TY  - CONF
AU  - Lupšić, Ema
AU  - Stepanović, Ana
AU  - Stojković, Pavle
AU  - Terzić-Jpvanović, Nataša
AU  - Novaković, Miroslav
AU  - Nedialkov, Paraskev
AU  - Trendafilova, Antoaneta
AU  - Opsenica, Igor M.
AU  - Pešić, Milica
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5928
AB  - Background: Glioblastoma is a highly aggressive and resistant brain tumor. P-glycoprotein
(P-gp) constitutes the blood-brain barrier and is expressed on the cell membrane of multidrugresistant (MDR) glioblastoma cells. Our objective was to investigate the anti-glioblastoma
effects of sclareol (SCL), a natural diterpene alcohol, and its two derivatives (11c and 12l).
Methods: Our cellular model included human glioblastoma U87 cell line without P-gp
expression, its MDR counterpart U87-TxR with P-gp expression, and normal lung fibroblasts
MRC-5. Cytotoxic effects were examined by MTT. P-gp function, cell cycle disturbance,
time-dependent cell death induction, the level of reactive oxygen and nitrogen species, and
changes in the mitochondrial membrane potential were studied by flow cytometry. Results:
SCL and its derivatives evaded the MDR in glioblastoma cells, showing lower IC50 values in
U87-TxR than in U87, referred to as collateral sensitivity. Both derivatives were more potent
than SCL, while 12l was active in the nanomolar range. 11c and 12l displayed greater
selectivity towards glioblastoma cells compared to SCL. All compounds significantly
disturbed the cell cycle and induced cell death: SCL - late apoptosis and necrosis, 11c - only
early apoptosis, and 12l - early and late apoptosis. SCL and its derivatives acted as
antioxidants, while 11c and 12l decreased mitochondrial membrane potential. Conclusion:
SCL derivatives were more potent than SCL. The observed collateral sensitivity in
glioblastoma cells can be explained by oxidative stress modulation because although resistant
due to P-gp expression, U87-TxR cells are more susceptible to changes in oxidative status
than U87 cells.
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  - Evading multidrug resistance in glioblastoma with natural compound sclareol and its novel derivatives
SP  - 72
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5928
ER  - 

@conference{
author = "Lupšić, Ema and Stepanović, Ana and Stojković, Pavle and Terzić-Jpvanović, Nataša and Novaković, Miroslav and Nedialkov, Paraskev and Trendafilova, Antoaneta and Opsenica, Igor M. and Pešić, Milica",
year = "2023",
abstract = "Background: Glioblastoma is a highly aggressive and resistant brain tumor. P-glycoprotein
(P-gp) constitutes the blood-brain barrier and is expressed on the cell membrane of multidrugresistant (MDR) glioblastoma cells. Our objective was to investigate the anti-glioblastoma
effects of sclareol (SCL), a natural diterpene alcohol, and its two derivatives (11c and 12l).
Methods: Our cellular model included human glioblastoma U87 cell line without P-gp
expression, its MDR counterpart U87-TxR with P-gp expression, and normal lung fibroblasts
MRC-5. Cytotoxic effects were examined by MTT. P-gp function, cell cycle disturbance,
time-dependent cell death induction, the level of reactive oxygen and nitrogen species, and
changes in the mitochondrial membrane potential were studied by flow cytometry. Results:
SCL and its derivatives evaded the MDR in glioblastoma cells, showing lower IC50 values in
U87-TxR than in U87, referred to as collateral sensitivity. Both derivatives were more potent
than SCL, while 12l was active in the nanomolar range. 11c and 12l displayed greater
selectivity towards glioblastoma cells compared to SCL. All compounds significantly
disturbed the cell cycle and induced cell death: SCL - late apoptosis and necrosis, 11c - only
early apoptosis, and 12l - early and late apoptosis. SCL and its derivatives acted as
antioxidants, while 11c and 12l decreased mitochondrial membrane potential. Conclusion:
SCL derivatives were more potent than SCL. The observed collateral sensitivity in
glioblastoma cells can be explained by oxidative stress modulation because although resistant
due to P-gp expression, U87-TxR cells are more susceptible to changes in oxidative status
than U87 cells.",
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 = "Evading multidrug resistance in glioblastoma with natural compound sclareol and its novel derivatives",
pages = "72",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5928"
}

Lupšić, E., Stepanović, A., Stojković, P., Terzić-Jpvanović, N., Novaković, M., Nedialkov, P., Trendafilova, A., Opsenica, I. M.,& Pešić, M.. (2023). Evading multidrug resistance in glioblastoma with natural compound sclareol and its novel derivatives. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 72.
https://hdl.handle.net/21.15107/rcub_ibiss_5928

Lupšić E, Stepanović A, Stojković P, Terzić-Jpvanović N, Novaković M, Nedialkov P, Trendafilova A, Opsenica IM, Pešić M. Evading multidrug resistance in glioblastoma with natural compound sclareol and its novel derivatives. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:72.
https://hdl.handle.net/21.15107/rcub_ibiss_5928 .

