TY  - JOUR
AU  - Jadranin, Milka
AU  - Savić, Danica
AU  - Lupšić, Ema
AU  - Podolski-Renić, Ana
AU  - Pešić, Milica
AU  - Tešević, Vele
AU  - Milosavljević, Slobodan M.
AU  - Krstić, Gordana B.
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/7540
AB  - Euphorbia seguieriana ssp. seguieriana Necker (ES) and Euphorbia cyparissias (EC) with a habitat in the Deliblato Sands were the subject of this examination. The latexes of these so far insufficiently investigated species of the Euphorbia genus are used in traditional medicine for the treatment of wounds and warts on the skin. To determine their chemical composition, non-targeted screening of the latexes’ chloroform extracts was performed using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry employing an electrospray ionization source (LC-ESI QTOF MS). The analysis of the obtained results showed that the latexes of ES and EC represent rich sources of diterpenes, tentatively identified as jatrophanes, ingenanes, tiglianes, myrsinanes, premyrsinanes, and others. Examination of the anticancer activity of the ES and EC latex extracts showed that both extracts significantly inhibited the growth of the non-small cell lung carcinoma NCI-H460 and glioblastoma U87 cell lines as well as of their corresponding multi-drug resistant (MDR) cell lines, NCI-H460/R and U87-TxR. The obtained results also revealed that the ES and EC extracts inhibited the function of P-glycoprotein (P-gp) in MDR cancer cells, whose overexpression is one of the main mechanisms underlying MDR.
PB  - MDPI
T2  - Plants
T1  - LC-ESI QToF MS Non-Targeted Screening of Latex Extracts of Euphorbia seguieriana ssp. seguieriana Necker and Euphorbia cyparissias and Determination of Their Potential Anticancer Activity
VL  - 12
IS  - 24
SP  - 4181
DO  - 10.3390/plants12244181
ER  - 

@article{
author = "Jadranin, Milka and Savić, Danica and Lupšić, Ema and Podolski-Renić, Ana and Pešić, Milica and Tešević, Vele and Milosavljević, Slobodan M. and Krstić, Gordana B.",
year = "2023",
abstract = "Euphorbia seguieriana ssp. seguieriana Necker (ES) and Euphorbia cyparissias (EC) with a habitat in the Deliblato Sands were the subject of this examination. The latexes of these so far insufficiently investigated species of the Euphorbia genus are used in traditional medicine for the treatment of wounds and warts on the skin. To determine their chemical composition, non-targeted screening of the latexes’ chloroform extracts was performed using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry employing an electrospray ionization source (LC-ESI QTOF MS). The analysis of the obtained results showed that the latexes of ES and EC represent rich sources of diterpenes, tentatively identified as jatrophanes, ingenanes, tiglianes, myrsinanes, premyrsinanes, and others. Examination of the anticancer activity of the ES and EC latex extracts showed that both extracts significantly inhibited the growth of the non-small cell lung carcinoma NCI-H460 and glioblastoma U87 cell lines as well as of their corresponding multi-drug resistant (MDR) cell lines, NCI-H460/R and U87-TxR. The obtained results also revealed that the ES and EC extracts inhibited the function of P-glycoprotein (P-gp) in MDR cancer cells, whose overexpression is one of the main mechanisms underlying MDR.",
publisher = "MDPI",
journal = "Plants",
title = "LC-ESI QToF MS Non-Targeted Screening of Latex Extracts of Euphorbia seguieriana ssp. seguieriana Necker and Euphorbia cyparissias and Determination of Their Potential Anticancer Activity",
volume = "12",
number = "24",
pages = "4181",
doi = "10.3390/plants12244181"
}

Jadranin, M., Savić, D., Lupšić, E., Podolski-Renić, A., Pešić, M., Tešević, V., Milosavljević, S. M.,& Krstić, G. B.. (2023). LC-ESI QToF MS Non-Targeted Screening of Latex Extracts of Euphorbia seguieriana ssp. seguieriana Necker and Euphorbia cyparissias and Determination of Their Potential Anticancer Activity. in Plants
MDPI., 12(24), 4181.
https://doi.org/10.3390/plants12244181

Jadranin M, Savić D, Lupšić E, Podolski-Renić A, Pešić M, Tešević V, Milosavljević SM, Krstić GB. LC-ESI QToF MS Non-Targeted Screening of Latex Extracts of Euphorbia seguieriana ssp. seguieriana Necker and Euphorbia cyparissias and Determination of Their Potential Anticancer Activity. in Plants. 2023;12(24):4181.
doi:10.3390/plants12244181 .

