cell viability leading to varied cell-type specific phenotypes. We demonstrated that the antihypertensive drug rilmenidine, a selective imidazoline I1 receptor agonist, modulates proliferation and stimulates the proapoptotic protein Bax thus inducing the perturbation of the mitochondrial pathway and apoptosis in human leukemic K562 cells. Rilmenidine acts through a mechanism which involves deactivation of Ras/MAP kinases ERK, p38 and JNK. Moreover, rilmenidine renders K562 cells, which are particularly resistant to chemotherapeutic agents, susceptible to the DNA damaging drug doxorubicin. The rilmenidine co-treatment with doxorubicin reverses G2/M arrest and triggers apoptotic response to DNA damage. Our data offer new insights into the pathways associated with imidazoline I1 receptor activation in K562 cells suggesting rilmenidine as a valuable tool to deepen our understanding of imidazoline I1 receptor signaling in hematologic malignancies and to search for medicinally active agents.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Journal of Pharmaceutical Sciences",
title = "Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells",
volume = "81",
pages = "172-180",
doi = "10.1016/j.ejps.2015.10.017"
}

Srdić-Rajić, T., Nikolić, K., Cavić, M., Đokić, I., Gemović, B., Perović, V.,& Veljković, N.. (2016). Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells. in European Journal of Pharmaceutical Sciences
Elsevier Science BV, Amsterdam., 81, 172-180.
https://doi.org/10.1016/j.ejps.2015.10.017

Srdić-Rajić T, Nikolić K, Cavić M, Đokić I, Gemović B, Perović V, Veljković N. Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells. in European Journal of Pharmaceutical Sciences. 2016;81:172-180.
doi:10.1016/j.ejps.2015.10.017 .

Srdić-Rajić, Tatjana, Nikolić, Katarina, Cavić, Milena, Đokić, Ivana, Gemović, Branislava, Perović, Vladimir, Veljković, Nevena, "Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells" in European Journal of Pharmaceutical Sciences, 81 (2016):172-180,
https://doi.org/10.1016/j.ejps.2015.10.017 . .

TY  - JOUR
AU  - Vučićević, Jelica
AU  - Srdić-Rajić, Tatjana
AU  - Pieroni, Marco
AU  - Laurila, Jonne M. M.
AU  - Perović, Vladimir
AU  - Tassini, Sabrina
AU  - Azzali, Elisa
AU  - Costantino, Gabriele
AU  - Glisić, Sanja
AU  - Agbaba, Danica
AU  - Scheinin, Mika
AU  - Nikolić, Katarina
AU  - Radi, Marco
AU  - Veljković, Nevena
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2526
AB  - The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Bioorganic & Medicinal Chemistry
T1  - A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin
VL  - 24
IS  - 14
SP  - 3174
EP  - 3183
DO  - 10.1016/j.bmc.2016.05.043
ER  - 

@article{
author = "Vučićević, Jelica and Srdić-Rajić, Tatjana and Pieroni, Marco and Laurila, Jonne M. M. and Perović, Vladimir and Tassini, Sabrina and Azzali, Elisa and Costantino, Gabriele and Glisić, Sanja and Agbaba, Danica and Scheinin, Mika and Nikolić, Katarina and Radi, Marco and Veljković, Nevena",
year = "2016",
abstract = "The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Bioorganic & Medicinal Chemistry",
title = "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin",
volume = "24",
number = "14",
pages = "3174-3183",
doi = "10.1016/j.bmc.2016.05.043"
}

Vučićević, J., Srdić-Rajić, T., Pieroni, M., Laurila, J. M. M., Perović, V., Tassini, S., Azzali, E., Costantino, G., Glisić, S., Agbaba, D., Scheinin, M., Nikolić, K., Radi, M.,& Veljković, N.. (2016). A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin. in Bioorganic & Medicinal Chemistry
Pergamon-Elsevier Science Ltd, Oxford., 24(14), 3174-3183.
https://doi.org/10.1016/j.bmc.2016.05.043

Vučićević J, Srdić-Rajić T, Pieroni M, Laurila JMM, Perović V, Tassini S, Azzali E, Costantino G, Glisić S, Agbaba D, Scheinin M, Nikolić K, Radi M, Veljković N. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin. in Bioorganic & Medicinal Chemistry. 2016;24(14):3174-3183.
doi:10.1016/j.bmc.2016.05.043 .

Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir, Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glisić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina, Radi, Marco, Veljković, Nevena, "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin" in Bioorganic & Medicinal Chemistry, 24, no. 14 (2016):3174-3183,
https://doi.org/10.1016/j.bmc.2016.05.043 . .

TY  - CONF
AU  - Konić-Ristić, Aleksandra
AU  - Zrnić-Ćirić, Milica
AU  - Stanković, Ivan
AU  - Srdić-Rajić, Tatjana
AU  - Kardum, Nevena
AU  - Glibetić, Marija
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5398
AB  - It has been suggested that impairment of intestinal wall integrity may contribute to the low-grade inflammation in subjects with metabolic distribances and foster progression of cardiovascular, liver or neurological diseases. Recent studies provide evidence that dietary polyphenols may important role in gut health and homeostasis, as one of the proposed mechanisms of their beneficial systemic effects.
PB  - Institut National de la Recherche Agronomique (INRA), France
PB  - Institut National de la Santé et de la Recherche Médicale (INSERM), France
C3  - 7th International Conference on Polyphenols and Health (ICPH 2015), 27 - 30 October 2015, Congress Center Tours, France
T1  - Long term consumption of Aronia juice decreases serum zonulin levels and the expression of cd11b on monocytes in subjects at high cvd risk
SP  - 198
EP  - 198
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5398
ER  - 