Lupšić, Ema, Stepanović, Ana, Stojković, Pavle, Terzić-Jpvanović, Nataša, Novaković, Miroslav, Nedialkov, Paraskev, Trendafilova, Antoaneta, Opsenica, Igor M., Pešić, Milica, "Evading multidrug resistance in glioblastoma with natural compound sclareol and its novel derivatives" in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):72,
https://hdl.handle.net/21.15107/rcub_ibiss_5928 .

TY  - JOUR
AU  - Stojković, Pavle
AU  - Stepanović, Ana
AU  - Lupšić, Ema
AU  - Terzić Jovanović, Nataša
AU  - Novaković, Miroslav
AU  - Nedialkov, Paraskev
AU  - Trendafilova, Antoaneta
AU  - Pešić, Milica
AU  - Opsenica, Igor M.
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5910
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  - Academic Press Inc.
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
DO  - 10.1016/j.bioorg.2023.106605
SP  - 106605
ER  - 

@article{
author = "Stojković, Pavle and Stepanović, Ana and Lupšić, Ema and Terzić Jovanović, Nataša and Novaković, Miroslav and Nedialkov, Paraskev and Trendafilova, Antoaneta and Pešić, Milica and Opsenica, Igor M.",
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 = "Academic Press Inc.",
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",
doi = "10.1016/j.bioorg.2023.106605",
pages = "106605"
}

Stojković, P., Stepanović, A., Lupšić, E., Terzić Jovanović, N., Novaković, M., Nedialkov, P., Trendafilova, A., Pešić, M.,& Opsenica, I. M.. (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
Academic Press Inc.., 138, 106605.
https://doi.org/10.1016/j.bioorg.2023.106605

Stojković P, Stepanović A, Lupšić E, Terzić Jovanović N, Novaković M, Nedialkov P, Trendafilova A, Pešić M, Opsenica IM. 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, Stepanović, Ana, Lupšić, Ema, Terzić Jovanović, Nataša, Novaković, Miroslav, Nedialkov, Paraskev, Trendafilova, Antoaneta, Pešić, Milica, Opsenica, Igor M., "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  - http://radar.ibiss.bg.ac.rs/handle/123456789/5890
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  - Cambridge: Royal Society of Chemistry
T2  - New Journal of Chemistry
T1  - Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells
IS  - 14
VL  - 47
DO  - 10.1039/D3NJ00427A
SP  - 6844
EP  - 6855
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 = "Cambridge: Royal Society of Chemistry",
journal = "New Journal of Chemistry",
title = "Novel artesunate–pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells",
number = "14",
volume = "47",
doi = "10.1039/D3NJ00427A",
pages = "6844-6855"
}

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
Cambridge: 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 . .

TY  - JOUR
AU  - Jelača, Sanja
AU  - Dajić-Stevanović, Zora
AU  - Vuković, Nenad
AU  - Kolašinac, Stefan
AU  - Trendafilova, Antoaneta
AU  - Nedialkov, Paraskev
AU  - Stanković, Miroslava
AU  - Tanić, Nasta
AU  - Tanić, Nikola
AU  - Acović, Aleksandar
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5300
AB  - Alchemilla vulgaris L. (lady’s mantle) was used for centuries in Europe and Balkan countries for treatments of numerous conditions and diseases of the reproductive system, yet some of the biological activities of lady’s mantle have been poorly studied and neglected. The present study aimed to estimate the potential of A. vulgaris ethanolic extract from Southeast Serbia to prevent and suppress tumor development in vitro, validated by antioxidant, genoprotective, and cytotoxic properties. A total of 45 compounds were detected by UHPLC–HRMS analysis in A. vulgaris ethanolic extract. Measurement of antioxidant activity revealed the significant potential of the tested extract to scavenge free radicals. In addition, the analysis of micronuclei showed an in vitro protective effect on chromosome aberrations in peripheral human lymphocytes. A. vulgaris extract strongly suppressed the growth of human cell lines derived from different types of tumors (MCF-7, A375, A549, and HCT116). The observed antitumor effect is realized through the blockade of cell division, caspase-dependent apoptosis, and autophagic cell death. Our study has shown that Alchemilla vulgaris L. is a valuable source of bioactive compounds able to protect the subcellular structure from damage, thus preventing tumorigenesis as well as suppressing tumor cell growth.
PB  - Basel: MDPI
T2  - Molecules
T1  - Beyond Traditional Use of Alchemilla vulgaris: Genoprotective and Antitumor Activity In Vitro
IS  - 23
VL  - 27
DO  - 10.3390/molecules27238113
SP  - 8113
ER  - 