Jadranin, Milka, Savić, Danica, Lupšić, Ema, Podolski-Renić, Ana, Pešić, Milica, Tešević, Vele, Milosavljević, Slobodan M., Krstić, Gordana B., "LC-ESI QToF MS Non-Targeted Screening of Latex Extracts of Euphorbia seguieriana ssp. seguieriana Necker and Euphorbia cyparissias and Determination of Their Potential Anticancer Activity" in Plants, 12, no. 24 (2023):4181,
https://doi.org/10.3390/plants12244181 . .

TY  - CONF
AU  - Stepanović, Ana
AU  - Lupšić, Ema
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Pajović, Milica
AU  - Jovanović Stojanov, Sofija
AU  - Dragoj, Miodrag
AU  - Terzić Jovanović, Nataša
AU  - Opsenica, Igor
AU  - Pešić, Milica
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/6678
AB  - Background: Doxorubicin (DOX) has been very effective against glioblastoma invitro. Its application in vivo is hampered because it cannot pass the blood–brainbarrier (BBB). Significant research efforts are invested to overcome this limitation.Sclareol (SC) is an aromatic compound naturally found in clary sage. Thecombination of SC and DOX showed promising effects in different tumor types invitro and in vivo. Therefore, we tested their combination and innovative hybridmolecules (SC:DOX) on glioblastoma cells with the expression of P-glycoprotein, amajor component of BBB and cancer multidrug resistance marker. Methods:Cytotoxicity and selectivity towards glioblastoma cells of SC, DOX, theircombination, and SC:DOX were examined by MTT assay. The effect of SC on DOXaccumulation was determined by flow cytometry. We also studied SC:DOXaccumulation, cellular uptake, localization imaging, and DNA damage induction.Results: The effects of simultaneous SC and DOX treatments demonstrated theconsiderable potential of SC to reverse DOX resistance in glioblastoma cells andincrease DOX accumulation. SC:DOX hybrids, named CON1 and CON2 were lesscytotoxic than DOX, but with reduced resistance and increased selectivity towardsglioblastoma cells. Cellular uptake of CON1 and CON2 was increased in glioblastomacells compared to DOX. Perinuclear localization of CON1 and CON2 vs. nuclearlocalization of DOX as well as no DNA damaging effects suggest a differentmechanism of action for SC:DOX. Conclusion: The combination of SC and DOX, andtheir innovative hybrids, could be considered a promising strategy that can overcomethe limitations of DOX application in glioblastoma.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts - 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - New anti-glioblastoma strategy with natural compounds sclareol and doxorubicin
SP  - 71
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5905
ER  - 

@conference{
author = "Stepanović, Ana and Lupšić, Ema and Dinić, Jelena and Podolski-Renić, Ana and Pajović, Milica and Jovanović Stojanov, Sofija and Dragoj, Miodrag and Terzić Jovanović, Nataša and Opsenica, Igor and Pešić, Milica",
year = "2023",
abstract = "Background: Doxorubicin (DOX) has been very effective against glioblastoma invitro. Its application in vivo is hampered because it cannot pass the blood–brainbarrier (BBB). Significant research efforts are invested to overcome this limitation.Sclareol (SC) is an aromatic compound naturally found in clary sage. Thecombination of SC and DOX showed promising effects in different tumor types invitro and in vivo. Therefore, we tested their combination and innovative hybridmolecules (SC:DOX) on glioblastoma cells with the expression of P-glycoprotein, amajor component of BBB and cancer multidrug resistance marker. Methods:Cytotoxicity and selectivity towards glioblastoma cells of SC, DOX, theircombination, and SC:DOX were examined by MTT assay. The effect of SC on DOXaccumulation was determined by flow cytometry. We also studied SC:DOXaccumulation, cellular uptake, localization imaging, and DNA damage induction.Results: The effects of simultaneous SC and DOX treatments demonstrated theconsiderable potential of SC to reverse DOX resistance in glioblastoma cells andincrease DOX accumulation. SC:DOX hybrids, named CON1 and CON2 were lesscytotoxic than DOX, but with reduced resistance and increased selectivity towardsglioblastoma cells. Cellular uptake of CON1 and CON2 was increased in glioblastomacells compared to DOX. Perinuclear localization of CON1 and CON2 vs. nuclearlocalization of DOX as well as no DNA damaging effects suggest a differentmechanism of action for SC:DOX. Conclusion: The combination of SC and DOX, andtheir innovative hybrids, could be considered a promising strategy that can overcomethe limitations of DOX application in glioblastoma.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts - 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "New anti-glioblastoma strategy with natural compounds sclareol and doxorubicin",
pages = "71",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5905"
}

