TY  - JOUR
AU  - Dobričić, Vladimir
AU  - Savić, Jelena
AU  - Tomašić, Tihomir
AU  - Durcik, Martina
AU  - Zidar, Nace
AU  - Peterlin-Mašič, Lucija
AU  - Ilaš, Janez
AU  - Kikelj, Danijel
AU  - Čudina, Olivera
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5431
AB  - Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication
and represent important antibacterial drug targets. To be successful as drug candidates, newly synthesized compounds must possess optimal lipophilicity, which enables efficient delivery to the site of action. In this study, retention behavior of twenty-three previously synthesized dual DNA gyrase and topoisomerase IV inhibitors was tested in RP-HPLC system, consisting of C8 column and acetonitrile/phosphate buffer (pH 5.5 and pH 7.4) mobile phase. logD was calculated at both pH values and the best correlation with logD was obtained for retention parameter φ0, indicating that this RP-HPLC system could be used as an alternative to the shake-flask determination of lipophilicity. Subsequent QSRR analysis revealed that intrinsic lipophilicity (logP) and molecular weight (bcutm13) have a positive, while solubility (bcutp3) has a negative influence on this  retention parameter.
PB  - Akadémiai Kiadó
T2  - Acta Chromatographica
T1  - High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors
VL  - 36
IS  - 1
SP  - 45
EP  - 51
DO  - 10.1556/1326.2022.01096
ER  - 

@article{
author = "Dobričić, Vladimir and Savić, Jelena and Tomašić, Tihomir and Durcik, Martina and Zidar, Nace and Peterlin-Mašič, Lucija and Ilaš, Janez and Kikelj, Danijel and Čudina, Olivera",
year = "2024",
abstract = "Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication
and represent important antibacterial drug targets. To be successful as drug candidates, newly synthesized compounds must possess optimal lipophilicity, which enables efficient delivery to the site of action. In this study, retention behavior of twenty-three previously synthesized dual DNA gyrase and topoisomerase IV inhibitors was tested in RP-HPLC system, consisting of C8 column and acetonitrile/phosphate buffer (pH 5.5 and pH 7.4) mobile phase. logD was calculated at both pH values and the best correlation with logD was obtained for retention parameter φ0, indicating that this RP-HPLC system could be used as an alternative to the shake-flask determination of lipophilicity. Subsequent QSRR analysis revealed that intrinsic lipophilicity (logP) and molecular weight (bcutm13) have a positive, while solubility (bcutp3) has a negative influence on this  retention parameter.",
publisher = "Akadémiai Kiadó",
journal = "Acta Chromatographica",
title = "High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors",
volume = "36",
number = "1",
pages = "45-51",
doi = "10.1556/1326.2022.01096"
}

Dobričić, V., Savić, J., Tomašić, T., Durcik, M., Zidar, N., Peterlin-Mašič, L., Ilaš, J., Kikelj, D.,& Čudina, O.. (2024). High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors. in Acta Chromatographica
Akadémiai Kiadó., 36(1), 45-51.
https://doi.org/10.1556/1326.2022.01096

Dobričić V, Savić J, Tomašić T, Durcik M, Zidar N, Peterlin-Mašič L, Ilaš J, Kikelj D, Čudina O. High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors. in Acta Chromatographica. 2024;36(1):45-51.
doi:10.1556/1326.2022.01096 .

Dobričić, Vladimir, Savić, Jelena, Tomašić, Tihomir, Durcik, Martina, Zidar, Nace, Peterlin-Mašič, Lucija, Ilaš, Janez, Kikelj, Danijel, Čudina, Olivera, "High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors" in Acta Chromatographica, 36, no. 1 (2024):45-51,
https://doi.org/10.1556/1326.2022.01096 . .

TY  - CONF
AU  - Dobričić, Vladimir
AU  - Marodi, Marko
AU  - Marković, Bojan
AU  - Tomašič, Tihomir
AU  - Zidar, Nace
AU  - Peterlin Mašič, Lucija
AU  - Ilaš, Janez
AU  - Kikelj, Danijel
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5460
AB  - In this study, estimation of gastrointestinal absorption of thirteen selected dual DNA gyrase and topoisomerase IV
inhibitors was carried out using PAMPA test. Diffusion through artificial membrane, consisting of egg lecithin solution
in dodecane (first PAMPA model) and a mixture of hexadecane and hexane (second PAMPA model), was monitored
[1,2]. The starting solutions (pH 5.5) and the acceptor medium (pH 7.4) were prepared to contain 2% dimethyl
sulfoxide. Concentrations of tested compounds in starting solutions, donor and acceptor medium after incubation
were measured using LC-MS/MS method. Permeability coefficients were calculated and good correlation was
observed between results obtained using these two PAMPA models. Subsequently, the hexadecane/hexane model
was selected for the evaluation of gastrointestinal absorption of the remaining ten compounds.
Derivatives with the highest permeability in hexadecane/hexane model were TZS-34 and TCF-3a (logPe: -5.37 and
-4.93, respectively) whereas TLK-13 and NZ-97 had the lowest permeability (logPe: -9.91 and -9.85, respectively).
Therefore, the highest gastrointestinal absorption can be expected from TZS-34 and TCF-3a, and lowest from TLK-13
and NZ-97 (Figure 1). High membrane retention observed for compounds TEL-28 (72%) and TAZ-2b (30 %) might be a
reason for lower permeability than expected based on their lipophilicity.
PB  - MuTaLig COST ACTION CA15135
C3  - Fourth WG Meeting CA15135, Cost Action CA15135, 5 - 7. March, 2020. Bornova, Izmir, Book of the Abstracts
T1  - Estimation of gastrointestinal absorption of a series of dual DNA Gyrase and Topoisomerase IV inhibitors using Pampa technique
SP  - 41
EP  - 41
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5460
ER  - 