@article{
author = "Jelača, Sanja and Dajić-Stevanović, Zora and Vuković, Nenad and Kolašinac, Stefan and Trendafilova, Antoaneta and Nedialkov, Paraskev and Stanković, Miroslava and Tanić, Nasta and Tanić, Nikola and Acović, Aleksandar and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2022",
abstract = "Alchemilla vulgaris L. (lady’s mantle) was used for centuries in Europe and Balkan countries for treatments of numerous conditions and diseases of the reproductive system, yet some of the biological activities of lady’s mantle have been poorly studied and neglected. The present study aimed to estimate the potential of A. vulgaris ethanolic extract from Southeast Serbia to prevent and suppress tumor development in vitro, validated by antioxidant, genoprotective, and cytotoxic properties. A total of 45 compounds were detected by UHPLC–HRMS analysis in A. vulgaris ethanolic extract. Measurement of antioxidant activity revealed the significant potential of the tested extract to scavenge free radicals. In addition, the analysis of micronuclei showed an in vitro protective effect on chromosome aberrations in peripheral human lymphocytes. A. vulgaris extract strongly suppressed the growth of human cell lines derived from different types of tumors (MCF-7, A375, A549, and HCT116). The observed antitumor effect is realized through the blockade of cell division, caspase-dependent apoptosis, and autophagic cell death. Our study has shown that Alchemilla vulgaris L. is a valuable source of bioactive compounds able to protect the subcellular structure from damage, thus preventing tumorigenesis as well as suppressing tumor cell growth.",
publisher = "Basel: MDPI",
journal = "Molecules",
title = "Beyond Traditional Use of Alchemilla vulgaris: Genoprotective and Antitumor Activity In Vitro",
number = "23",
volume = "27",
doi = "10.3390/molecules27238113",
pages = "8113"
}

Jelača, S., Dajić-Stevanović, Z., Vuković, N., Kolašinac, S., Trendafilova, A., Nedialkov, P., Stanković, M., Tanić, N., Tanić, N., Acović, A., Mijatović, S.,& Maksimović-Ivanić, D.. (2022). Beyond Traditional Use of Alchemilla vulgaris: Genoprotective and Antitumor Activity In Vitro. in Molecules
Basel: MDPI., 27(23), 8113.
https://doi.org/10.3390/molecules27238113

Jelača S, Dajić-Stevanović Z, Vuković N, Kolašinac S, Trendafilova A, Nedialkov P, Stanković M, Tanić N, Tanić N, Acović A, Mijatović S, Maksimović-Ivanić D. Beyond Traditional Use of Alchemilla vulgaris: Genoprotective and Antitumor Activity In Vitro. in Molecules. 2022;27(23):8113.
doi:10.3390/molecules27238113 .

Jelača, Sanja, Dajić-Stevanović, Zora, Vuković, Nenad, Kolašinac, Stefan, Trendafilova, Antoaneta, Nedialkov, Paraskev, Stanković, Miroslava, Tanić, Nasta, Tanić, Nikola, Acović, Aleksandar, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Beyond Traditional Use of Alchemilla vulgaris: Genoprotective and Antitumor Activity In Vitro" in Molecules, 27, no. 23 (2022):8113,
https://doi.org/10.3390/molecules27238113 . .

TY  - CONF
AU  - Stojković, Pavle
AU  - Stepanović, Ana
AU  - Terzić Jovanović, Nataša
AU  - Novaković, Miroslav
AU  - Trendafilova, Antoaneta
AU  - Pešić, Milica
AU  - Opsenica, Igor M.
PY  - 2022
UR  - https://euchems2022.eu/images/abstracts.pdf
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5372
AB  - Sclareol is a labdane diterpenoid found in clary sage (Salvia sclarea L.) with various biological activities,
most notably anticancer and cytotoxic activity [1]. There are several examples of synthetic derivatives
of sclareol with antischistosomal [2], antifungal [3], and anticancer activity [4]. Since it is known that
modifications of biologically active molecules can lead to the improvement of physicochemical
properties and modes of interactions with target cells, we have envisioned the derivatization of sclareol
to obtain molecules with more potent cytotoxic activity.
Sclareol used as a starting material in this research was isolated from Clary sage harvested in Bulgaria.
New compounds were obtained by derivatization of sclareol at its Δ14,15 double bond using oxidative
Heck coupling catalyzed by palladium-acetate with copper(II)-acetate as oxidant, followed by the
introduction of different diamine-moieties. Finally, the terminal amino-group was coupled with a
nitrogen-rich heterocycle to obtain desired compounds. During the course of the synthesis, both tertiary
and tertiary allylic hydroxyl groups remained unchanged, which was of particular interest, since it was
shown that the tertiary allylic group is crucial for the biological activity of sclareol.
Synthesized compounds were tested on human cancer cell lines, primarily glioblastoma cells. It was
shown that certain derivatives have caused a significant reduction of glioblastoma cell viability at low
concentrations. Moreover, some derivatives inhibited cell membrane transporter P-glycoprotein (P-gp)
responsible for multidrug resistance and increased accumulation of doxorubicin to the same extent as
tariquidar (a well-known P-gp inhibitor). Most importantly, novel molecules exhibited more potent
biological activity than sclareol itself.
PB  - Sociedade Portuguesa de Química
C3  - Abstract Book: 8th EuChemS Chemistry Congress; 2022 Aug 28 - Sep 1; Lisbon, Portugal
T1  - Synthesis of novel sclareol derivatives and evaluation of their anticancer activity
SP  - 604
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5372
ER  - 