Stepanović, A., Lupšić, E., Dinić, J., Podolski-Renić, A., Pajović, M., Jovanović Stojanov, S., Dragoj, M., Terzić Jovanović, N., Opsenica, I.,& Pešić, M.. (2023). New anti-glioblastoma strategy with natural compounds sclareol and doxorubicin. in Book of abstracts - 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 71.
https://hdl.handle.net/21.15107/rcub_ibiss_5905

Stepanović A, Lupšić E, Dinić J, Podolski-Renić A, Pajović M, Jovanović Stojanov S, Dragoj M, Terzić Jovanović N, Opsenica I, Pešić M. New anti-glioblastoma strategy with natural compounds sclareol and doxorubicin. in Book of abstracts - 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:71.
https://hdl.handle.net/21.15107/rcub_ibiss_5905 .

Stepanović, Ana, Lupšić, Ema, Dinić, Jelena, Podolski-Renić, Ana, Pajović, Milica, Jovanović Stojanov, Sofija, Dragoj, Miodrag, Terzić Jovanović, Nataša, Opsenica, Igor, Pešić, Milica, "New anti-glioblastoma strategy with natural compounds sclareol and doxorubicin" in Book of abstracts - 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):71,
https://hdl.handle.net/21.15107/rcub_ibiss_5905 .

TY  - CONF
AU  - Jadranin, Milka
AU  - Krstić, Gordana
AU  - Savić, Danica
AU  - Novaković, Miroslav
AU  - Lekić, Stefan
AU  - Tešević, Vele
AU  - Pešić, Milica
AU  - Podolski-Renić, Ana
AU  - Lupšić, Ema
AU  - Milosavljević, Slobodan
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/7270
AB  - Euphorbia cyparissias L. (cypress spurge) is one of the many species of the genus Euphorbia. Like other plant species of the genus, E. cyparissias is a source of biologically active compounds [1, 2]. The aim of this research was to profile the chloroform-methanol latex extract and detect the type of secondary metabolites of Serbian E. cyparissias, collected in Deliblato Sand 
(Serbia) in May 2022, using liquid chromatography – electrospray ionisation mass spectrometry. Based on the obtained results, terpene derivatives have been found as the most abundant in the latex extract, mainly diterpenes (jatrophanes and ingenanes) and triterpenes. Also, the anticancer activ ity of the latex extract on the cell lines NCI-H460, NCI-H460/R, U87, U87/
TxR and MRC-5, as well as the ability to inhibit P-gp, were examined. Latex extract exhibited anticancer activity against all tested cell lines, and also 
proved to be a strong P-gp inhibitor. The obtained results are in accordance with the literature data because jatrophanes are well-known strong P-gp 
inhibitors [3]. These preliminary results indicate that this plant material is a rich source of biologically active compounds and detailed phytochemical research of E. cyparissias is further planned.
PB  - International Conference on Natural Products Utilization - ICNPU2023
C3  - Book of Abstracts - The 5th International Conference on Natural Products Utilization: from Plants to Pharmacy Shelf (ICNPU-2023), 30 May–02 June 2023, Sts. Constantine and Helena - Varna, Bulgaria
T1  - Analysis of terpenoids from the latex of Euphorbia cyparissias by liquid chromatography-electrospray ionization mass spectrometry
SP  - 184
EP  - 185
UR  - https://hdl.handle.net/21.15107/rcub_cer_7270
ER  - 