@conference{
author = "Dobričić, Vladimir and Marodi, Marko and Marković, Bojan and Tomašič, Tihomir and Zidar, Nace and Peterlin Mašič, Lucija and Ilaš, Janez and Kikelj, Danijel",
year = "2020",
abstract = "In this study, estimation of gastrointestinal absorption of thirteen selected dual DNA gyrase and topoisomerase IV
inhibitors was carried out using PAMPA test. Diffusion through artificial membrane, consisting of egg lecithin solution
in dodecane (first PAMPA model) and a mixture of hexadecane and hexane (second PAMPA model), was monitored
[1,2]. The starting solutions (pH 5.5) and the acceptor medium (pH 7.4) were prepared to contain 2% dimethyl
sulfoxide. Concentrations of tested compounds in starting solutions, donor and acceptor medium after incubation
were measured using LC-MS/MS method. Permeability coefficients were calculated and good correlation was
observed between results obtained using these two PAMPA models. Subsequently, the hexadecane/hexane model
was selected for the evaluation of gastrointestinal absorption of the remaining ten compounds.
Derivatives with the highest permeability in hexadecane/hexane model were TZS-34 and TCF-3a (logPe: -5.37 and
-4.93, respectively) whereas TLK-13 and NZ-97 had the lowest permeability (logPe: -9.91 and -9.85, respectively).
Therefore, the highest gastrointestinal absorption can be expected from TZS-34 and TCF-3a, and lowest from TLK-13
and NZ-97 (Figure 1). High membrane retention observed for compounds TEL-28 (72%) and TAZ-2b (30 %) might be a
reason for lower permeability than expected based on their lipophilicity.",
publisher = "MuTaLig COST ACTION CA15135",
journal = "Fourth WG Meeting CA15135, Cost Action CA15135, 5 - 7. March, 2020. Bornova, Izmir, Book of the Abstracts",
title = "Estimation of gastrointestinal absorption of a series of dual DNA Gyrase and Topoisomerase IV inhibitors using Pampa technique",
pages = "41-41",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5460"
}

Dobričić, V., Marodi, M., Marković, B., Tomašič, T., Zidar, N., Peterlin Mašič, L., Ilaš, J.,& Kikelj, D.. (2020). Estimation of gastrointestinal absorption of a series of dual DNA Gyrase and Topoisomerase IV inhibitors using Pampa technique. in Fourth WG Meeting CA15135, Cost Action CA15135, 5 - 7. March, 2020. Bornova, Izmir, Book of the Abstracts
MuTaLig COST ACTION CA15135., 41-41.
https://hdl.handle.net/21.15107/rcub_farfar_5460

Dobričić V, Marodi M, Marković B, Tomašič T, Zidar N, Peterlin Mašič L, Ilaš J, Kikelj D. Estimation of gastrointestinal absorption of a series of dual DNA Gyrase and Topoisomerase IV inhibitors using Pampa technique. in Fourth WG Meeting CA15135, Cost Action CA15135, 5 - 7. March, 2020. Bornova, Izmir, Book of the Abstracts. 2020;:41-41.
https://hdl.handle.net/21.15107/rcub_farfar_5460 .

Dobričić, Vladimir, Marodi, Marko, Marković, Bojan, Tomašič, Tihomir, Zidar, Nace, Peterlin Mašič, Lucija, Ilaš, Janez, Kikelj, Danijel, "Estimation of gastrointestinal absorption of a series of dual DNA Gyrase and Topoisomerase IV inhibitors using Pampa technique" in Fourth WG Meeting CA15135, Cost Action CA15135, 5 - 7. March, 2020. Bornova, Izmir, Book of the Abstracts (2020):41-41,
https://hdl.handle.net/21.15107/rcub_farfar_5460 .