@conference{
author = "Konić-Ristić, Aleksandra and Zrnić-Ćirić, Milica and Stanković, Ivan and Srdić-Rajić, Tatjana and Kardum, Nevena and Glibetić, Marija",
year = "2015",
abstract = "It has been suggested that impairment of intestinal wall integrity may contribute to the low-grade inflammation in subjects with metabolic distribances and foster progression of cardiovascular, liver or neurological diseases. Recent studies provide evidence that dietary polyphenols may important role in gut health and homeostasis, as one of the proposed mechanisms of their beneficial systemic effects.",
publisher = "Institut National de la Recherche Agronomique (INRA), France, Institut National de la Santé et de la Recherche Médicale (INSERM), France",
journal = "7th International Conference on Polyphenols and Health (ICPH 2015), 27 - 30 October 2015, Congress Center Tours, France",
title = "Long term consumption of Aronia juice decreases serum zonulin levels and the expression of cd11b on monocytes in subjects at high cvd risk",
pages = "198-198",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5398"
}

Konić-Ristić, A., Zrnić-Ćirić, M., Stanković, I., Srdić-Rajić, T., Kardum, N.,& Glibetić, M.. (2015). Long term consumption of Aronia juice decreases serum zonulin levels and the expression of cd11b on monocytes in subjects at high cvd risk. in 7th International Conference on Polyphenols and Health (ICPH 2015), 27 - 30 October 2015, Congress Center Tours, France
Institut National de la Recherche Agronomique (INRA), France., 198-198.
https://hdl.handle.net/21.15107/rcub_farfar_5398

Konić-Ristić A, Zrnić-Ćirić M, Stanković I, Srdić-Rajić T, Kardum N, Glibetić M. Long term consumption of Aronia juice decreases serum zonulin levels and the expression of cd11b on monocytes in subjects at high cvd risk. in 7th International Conference on Polyphenols and Health (ICPH 2015), 27 - 30 October 2015, Congress Center Tours, France. 2015;:198-198.
https://hdl.handle.net/21.15107/rcub_farfar_5398 .

Konić-Ristić, Aleksandra, Zrnić-Ćirić, Milica, Stanković, Ivan, Srdić-Rajić, Tatjana, Kardum, Nevena, Glibetić, Marija, "Long term consumption of Aronia juice decreases serum zonulin levels and the expression of cd11b on monocytes in subjects at high cvd risk" in 7th International Conference on Polyphenols and Health (ICPH 2015), 27 - 30 October 2015, Congress Center Tours, France (2015):198-198,
https://hdl.handle.net/21.15107/rcub_farfar_5398 .

TY  - JOUR
AU  - Nikolić, Katarina
AU  - Veljković, Nevena
AU  - Gemović, Branislava
AU  - Srdić-Rajić, Tatjana
AU  - Agbaba, Danica
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1933
AB  - The group of imidazoline-1 receptors (I-1-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I-1-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I-1-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I-1-IR agonist), moxonidine (moderate I-1-IR agonist), and efaroxan (I-1-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I-1-IR ligands (agonists, partial agonists, and antagonists) were carried out on I-1-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I-1-IR agonistic and I-1-IR antagonistic activity and created regression model for prediction of I-1-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I-1-IR agonists and I-1-IR antagonists. The most promising I-1-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I-1-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I-1-IR antagonists or partial I-1-IR agonists. The performed theoretical study provides reliable system for evaluation of I-1-IR agonistic and I-1-IR antagonistic activity of novel I-1-IR ligands, as drug candidates with anticancer activities.
PB  - Bentham Science Publ Ltd, Sharjah
T2  - Combinatorial Chemistry & High Throughput Screening
T1  - Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study
VL  - 16
IS  - 4
SP  - 298
EP  - 319
DO  - 10.2174/1386207311316040004
ER  - 

@article{
author = "Nikolić, Katarina and Veljković, Nevena and Gemović, Branislava and Srdić-Rajić, Tatjana and Agbaba, Danica",
year = "2013",
abstract = "The group of imidazoline-1 receptors (I-1-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I-1-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I-1-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I-1-IR agonist), moxonidine (moderate I-1-IR agonist), and efaroxan (I-1-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I-1-IR ligands (agonists, partial agonists, and antagonists) were carried out on I-1-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I-1-IR agonistic and I-1-IR antagonistic activity and created regression model for prediction of I-1-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I-1-IR agonists and I-1-IR antagonists. The most promising I-1-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I-1-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I-1-IR antagonists or partial I-1-IR agonists. The performed theoretical study provides reliable system for evaluation of I-1-IR agonistic and I-1-IR antagonistic activity of novel I-1-IR ligands, as drug candidates with anticancer activities.",
publisher = "Bentham Science Publ Ltd, Sharjah",
journal = "Combinatorial Chemistry & High Throughput Screening",
title = "Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study",
volume = "16",
number = "4",
pages = "298-319",
doi = "10.2174/1386207311316040004"
}

Nikolić, K., Veljković, N., Gemović, B., Srdić-Rajić, T.,& Agbaba, D.. (2013). Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study. in Combinatorial Chemistry & High Throughput Screening
Bentham Science Publ Ltd, Sharjah., 16(4), 298-319.
https://doi.org/10.2174/1386207311316040004

Nikolić K, Veljković N, Gemović B, Srdić-Rajić T, Agbaba D. Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study. in Combinatorial Chemistry & High Throughput Screening. 2013;16(4):298-319.
doi:10.2174/1386207311316040004 .

Nikolić, Katarina, Veljković, Nevena, Gemović, Branislava, Srdić-Rajić, Tatjana, Agbaba, Danica, "Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study" in Combinatorial Chemistry & High Throughput Screening, 16, no. 4 (2013):298-319,
https://doi.org/10.2174/1386207311316040004 . .