@conference{
author = "Jadranin, Milka and Krstić, Gordana and Savić, Danica and Novaković, Miroslav and Lekić, Stefan and Tešević, Vele and Pešić, Milica and Podolski-Renić, Ana and Lupšić, Ema and Milosavljević, Slobodan",
year = "2023",
abstract = "Euphorbia cyparissias L. (cypress spurge) is one of the many species of the genus Euphorbia. Like other plant species of the genus, E. cyparissias is a source of biologically active compounds [1, 2]. The aim of this research was to profile the chloroform-methanol latex extract and detect the type of secondary metabolites of Serbian E. cyparissias, collected in Deliblato Sand 
(Serbia) in May 2022, using liquid chromatography – electrospray ionisation mass spectrometry. Based on the obtained results, terpene derivatives have been found as the most abundant in the latex extract, mainly diterpenes (jatrophanes and ingenanes) and triterpenes. Also, the anticancer activ ity of the latex extract on the cell lines NCI-H460, NCI-H460/R, U87, U87/
TxR and MRC-5, as well as the ability to inhibit P-gp, were examined. Latex extract exhibited anticancer activity against all tested cell lines, and also 
proved to be a strong P-gp inhibitor. The obtained results are in accordance with the literature data because jatrophanes are well-known strong P-gp 
inhibitors [3]. These preliminary results indicate that this plant material is a rich source of biologically active compounds and detailed phytochemical research of E. cyparissias is further planned.",
publisher = "International Conference on Natural Products Utilization - ICNPU2023",
journal = "Book of Abstracts - The 5th International Conference on Natural Products Utilization: from Plants to Pharmacy Shelf (ICNPU-2023), 30 May–02 June 2023, Sts. Constantine and Helena - Varna, Bulgaria",
title = "Analysis of terpenoids from the latex of Euphorbia cyparissias by liquid chromatography-electrospray ionization mass spectrometry",
pages = "184-185",
url = "https://hdl.handle.net/21.15107/rcub_cer_7270"
}

Jadranin, M., Krstić, G., Savić, D., Novaković, M., Lekić, S., Tešević, V., Pešić, M., Podolski-Renić, A., Lupšić, E.,& Milosavljević, S.. (2023). Analysis of terpenoids from the latex of Euphorbia cyparissias by liquid chromatography-electrospray ionization mass spectrometry. in Book of Abstracts - The 5th International Conference on Natural Products Utilization: from Plants to Pharmacy Shelf (ICNPU-2023), 30 May–02 June 2023, Sts. Constantine and Helena - Varna, Bulgaria
International Conference on Natural Products Utilization - ICNPU2023., 184-185.
https://hdl.handle.net/21.15107/rcub_cer_7270

Jadranin M, Krstić G, Savić D, Novaković M, Lekić S, Tešević V, Pešić M, Podolski-Renić A, Lupšić E, Milosavljević S. Analysis of terpenoids from the latex of Euphorbia cyparissias by liquid chromatography-electrospray ionization mass spectrometry. in Book of Abstracts - The 5th International Conference on Natural Products Utilization: from Plants to Pharmacy Shelf (ICNPU-2023), 30 May–02 June 2023, Sts. Constantine and Helena - Varna, Bulgaria. 2023;:184-185.
https://hdl.handle.net/21.15107/rcub_cer_7270 .

Jadranin, Milka, Krstić, Gordana, Savić, Danica, Novaković, Miroslav, Lekić, Stefan, Tešević, Vele, Pešić, Milica, Podolski-Renić, Ana, Lupšić, Ema, Milosavljević, Slobodan, "Analysis of terpenoids from the latex of Euphorbia cyparissias by liquid chromatography-electrospray ionization mass spectrometry" in Book of Abstracts - The 5th International Conference on Natural Products Utilization: from Plants to Pharmacy Shelf (ICNPU-2023), 30 May–02 June 2023, Sts. Constantine and Helena - Varna, Bulgaria (2023):184-185,
https://hdl.handle.net/21.15107/rcub_cer_7270 .

TY  - JOUR
AU  - Stojković, Pavle
AU  - Kostić, Ana
AU  - Lupšić, Ema
AU  - Terzić-Jovanović, Nataša
AU  - Novaković, Miroslav
AU  - Nedialkov, Paraskev
AU  - Trendafilova, Antoaneta
AU  - Pešić, Milica
AU  - Opsenica, Igor
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/7183
AB  - The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f consist of two TP units. After purification, all hybrids (12a-r and 13a-f), as well as their precursors (9a-e and 11a-c), were tested on human glioblastoma U87 cells. More than half of the tested synthesized molecules, 16 out of 31, caused a significant reduction of U87 cell viability (more than 75% reduction) at 30 µM. The concentration-dependent cytotoxicity of these 16 compounds was also examined on U87 cells, corresponding multidrug-resistant (MDR) U87-TxR cells with increased P-glycoprotein (P-gp) expression and activity, and normal lung fibroblasts MRC-5. Importantly, 12l and 12r were active in the nanomolar range, while seven compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) were more selective towards glioblastoma cells than SCL. All compounds except 12r evaded MDR, showing even better cytotoxicity in U87-TxR cells. In particular, 11c, 12a, 12g, 12j, 12k, 12m, 12n, and SCL showed collateral sensitivity. Hybrid compounds 12l, 12q, and 12r decreased P-gp activity to the same extent as a well-known P-gp inhibitor - tariquidar (TQ). Hybrid compound 12l and its precursor 11c affected different cellular processes including the cell cycle, cell death, and mitochondrial membrane potential, and changed the levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma cells. Collateral sensitivity towards MDR glioblastoma cells was caused by the modulation of oxidative stress accompanied by inhibition of mitochondria.
PB  - Elsevier
T2  - Bioorganic Chemistry
T1  - Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells
VL  - 138
SP  - 106605
DO  - 10.1016/j.bioorg.2023.106605
ER  - 

