TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Stockmann, Philipp
AU  - Mijatović, Sanja
AU  - Kuhnert, Lydia
AU  - Honscha, Walther
AU  - Hey-Hawkins, Evamarie
AU  - Maksimović-Ivanić, Danijela
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6489
AB  - Abstract: The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug
resistance, has the ability to transport a broad spectrum of substrates out of the cell and is,
therefore, considered as a potential target to improve cancer therapies or as an approach to combat
drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives
as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein
(BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most
promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell
lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently,
with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy
of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic
effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa,
DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480
cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest
expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the
effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly,
co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic
effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However,
a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition
by the carborane derivatives emerges as a possible reason.
PB  - Basel: MDPI
T2  - Pharmaceuticals
T1  - Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin
IS  - 11
VL  - 16
DO  - 10.3390/ph16111582
SP  - 1582
ER  - 

@article{
author = "Paskaš, Svetlana and Stockmann, Philipp and Mijatović, Sanja and Kuhnert, Lydia and Honscha, Walther and Hey-Hawkins, Evamarie and Maksimović-Ivanić, Danijela",
year = "2023",
abstract = "Abstract: The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug
resistance, has the ability to transport a broad spectrum of substrates out of the cell and is,
therefore, considered as a potential target to improve cancer therapies or as an approach to combat
drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives
as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein
(BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most
promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell
lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently,
with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy
of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic
effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa,
DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480
cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest
expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the
effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly,
co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic
effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However,
a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition
by the carborane derivatives emerges as a possible reason.",
publisher = "Basel: MDPI",
journal = "Pharmaceuticals",
title = "Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin",
number = "11",
volume = "16",
doi = "10.3390/ph16111582",
pages = "1582"
}

Paskaš, S., Stockmann, P., Mijatović, S., Kuhnert, L., Honscha, W., Hey-Hawkins, E.,& Maksimović-Ivanić, D.. (2023). Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin. in Pharmaceuticals
Basel: MDPI., 16(11), 1582.
https://doi.org/10.3390/ph16111582

Paskaš S, Stockmann P, Mijatović S, Kuhnert L, Honscha W, Hey-Hawkins E, Maksimović-Ivanić D. Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin. in Pharmaceuticals. 2023;16(11):1582.
doi:10.3390/ph16111582 .

Paskaš, Svetlana, Stockmann, Philipp, Mijatović, Sanja, Kuhnert, Lydia, Honscha, Walther, Hey-Hawkins, Evamarie, Maksimović-Ivanić, Danijela, "Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin" in Pharmaceuticals, 16, no. 11 (2023):1582,
https://doi.org/10.3390/ph16111582 . .

TY  - JOUR
AU  - Stockmann, Philipp
AU  - Kuhnert, Lydia
AU  - Krajnović, Tamara
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Honscha, Walther
AU  - Hey-Hawkins, Evamarie
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6436
AB  - Multidrug resistance is a major challenge in clinical cancer therapy. In particular, overexpression of certain ATP-binding cassette (ABC) transporter proteins, like the efflux transporter ABCG2, also known as breast cancer resistance protein (BCRP), has been associated with the development of resistance to applied chemotherapeutic agents in cancer therapies, and therefore targeted inhibition of BCRP-mediated transport might lead to reversal of this (multidrug) resistance (MDR). In a previous study, we have described the introduction of a boron-carbon cluster, namely closodicarbadodecaborane or carborane, as an inorganic pharmacophore into a polymethoxylated 2-phenylquinazolin-4-amine backbone. In this work, the scope was extended to the corresponding amide derivatives. As most of the amide derivatives suffered from poor solubility, only the amide derivative QCe and the two amine derivatives DMQCc and DMQCd were further investigated. Carboranes are often considered as sterically demanding phenyl mimetics or isosteres. Therefore, the organic phenyl and sterically demanding adamantyl analogues of the most promising carborane derivatives were also investigated. The studies showed that the previously described DMQCd, a penta-methoxylated N-carboranyl-2phenylquinazolin-4-amine, was by far superior to its organic analogues in terms of cytotoxicity, inhibition of the human ABCG2 transporter, as well as the ability to reverse BCRP-mediated mitoxantrone resistance in MDCKII-hABCG2 and HT29 colon cancer cells. Our results indicate that DMQCd is a promising candidate for further in vitro as well as in vivo studies in combination therapy for ABCG2-overexpressing cancers.
PB  - Wiley-VCH GmbH
T2  - ChemMedChem
T1  - Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres
DO  - 10.1002/cmdc.202300506
SP  - e202300506
ER  - 