@conference{
author = "Stojković, Pavle and Stepanović, Ana and Terzić Jovanović, Nataša and Novaković, Miroslav and Trendafilova, Antoaneta and Pešić, Milica and Opsenica, Igor M.",
year = "2022",
abstract = "Sclareol is a labdane diterpenoid found in clary sage (Salvia sclarea L.) with various biological activities,
most notably anticancer and cytotoxic activity [1]. There are several examples of synthetic derivatives
of sclareol with antischistosomal [2], antifungal [3], and anticancer activity [4]. Since it is known that
modifications of biologically active molecules can lead to the improvement of physicochemical
properties and modes of interactions with target cells, we have envisioned the derivatization of sclareol
to obtain molecules with more potent cytotoxic activity.
Sclareol used as a starting material in this research was isolated from Clary sage harvested in Bulgaria.
New compounds were obtained by derivatization of sclareol at its Δ14,15 double bond using oxidative
Heck coupling catalyzed by palladium-acetate with copper(II)-acetate as oxidant, followed by the
introduction of different diamine-moieties. Finally, the terminal amino-group was coupled with a
nitrogen-rich heterocycle to obtain desired compounds. During the course of the synthesis, both tertiary
and tertiary allylic hydroxyl groups remained unchanged, which was of particular interest, since it was
shown that the tertiary allylic group is crucial for the biological activity of sclareol.
Synthesized compounds were tested on human cancer cell lines, primarily glioblastoma cells. It was
shown that certain derivatives have caused a significant reduction of glioblastoma cell viability at low
concentrations. Moreover, some derivatives inhibited cell membrane transporter P-glycoprotein (P-gp)
responsible for multidrug resistance and increased accumulation of doxorubicin to the same extent as
tariquidar (a well-known P-gp inhibitor). Most importantly, novel molecules exhibited more potent
biological activity than sclareol itself.",
publisher = "Sociedade Portuguesa de Química",
journal = "Abstract Book: 8th EuChemS Chemistry Congress; 2022 Aug 28 - Sep 1; Lisbon, Portugal",
title = "Synthesis of novel sclareol derivatives and evaluation of their anticancer activity",
pages = "604",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5372"
}

Stojković, P., Stepanović, A., Terzić Jovanović, N., Novaković, M., Trendafilova, A., Pešić, M.,& Opsenica, I. M.. (2022). Synthesis of novel sclareol derivatives and evaluation of their anticancer activity. in Abstract Book: 8th EuChemS Chemistry Congress; 2022 Aug 28 - Sep 1; Lisbon, Portugal
Sociedade Portuguesa de Química., 604.
https://hdl.handle.net/21.15107/rcub_ibiss_5372

Stojković P, Stepanović A, Terzić Jovanović N, Novaković M, Trendafilova A, Pešić M, Opsenica IM. Synthesis of novel sclareol derivatives and evaluation of their anticancer activity. in Abstract Book: 8th EuChemS Chemistry Congress; 2022 Aug 28 - Sep 1; Lisbon, Portugal. 2022;:604.
https://hdl.handle.net/21.15107/rcub_ibiss_5372 .

Stojković, Pavle, Stepanović, Ana, Terzić Jovanović, Nataša, Novaković, Miroslav, Trendafilova, Antoaneta, Pešić, Milica, Opsenica, Igor M., "Synthesis of novel sclareol derivatives and evaluation of their anticancer activity" in Abstract Book: 8th EuChemS Chemistry Congress; 2022 Aug 28 - Sep 1; Lisbon, Portugal (2022):604,
https://hdl.handle.net/21.15107/rcub_ibiss_5372 .