@article{
author = "Stojković, Pavle and Kostić, Ana and Lupšić, Ema and Terzić-Jovanović, Nataša and Novaković, Miroslav and Nedialkov, Paraskev and Trendafilova, Antoaneta and Pešić, Milica and Opsenica, Igor",
year = "2023",
abstract = "The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f consist of two TP units. After purification, all hybrids (12a-r and 13a-f), as well as their precursors (9a-e and 11a-c), were tested on human glioblastoma U87 cells. More than half of the tested synthesized molecules, 16 out of 31, caused a significant reduction of U87 cell viability (more than 75% reduction) at 30 µM. The concentration-dependent cytotoxicity of these 16 compounds was also examined on U87 cells, corresponding multidrug-resistant (MDR) U87-TxR cells with increased P-glycoprotein (P-gp) expression and activity, and normal lung fibroblasts MRC-5. Importantly, 12l and 12r were active in the nanomolar range, while seven compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) were more selective towards glioblastoma cells than SCL. All compounds except 12r evaded MDR, showing even better cytotoxicity in U87-TxR cells. In particular, 11c, 12a, 12g, 12j, 12k, 12m, 12n, and SCL showed collateral sensitivity. Hybrid compounds 12l, 12q, and 12r decreased P-gp activity to the same extent as a well-known P-gp inhibitor - tariquidar (TQ). Hybrid compound 12l and its precursor 11c affected different cellular processes including the cell cycle, cell death, and mitochondrial membrane potential, and changed the levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma cells. Collateral sensitivity towards MDR glioblastoma cells was caused by the modulation of oxidative stress accompanied by inhibition of mitochondria.",
publisher = "Elsevier",
journal = "Bioorganic Chemistry",
title = "Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells",
volume = "138",
pages = "106605",
doi = "10.1016/j.bioorg.2023.106605"
}

Stojković, P., Kostić, A., Lupšić, E., Terzić-Jovanović, N., Novaković, M., Nedialkov, P., Trendafilova, A., Pešić, M.,& Opsenica, I.. (2023). Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells. in Bioorganic Chemistry
Elsevier., 138, 106605.
https://doi.org/10.1016/j.bioorg.2023.106605

Stojković P, Kostić A, Lupšić E, Terzić-Jovanović N, Novaković M, Nedialkov P, Trendafilova A, Pešić M, Opsenica I. Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells. in Bioorganic Chemistry. 2023;138:106605.
doi:10.1016/j.bioorg.2023.106605 .

Stojković, Pavle, Kostić, Ana, Lupšić, Ema, Terzić-Jovanović, Nataša, Novaković, Miroslav, Nedialkov, Paraskev, Trendafilova, Antoaneta, Pešić, Milica, Opsenica, Igor, "Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells" in Bioorganic Chemistry, 138 (2023):106605,
https://doi.org/10.1016/j.bioorg.2023.106605 . .