TY  - JOUR
AU  - Rupar, Jelena
AU  - Dobričić, Vladimir
AU  - Grahovac, Jelena
AU  - Radulović, Siniša
AU  - Skok, Žiga
AU  - Ilaš, Janez
AU  - Aleksić, Mara
AU  - Brborić, Jasmina
AU  - Čudina, Olivera
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3606
AB  - A series of eleven 9-acridinyl amino acid derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 cancer cell lines and normal diploid cell line MRC5 using the MTT assay. Compounds 6, 7, 8 and 9 were the most active, with IC50 values comparable to or lower than that of chemotherapeutic agent amsacrine. 8 and 9 were especially effective in the A549 cell line (IC50 ≈ 6 μM), which is of special interest since amsacrine is not sufficiently active in lung cancer patients. Cell cycle analysis revealed that 7 and 9 caused G2/M block, amsacrine caused arrest in the S phase, while 6 and 8 induced apoptotic cell death independently of the cell cycle regulation. In comparison to amsacrine, 6, 7, 8, and 9 showed similar inhibitory potential towards topoisomerase II, whereas only 7 showed DNA intercalation properties. In contrast to amsacrine, 6, 7, 8 and 9 showed a lack of toxicity towards unstimulated normal human leucocytes.
PB  - Royal Society of Chemistry
T2  - RSC Medicinal Chemistry
T1  - Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives
VL  - 11
IS  - 3
SP  - 378
EP  - 386
DO  - 10.1039/c9md00597h
DO  - 2-s2.0-85083014447
ER  - 

@article{
author = "Rupar, Jelena and Dobričić, Vladimir and Grahovac, Jelena and Radulović, Siniša and Skok, Žiga and Ilaš, Janez and Aleksić, Mara and Brborić, Jasmina and Čudina, Olivera",
year = "2020",
abstract = "A series of eleven 9-acridinyl amino acid derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 cancer cell lines and normal diploid cell line MRC5 using the MTT assay. Compounds 6, 7, 8 and 9 were the most active, with IC50 values comparable to or lower than that of chemotherapeutic agent amsacrine. 8 and 9 were especially effective in the A549 cell line (IC50 ≈ 6 μM), which is of special interest since amsacrine is not sufficiently active in lung cancer patients. Cell cycle analysis revealed that 7 and 9 caused G2/M block, amsacrine caused arrest in the S phase, while 6 and 8 induced apoptotic cell death independently of the cell cycle regulation. In comparison to amsacrine, 6, 7, 8, and 9 showed similar inhibitory potential towards topoisomerase II, whereas only 7 showed DNA intercalation properties. In contrast to amsacrine, 6, 7, 8 and 9 showed a lack of toxicity towards unstimulated normal human leucocytes.",
publisher = "Royal Society of Chemistry",
journal = "RSC Medicinal Chemistry",
title = "Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives",
volume = "11",
number = "3",
pages = "378-386",
doi = "10.1039/c9md00597h, 2-s2.0-85083014447"
}

Rupar, J., Dobričić, V., Grahovac, J., Radulović, S., Skok, Ž., Ilaš, J., Aleksić, M., Brborić, J.,& Čudina, O.. (2020). Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives. in RSC Medicinal Chemistry
Royal Society of Chemistry., 11(3), 378-386.
https://doi.org/10.1039/c9md00597h

Rupar J, Dobričić V, Grahovac J, Radulović S, Skok Ž, Ilaš J, Aleksić M, Brborić J, Čudina O. Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives. in RSC Medicinal Chemistry. 2020;11(3):378-386.
doi:10.1039/c9md00597h .

Rupar, Jelena, Dobričić, Vladimir, Grahovac, Jelena, Radulović, Siniša, Skok, Žiga, Ilaš, Janez, Aleksić, Mara, Brborić, Jasmina, Čudina, Olivera, "Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives" in RSC Medicinal Chemistry, 11, no. 3 (2020):378-386,
https://doi.org/10.1039/c9md00597h . .

