TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Murganić, Blagoje
AU  - Kuhnert, Robert
AU  - Hey-Hawkins, Evamarie
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2022
UR  - https://www.mdpi.com/1420-3049/27/14/4503
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC9321230
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5088
AB  - Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC50 values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.
PB  - Basel: MDPI
T2  - Molecules (Basel, Switzerland)
T1  - Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.
IS  - 14
VL  - 27
DO  - 10.3390/molecules27144503
SP  - 4503
ER  - 

@article{
author = "Paskaš, Svetlana and Murganić, Blagoje and Kuhnert, Robert and Hey-Hawkins, Evamarie and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2022",
abstract = "Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC50 values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.",
publisher = "Basel: MDPI",
journal = "Molecules (Basel, Switzerland)",
title = "Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.",
number = "14",
volume = "27",
doi = "10.3390/molecules27144503",
pages = "4503"
}

Paskaš, S., Murganić, B., Kuhnert, R., Hey-Hawkins, E., Mijatović, S.,& Maksimović-Ivanić, D.. (2022). Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.. in Molecules (Basel, Switzerland)
Basel: MDPI., 27(14), 4503.
https://doi.org/10.3390/molecules27144503

Paskaš S, Murganić B, Kuhnert R, Hey-Hawkins E, Mijatović S, Maksimović-Ivanić D. Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.. in Molecules (Basel, Switzerland). 2022;27(14):4503.
doi:10.3390/molecules27144503 .

Paskaš, Svetlana, Murganić, Blagoje, Kuhnert, Robert, Hey-Hawkins, Evamarie, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo." in Molecules (Basel, Switzerland), 27, no. 14 (2022):4503,
https://doi.org/10.3390/molecules27144503 . .

TY  - JOUR
AU  - Kuhnert, Robert
AU  - Kuhnert, Lydia
AU  - Sárosi, Menyhárt‐B.
AU  - George, Sven
AU  - Drača, Dijana
AU  - Paskaš, Svetlana
AU  - Hofmann, Bettina
AU  - Steinhilber, Dieter
AU  - Honscha, Walther
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Hey-Hawkins, Evamarie
PY  - 2022
UR  - https://onlinelibrary.wiley.com/doi/10.1002/cmdc.202100588
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4686
AB  - 12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO).
PB  - Weinheim: John Wiley and Sons Ltd.
T2  - ChemMedChem
T1  - Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity
IS  - 1
VL  - 17
DO  - 10.1002/cmdc.202100588
SP  - e202100588
ER  - 

@article{
author = "Kuhnert, Robert and Kuhnert, Lydia and Sárosi, Menyhárt‐B. and George, Sven and Drača, Dijana and Paskaš, Svetlana and Hofmann, Bettina and Steinhilber, Dieter and Honscha, Walther and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Hey-Hawkins, Evamarie",
year = "2022",
abstract = "12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO).",
publisher = "Weinheim: John Wiley and Sons Ltd.",
journal = "ChemMedChem",
title = "Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity",
number = "1",
volume = "17",
doi = "10.1002/cmdc.202100588",
pages = "e202100588"
}

Kuhnert, R., Kuhnert, L., Sárosi, Menyhárt‐B., George, S., Drača, D., Paskaš, S., Hofmann, B., Steinhilber, D., Honscha, W., Mijatović, S., Maksimović-Ivanić, D.,& Hey-Hawkins, E.. (2022). Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity. in ChemMedChem
Weinheim: John Wiley and Sons Ltd.., 17(1), e202100588.
https://doi.org/10.1002/cmdc.202100588

Kuhnert R, Kuhnert L, Sárosi M, George S, Drača D, Paskaš S, Hofmann B, Steinhilber D, Honscha W, Mijatović S, Maksimović-Ivanić D, Hey-Hawkins E. Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity. in ChemMedChem. 2022;17(1):e202100588.
doi:10.1002/cmdc.202100588 .

Kuhnert, Robert, Kuhnert, Lydia, Sárosi, Menyhárt‐B., George, Sven, Drača, Dijana, Paskaš, Svetlana, Hofmann, Bettina, Steinhilber, Dieter, Honscha, Walther, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey-Hawkins, Evamarie, "Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity" in ChemMedChem, 17, no. 1 (2022):e202100588,
https://doi.org/10.1002/cmdc.202100588 . .