TY  - JOUR
AU  - Koračak, Ljiljana
AU  - Lupšić, Ema
AU  - Terzić-Jovanović, Nataša
AU  - Jovanović, Mirna
AU  - Novaković, Miroslav
AU  - Nedialkov, Paraskev
AU  - Trendafilova, Antoaneta
AU  - Zlatović, Mario
AU  - Pešić, Milica
AU  - Opsenica, Igor
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/7172
AB  - The synthesis of 17 hybrid molecules, consisting of artesunate, a derivative of naturally occurring artemisinin, and synthetic 4-aryl-2-aminopyrimidines, is described. New compounds were designed to improve the parent compounds' cytotoxic properties, activity, and selectivity. The synthesized hybrid molecules (15a–f with ethylenediamine linker and 16a–k with piperazine linker), as well as their precursors – pyrimidine derivatives (13a–f and 14a–k), artemisinin, and artesunate, were tested on sensitive and multidrug-resistant (MDR) human non-small cell lung carcinoma (NSCLC) cells. All hybrid compounds with piperazine linker 16a–k were selective toward NSCLC cells and displayed IC50 values below 5 μM. Although they showed similar anticancer potency as artesunate, their selectivity against cancer cells was considerably improved. Importantly, 16h–k hybrid compounds were able to evade MDR phenotype, inhibit P-glycoprotein (P-gp) activity, and increase the sensitivity of MDR NSCLC cells to doxorubicin (DOX). The inhibition of P-gp activity induced by 16h–j was stronger than the one obtained with artesunate. Among these four hybrid compounds, 16k was the most potent anticancer agent with similar IC50 values of around 1.5 μM (for comparison – over 3.1 μM for artesunate) in sensitive and MDR NSCLC cells.
PB  - Royal Society of Chemistry
T2  - New Journal of Chemistry
T1  - Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells
VL  - 47
IS  - 14
SP  - 6844
EP  - 6855
DO  - 10.1039/D3NJ00427A
ER  - 

@article{
author = "Koračak, Ljiljana and Lupšić, Ema and Terzić-Jovanović, Nataša and Jovanović, Mirna and Novaković, Miroslav and Nedialkov, Paraskev and Trendafilova, Antoaneta and Zlatović, Mario and Pešić, Milica and Opsenica, Igor",
year = "2023",
abstract = "The synthesis of 17 hybrid molecules, consisting of artesunate, a derivative of naturally occurring artemisinin, and synthetic 4-aryl-2-aminopyrimidines, is described. New compounds were designed to improve the parent compounds' cytotoxic properties, activity, and selectivity. The synthesized hybrid molecules (15a–f with ethylenediamine linker and 16a–k with piperazine linker), as well as their precursors – pyrimidine derivatives (13a–f and 14a–k), artemisinin, and artesunate, were tested on sensitive and multidrug-resistant (MDR) human non-small cell lung carcinoma (NSCLC) cells. All hybrid compounds with piperazine linker 16a–k were selective toward NSCLC cells and displayed IC50 values below 5 μM. Although they showed similar anticancer potency as artesunate, their selectivity against cancer cells was considerably improved. Importantly, 16h–k hybrid compounds were able to evade MDR phenotype, inhibit P-glycoprotein (P-gp) activity, and increase the sensitivity of MDR NSCLC cells to doxorubicin (DOX). The inhibition of P-gp activity induced by 16h–j was stronger than the one obtained with artesunate. Among these four hybrid compounds, 16k was the most potent anticancer agent with similar IC50 values of around 1.5 μM (for comparison – over 3.1 μM for artesunate) in sensitive and MDR NSCLC cells.",
publisher = "Royal Society of Chemistry",
journal = "New Journal of Chemistry",
title = "Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells",
volume = "47",
number = "14",
pages = "6844-6855",
doi = "10.1039/D3NJ00427A"
}

Koračak, L., Lupšić, E., Terzić-Jovanović, N., Jovanović, M., Novaković, M., Nedialkov, P., Trendafilova, A., Zlatović, M., Pešić, M.,& Opsenica, I.. (2023). Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells. in New Journal of Chemistry
Royal Society of Chemistry., 47(14), 6844-6855.
https://doi.org/10.1039/D3NJ00427A

Koračak L, Lupšić E, Terzić-Jovanović N, Jovanović M, Novaković M, Nedialkov P, Trendafilova A, Zlatović M, Pešić M, Opsenica I. Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells. in New Journal of Chemistry. 2023;47(14):6844-6855.
doi:10.1039/D3NJ00427A .

Koračak, Ljiljana, Lupšić, Ema, Terzić-Jovanović, Nataša, Jovanović, Mirna, Novaković, Miroslav, Nedialkov, Paraskev, Trendafilova, Antoaneta, Zlatović, Mario, Pešić, Milica, Opsenica, Igor, "Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells" in New Journal of Chemistry, 47, no. 14 (2023):6844-6855,
https://doi.org/10.1039/D3NJ00427A . .