TY  - CONF
AU  - Dobričić, Vladimir
AU  - Savić, Jelena
AU  - Tomašič, Tihomir
AU  - Zidar, Nace
AU  - Peterlin Mašič, Lucija
AU  - Ilaš, Janez
AU  - Kikelj, Danijel
AU  - Čudina, Olivera
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5461
AB  - In this study, lipophilicity of twenty-three DNA gyrase and topoisomerase IV ATPase inhibitors was estimated at two
pH values (5.5 and 7.4) using reversed-phase high-performance liquid chromatography (RP-HPLC) [1,2]. Retention
behavior was tested on HP 1100 HPLC chromatograph, using column Zorbax Eclipse Plus C8 (150 X 4.6 mm, 5 µm
particle size). Mobile phase consisted of acetonitrile and phosphate buffer (pH was adjusted to 5.5 or 7.4). Each
compound was tested in four different ratios of acetonitrile and buffer (acetonitrile ranged from 20% to 65%). Column
temperature was 25 °C, flow rate 1 mL/min, injection volume 20 µL and detection was performed at 254 nm. For each
compound, capacity factor (k) was calculated and logk values were plotted against percentage of acetonitrile. Finally,
following chromatography parameters were calculated: logkw (y-axis intercept), a (slope) and ϕ0 (-logkw/a).
Derivatives with the highest lipophilicity were TEL-28 and NDL-20, whereas NZ97 had the lowest lipophilicity (at both
pH values, Figure 1). The majority of compounds possess similar or slightly different lipophilicities at both pH values,
but the highest differences were observed for TAZ-7, LMD-17 and NCH-4d, which could significantly affect their
biological properties (particularly gastrointestinal absorption, distribution and biological activity).
PB  - MuTaLig COST ACTION CA15135
C3  - Third WG Meeting CA15135, Cost Action CA15135, Februar 23 - 24. 2019. Pariz, Francuska
T1  - RP-HPLC evaluation of lipophilicity of a series of dual DNA gyrase and topoisomerase IV inhibitors
SP  - 32
EP  - 32
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5461
ER  - 

@conference{
author = "Dobričić, Vladimir and Savić, Jelena and Tomašič, Tihomir and Zidar, Nace and Peterlin Mašič, Lucija and Ilaš, Janez and Kikelj, Danijel and Čudina, Olivera",
year = "2019",
abstract = "In this study, lipophilicity of twenty-three DNA gyrase and topoisomerase IV ATPase inhibitors was estimated at two
pH values (5.5 and 7.4) using reversed-phase high-performance liquid chromatography (RP-HPLC) [1,2]. Retention
behavior was tested on HP 1100 HPLC chromatograph, using column Zorbax Eclipse Plus C8 (150 X 4.6 mm, 5 µm
particle size). Mobile phase consisted of acetonitrile and phosphate buffer (pH was adjusted to 5.5 or 7.4). Each
compound was tested in four different ratios of acetonitrile and buffer (acetonitrile ranged from 20% to 65%). Column
temperature was 25 °C, flow rate 1 mL/min, injection volume 20 µL and detection was performed at 254 nm. For each
compound, capacity factor (k) was calculated and logk values were plotted against percentage of acetonitrile. Finally,
following chromatography parameters were calculated: logkw (y-axis intercept), a (slope) and ϕ0 (-logkw/a).
Derivatives with the highest lipophilicity were TEL-28 and NDL-20, whereas NZ97 had the lowest lipophilicity (at both
pH values, Figure 1). The majority of compounds possess similar or slightly different lipophilicities at both pH values,
but the highest differences were observed for TAZ-7, LMD-17 and NCH-4d, which could significantly affect their
biological properties (particularly gastrointestinal absorption, distribution and biological activity).",
publisher = "MuTaLig COST ACTION CA15135",
journal = "Third WG Meeting CA15135, Cost Action CA15135, Februar 23 - 24. 2019. Pariz, Francuska",
title = "RP-HPLC evaluation of lipophilicity of a series of dual DNA gyrase and topoisomerase IV inhibitors",
pages = "32-32",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5461"
}

Dobričić, V., Savić, J., Tomašič, T., Zidar, N., Peterlin Mašič, L., Ilaš, J., Kikelj, D.,& Čudina, O.. (2019). RP-HPLC evaluation of lipophilicity of a series of dual DNA gyrase and topoisomerase IV inhibitors. in Third WG Meeting CA15135, Cost Action CA15135, Februar 23 - 24. 2019. Pariz, Francuska
MuTaLig COST ACTION CA15135., 32-32.
https://hdl.handle.net/21.15107/rcub_farfar_5461

Dobričić V, Savić J, Tomašič T, Zidar N, Peterlin Mašič L, Ilaš J, Kikelj D, Čudina O. RP-HPLC evaluation of lipophilicity of a series of dual DNA gyrase and topoisomerase IV inhibitors. in Third WG Meeting CA15135, Cost Action CA15135, Februar 23 - 24. 2019. Pariz, Francuska. 2019;:32-32.
https://hdl.handle.net/21.15107/rcub_farfar_5461 .

Dobričić, Vladimir, Savić, Jelena, Tomašič, Tihomir, Zidar, Nace, Peterlin Mašič, Lucija, Ilaš, Janez, Kikelj, Danijel, Čudina, Olivera, "RP-HPLC evaluation of lipophilicity of a series of dual DNA gyrase and topoisomerase IV inhibitors" in Third WG Meeting CA15135, Cost Action CA15135, Februar 23 - 24. 2019. Pariz, Francuska (2019):32-32,
https://hdl.handle.net/21.15107/rcub_farfar_5461 .