TY  - JOUR
AU  - Kuhnert, Robert
AU  - Sárosi, Menyhárt-Botond
AU  - George, Sven
AU  - Lönnecke, Peter
AU  - Hofmann, Bettina
AU  - Steinhilber, Dieter
AU  - Steinmann, Sara
AU  - Schneider-Stock, Regine
AU  - Murganić, Blagoje
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Hey-Hawkins, Evamarie
PY  - 2018
UR  - http://doi.wiley.com/10.1002/cmdc.201800651
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3225
AB  - 5-Lipoxygenase converts arachidonic acid into leukotrienes, which are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. Herein we report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity toward several melanoma and colon cancer cell lines. For the colon cancer cell line HCT116, the co-inhibition of heat shock protein 90 was observed.
T2  - ChemMedChem
T2  - ChemMedChem
T1  - Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells.
DO  - 10.1002/cmdc.201800651
ER  - 

@article{
author = "Kuhnert, Robert and Sárosi, Menyhárt-Botond and George, Sven and Lönnecke, Peter and Hofmann, Bettina and Steinhilber, Dieter and Steinmann, Sara and Schneider-Stock, Regine and Murganić, Blagoje and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Hey-Hawkins, Evamarie",
year = "2018",
abstract = "5-Lipoxygenase converts arachidonic acid into leukotrienes, which are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. Herein we report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity toward several melanoma and colon cancer cell lines. For the colon cancer cell line HCT116, the co-inhibition of heat shock protein 90 was observed.",
journal = "ChemMedChem, ChemMedChem",
title = "Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells.",
doi = "10.1002/cmdc.201800651"
}

Kuhnert, R., Sárosi, M., George, S., Lönnecke, P., Hofmann, B., Steinhilber, D., Steinmann, S., Schneider-Stock, R., Murganić, B., Mijatović, S., Maksimović-Ivanić, D.,& Hey-Hawkins, E.. (2018). Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells.. in ChemMedChem.
https://doi.org/10.1002/cmdc.201800651

Kuhnert R, Sárosi M, George S, Lönnecke P, Hofmann B, Steinhilber D, Steinmann S, Schneider-Stock R, Murganić B, Mijatović S, Maksimović-Ivanić D, Hey-Hawkins E. Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells.. in ChemMedChem. 2018;.
doi:10.1002/cmdc.201800651 .

Kuhnert, Robert, Sárosi, Menyhárt-Botond, George, Sven, Lönnecke, Peter, Hofmann, Bettina, Steinhilber, Dieter, Steinmann, Sara, Schneider-Stock, Regine, Murganić, Blagoje, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey-Hawkins, Evamarie, "Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells." in ChemMedChem (2018),
https://doi.org/10.1002/cmdc.201800651 . .

TY  - JOUR
AU  - Kuhnert, Robert
AU  - Sárosi, Menyhárt-Botond
AU  - George, Sven
AU  - Lönnecke, Peter
AU  - Hofmann, Bettina
AU  - Steinhilber, Dieter
AU  - Murganić, Blagoje
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Hey-Hawkins, Evamarie
PY  - 2017
UR  - http://doi.wiley.com/10.1002/cmdc.201700309
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2789
AB  - The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in invivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms.
T2  - ChemMedChem
T1  - CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway
IS  - 13
VL  - 12
DO  - 10.1002/cmdc.201700309
SP  - 1081
EP  - 1086
ER  - 

@article{
author = "Kuhnert, Robert and Sárosi, Menyhárt-Botond and George, Sven and Lönnecke, Peter and Hofmann, Bettina and Steinhilber, Dieter and Murganić, Blagoje and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Hey-Hawkins, Evamarie",
year = "2017",
abstract = "The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in invivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms.",
journal = "ChemMedChem",
title = "CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway",
number = "13",
volume = "12",
doi = "10.1002/cmdc.201700309",
pages = "1081-1086"
}

Kuhnert, R., Sárosi, M., George, S., Lönnecke, P., Hofmann, B., Steinhilber, D., Murganić, B., Mijatović, S., Maksimović-Ivanić, D.,& Hey-Hawkins, E.. (2017). CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway. in ChemMedChem, 12(13), 1081-1086.
https://doi.org/10.1002/cmdc.201700309

Kuhnert R, Sárosi M, George S, Lönnecke P, Hofmann B, Steinhilber D, Murganić B, Mijatović S, Maksimović-Ivanić D, Hey-Hawkins E. CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway. in ChemMedChem. 2017;12(13):1081-1086.
doi:10.1002/cmdc.201700309 .

Kuhnert, Robert, Sárosi, Menyhárt-Botond, George, Sven, Lönnecke, Peter, Hofmann, Bettina, Steinhilber, Dieter, Murganić, Blagoje, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey-Hawkins, Evamarie, "CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway" in ChemMedChem, 12, no. 13 (2017):1081-1086,
https://doi.org/10.1002/cmdc.201700309 . .