@article{
author = "Stockmann, Philipp and Kuhnert, Lydia and Krajnović, Tamara and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Honscha, Walther and Hey-Hawkins, Evamarie",
year = "2023",
abstract = "Multidrug resistance is a major challenge in clinical cancer therapy. In particular, overexpression of certain ATP-binding cassette (ABC) transporter proteins, like the efflux transporter ABCG2, also known as breast cancer resistance protein (BCRP), has been associated with the development of resistance to applied chemotherapeutic agents in cancer therapies, and therefore targeted inhibition of BCRP-mediated transport might lead to reversal of this (multidrug) resistance (MDR). In a previous study, we have described the introduction of a boron-carbon cluster, namely closodicarbadodecaborane or carborane, as an inorganic pharmacophore into a polymethoxylated 2-phenylquinazolin-4-amine backbone. In this work, the scope was extended to the corresponding amide derivatives. As most of the amide derivatives suffered from poor solubility, only the amide derivative QCe and the two amine derivatives DMQCc and DMQCd were further investigated. Carboranes are often considered as sterically demanding phenyl mimetics or isosteres. Therefore, the organic phenyl and sterically demanding adamantyl analogues of the most promising carborane derivatives were also investigated. The studies showed that the previously described DMQCd, a penta-methoxylated N-carboranyl-2phenylquinazolin-4-amine, was by far superior to its organic analogues in terms of cytotoxicity, inhibition of the human ABCG2 transporter, as well as the ability to reverse BCRP-mediated mitoxantrone resistance in MDCKII-hABCG2 and HT29 colon cancer cells. Our results indicate that DMQCd is a promising candidate for further in vitro as well as in vivo studies in combination therapy for ABCG2-overexpressing cancers.",
publisher = "Wiley-VCH GmbH",
journal = "ChemMedChem",
title = "Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres",
doi = "10.1002/cmdc.202300506",
pages = "e202300506"
}

Stockmann, P., Kuhnert, L., Krajnović, T., Mijatović, S., Maksimović-Ivanić, D., Honscha, W.,& Hey-Hawkins, E.. (2023). Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres. in ChemMedChem
Wiley-VCH GmbH., e202300506.
https://doi.org/10.1002/cmdc.202300506

Stockmann P, Kuhnert L, Krajnović T, Mijatović S, Maksimović-Ivanić D, Honscha W, Hey-Hawkins E. Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres. in ChemMedChem. 2023;:e202300506.
doi:10.1002/cmdc.202300506 .

Stockmann, Philipp, Kuhnert, Lydia, Krajnović, Tamara, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Honscha, Walther, Hey-Hawkins, Evamarie, "Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres" in ChemMedChem (2023):e202300506,
https://doi.org/10.1002/cmdc.202300506 . .

TY  - JOUR
AU  - Stockmann, Philipp
AU  - Kuhnert, Lydia
AU  - Krajnović, Tamara
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Honscha, Walther
AU  - Hey-Hawkins, Evamarie
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6425
AB  - Multidrug resistance is a major challenge in clinical cancer therapy. In particular, overexpression of certain ATP-binding cassette (ABC) transporter proteins, like the efflux transporter ABCG2, also known as breast cancer resistance protein (BCRP), has been associated with the development of resistance to applied chemotherapeutic agents in cancer therapies, and therefore targeted inhibition of BCRP-mediated transport might lead to reversal of this (multidrug) resistance (MDR). In a previous study, we have described the introduction of a boron-carbon cluster, namely closodicarbadodecaborane or carborane, as an inorganic pharmacophore into a polymethoxylated 2-phenylquinazolin-4-amine backbone. In this work, the scope was extended to the corresponding amide derivatives. As most of the amide derivatives suffered from poor solubility, only the amide derivative QCe and the two amine derivatives DMQCc and DMQCd were further investigated. Carboranes are often considered as sterically demanding phenyl mimetics or isosteres. Therefore, the organic phenyl and sterically demanding adamantyl analogues of the most promising carborane derivatives were also investigated. The studies showed that the previously described DMQCd, a penta-methoxylated N-carboranyl-2phenylquinazolin-4-amine, was by far superior to its organic analogues in terms of cytotoxicity, inhibition of the human ABCG2 transporter, as well as the ability to reverse BCRP-mediated mitoxantrone resistance in MDCKII-hABCG2 and HT29 colon cancer cells. Our results indicate that DMQCd is a promising candidate for further in vitro as well as in vivo studies in combination therapy for ABCG2-overexpressing cancers.
PB  - Wiley-VCH GmbH
T2  - ChemMedChem
T1  - Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres
DO  - 10.1002/cmdc.202300506
SP  - e202300506
ER  - 

@article{
author = "Stockmann, Philipp and Kuhnert, Lydia and Krajnović, Tamara and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Honscha, Walther and Hey-Hawkins, Evamarie",
year = "2023",
abstract = "Multidrug resistance is a major challenge in clinical cancer therapy. In particular, overexpression of certain ATP-binding cassette (ABC) transporter proteins, like the efflux transporter ABCG2, also known as breast cancer resistance protein (BCRP), has been associated with the development of resistance to applied chemotherapeutic agents in cancer therapies, and therefore targeted inhibition of BCRP-mediated transport might lead to reversal of this (multidrug) resistance (MDR). In a previous study, we have described the introduction of a boron-carbon cluster, namely closodicarbadodecaborane or carborane, as an inorganic pharmacophore into a polymethoxylated 2-phenylquinazolin-4-amine backbone. In this work, the scope was extended to the corresponding amide derivatives. As most of the amide derivatives suffered from poor solubility, only the amide derivative QCe and the two amine derivatives DMQCc and DMQCd were further investigated. Carboranes are often considered as sterically demanding phenyl mimetics or isosteres. Therefore, the organic phenyl and sterically demanding adamantyl analogues of the most promising carborane derivatives were also investigated. The studies showed that the previously described DMQCd, a penta-methoxylated N-carboranyl-2phenylquinazolin-4-amine, was by far superior to its organic analogues in terms of cytotoxicity, inhibition of the human ABCG2 transporter, as well as the ability to reverse BCRP-mediated mitoxantrone resistance in MDCKII-hABCG2 and HT29 colon cancer cells. Our results indicate that DMQCd is a promising candidate for further in vitro as well as in vivo studies in combination therapy for ABCG2-overexpressing cancers.",
publisher = "Wiley-VCH GmbH",
journal = "ChemMedChem",
title = "Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres",
doi = "10.1002/cmdc.202300506",
pages = "e202300506"
}

Stockmann, P., Kuhnert, L., Krajnović, T., Mijatović, S., Maksimović-Ivanić, D., Honscha, W.,& Hey-Hawkins, E.. (2023). Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres. in ChemMedChem
Wiley-VCH GmbH., e202300506.
https://doi.org/10.1002/cmdc.202300506

Stockmann P, Kuhnert L, Krajnović T, Mijatović S, Maksimović-Ivanić D, Honscha W, Hey-Hawkins E. Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres. in ChemMedChem. 2023;:e202300506.
doi:10.1002/cmdc.202300506 .

Stockmann, Philipp, Kuhnert, Lydia, Krajnović, Tamara, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Honscha, Walther, Hey-Hawkins, Evamarie, "Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres" in ChemMedChem (2023):e202300506,
https://doi.org/10.1002/cmdc.202300506 . .

TY  - JOUR
AU  - Stockmann, Philipp
AU  - Kuhnert, Lydia
AU  - Leinung, Wencke
AU  - Lakoma, Cathleen
AU  - Scholz, Birte
AU  - Paskaš, Svetlana
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Honscha, Walther
AU  - Hey-Hawkins, Evamarie
PY  - 2023
UR  - https://www.mdpi.com/1999-4923/15/1/241
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC9866861
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5434
AB  - The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents' pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.
PB  - Basel: MDPI
T2  - Pharmaceutics
T1  - The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors
IS  - 1
VL  - 15
DO  - 10.3390/pharmaceutics15010241
SP  - 241
ER  - 

@article{
author = "Stockmann, Philipp and Kuhnert, Lydia and Leinung, Wencke and Lakoma, Cathleen and Scholz, Birte and Paskaš, Svetlana and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Honscha, Walther and Hey-Hawkins, Evamarie",
year = "2023",
abstract = "The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents' pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.",
publisher = "Basel: MDPI",
journal = "Pharmaceutics",
title = "The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors",
number = "1",
volume = "15",
doi = "10.3390/pharmaceutics15010241",
pages = "241"
}

Stockmann, P., Kuhnert, L., Leinung, W., Lakoma, C., Scholz, B., Paskaš, S., Mijatović, S., Maksimović-Ivanić, D., Honscha, W.,& Hey-Hawkins, E.. (2023). The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. in Pharmaceutics
Basel: MDPI., 15(1), 241.
https://doi.org/10.3390/pharmaceutics15010241

Stockmann P, Kuhnert L, Leinung W, Lakoma C, Scholz B, Paskaš S, Mijatović S, Maksimović-Ivanić D, Honscha W, Hey-Hawkins E. The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. in Pharmaceutics. 2023;15(1):241.
doi:10.3390/pharmaceutics15010241 .

Stockmann, Philipp, Kuhnert, Lydia, Leinung, Wencke, Lakoma, Cathleen, Scholz, Birte, Paskaš, Svetlana, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Honscha, Walther, Hey-Hawkins, Evamarie, "The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors" in Pharmaceutics, 15, no. 1 (2023):241,
https://doi.org/10.3390/pharmaceutics15010241 . .

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 . .