TY  - JOUR
AU  - Fási, Laura
AU  - Di Meo, Florent
AU  - Kuo, Ching-Ying
AU  - Stojković Burić, Sonja
AU  - Martins, Ana
AU  - Kúsz, Norbert
AU  - Béni, Zoltán
AU  - Dékány, Miklós
AU  - Balogh, György Tibor
AU  - Pešić, Milica
AU  - Wang, Hui-Chun
AU  - Trouillas, Patrick
AU  - Hunyadi, Attila
PY  - 2019
UR  - http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01994
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3278
AB  - Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico DFT calculations suggested graviquinone as a kinetic product of pcm scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
T2  - Journal of Medicinal Chemistry
T1  - Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging.
IS  - 3
VL  - 62
DO  - 10.1021/acs.jmedchem.8b01994
SP  - 1657
EP  - 1668
ER  - 

@article{
author = "Fási, Laura and Di Meo, Florent and Kuo, Ching-Ying and Stojković Burić, Sonja and Martins, Ana and Kúsz, Norbert and Béni, Zoltán and Dékány, Miklós and Balogh, György Tibor and Pešić, Milica and Wang, Hui-Chun and Trouillas, Patrick and Hunyadi, Attila",
year = "2019",
abstract = "Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico DFT calculations suggested graviquinone as a kinetic product of pcm scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.",
journal = "Journal of Medicinal Chemistry",
title = "Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging.",
number = "3",
volume = "62",
doi = "10.1021/acs.jmedchem.8b01994",
pages = "1657-1668"
}

Fási, L., Di Meo, F., Kuo, C., Stojković Burić, S., Martins, A., Kúsz, N., Béni, Z., Dékány, M., Balogh, G. T., Pešić, M., Wang, H., Trouillas, P.,& Hunyadi, A.. (2019). Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging.. in Journal of Medicinal Chemistry, 62(3), 1657-1668.
https://doi.org/10.1021/acs.jmedchem.8b01994

Fási L, Di Meo F, Kuo C, Stojković Burić S, Martins A, Kúsz N, Béni Z, Dékány M, Balogh GT, Pešić M, Wang H, Trouillas P, Hunyadi A. Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging.. in Journal of Medicinal Chemistry. 2019;62(3):1657-1668.
doi:10.1021/acs.jmedchem.8b01994 .

Fási, Laura, Di Meo, Florent, Kuo, Ching-Ying, Stojković Burić, Sonja, Martins, Ana, Kúsz, Norbert, Béni, Zoltán, Dékány, Miklós, Balogh, György Tibor, Pešić, Milica, Wang, Hui-Chun, Trouillas, Patrick, Hunyadi, Attila, "Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging." in Journal of Medicinal Chemistry, 62, no. 3 (2019):1657-1668,
https://doi.org/10.1021/acs.jmedchem.8b01994 . .

TY  - JOUR
AU  - Bakulina, Olga
AU  - Bannykh, Anton
AU  - Jovanović, Mirna
AU  - Domračeva, Ilona
AU  - Podolski-Renić, Ana
AU  - Žalubovskis, Raivis
AU  - Pešić, Milica
AU  - Dar'in, Dmitry
AU  - Krasavin, Mikhail
PY  - 2019
UR  - https://www.tandfonline.com/doi/full/10.1080/14756366.2019.1575372
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6374954
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3266
AB  - Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes.
T2  - Journal of Enzyme Inhibition and Medicinal Chemistry
T1  - Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.
IS  - 1
VL  - 34
DO  - 10.1080/14756366.2019.1575372
SP  - 665
EP  - 671
ER  - 

@article{
author = "Bakulina, Olga and Bannykh, Anton and Jovanović, Mirna and Domračeva, Ilona and Podolski-Renić, Ana and Žalubovskis, Raivis and Pešić, Milica and Dar'in, Dmitry and Krasavin, Mikhail",
year = "2019",
abstract = "Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes.",
journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",
title = "Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.",
number = "1",
volume = "34",
doi = "10.1080/14756366.2019.1575372",
pages = "665-671"
}

Bakulina, O., Bannykh, A., Jovanović, M., Domračeva, I., Podolski-Renić, A., Žalubovskis, R., Pešić, M., Dar'in, D.,& Krasavin, M.. (2019). Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.. in Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1), 665-671.
https://doi.org/10.1080/14756366.2019.1575372

Bakulina O, Bannykh A, Jovanović M, Domračeva I, Podolski-Renić A, Žalubovskis R, Pešić M, Dar'in D, Krasavin M. Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.. in Journal of Enzyme Inhibition and Medicinal Chemistry. 2019;34(1):665-671.
doi:10.1080/14756366.2019.1575372 .

Bakulina, Olga, Bannykh, Anton, Jovanović, Mirna, Domračeva, Ilona, Podolski-Renić, Ana, Žalubovskis, Raivis, Pešić, Milica, Dar'in, Dmitry, Krasavin, Mikhail, "Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols." in Journal of Enzyme Inhibition and Medicinal Chemistry, 34, no. 1 (2019):665-671,
https://doi.org/10.1080/14756366.2019.1575372 . .

TY  - CONF
AU  - Danko, B.
AU  - Csabi, J.
AU  - Hsieh, T. J.
AU  - Wang, H. C.
AU  - Vidaković, Melita
AU  - Trouillas, P.
AU  - Toth, G.
AU  - Hunyadi, A.
PY  - 2015
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2340
UR  - https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1565306
AB  - Antioxidants are generally considered as „double-edged swords”: various health benefits are attributed to them since they can decrease oxidative stress caused by reactive oxygen species (ROS), but they can also increase it by directly or indirectly contributing to the formation of ROS [1]. On the other hand, a necessarily existing third face of antioxidants is generally overlooked, namely the specific bioactivities of their oxidized metabolites that are formed after scavenging ROS, and, as such, that must represent amounts proportional to the oxidative stress.

In the present work, a phenolic (apigenin; Ap) and a non-phenolic (20-hydroxyecdysone; 20E) antioxidant was studied for the biological importance of their oxidized metabolites. Protoapigenone (Pa), a p-quinol B-ring containing protoflavone known for its strong anticancer properties [2] was obtained from Ap upon oxidation with PIFA. In silico studies revealed the favorable formation of Pa from Ap when scavenging OH radicals, which was confirmed by HPLC-DAD when subjecting Ap to Fenton-reaction. Moreover, incubation with GSH yielded Ap from Pa, revealing an Ap-Pa redox cycle of outmost biomedical interest. 20E was subjected to base-catalyzed auto-oxidation, yielding B-ring modified derivatives including calonysterone and its desmotrope pair. In vitro activity of the compounds was tested on the phosphorylation of Akt (playing an important role in cell survival/apoptosis), and much stronger activities than that of 20E were observed. All major metabolites were detected from the Fenton-reaction of 20E.

Based on these examples, our results demonstrate that oxidized metabolites, forming when antioxidants scavenge ROS, can play specific role in the bioactivity of these compounds, and that such metabolites worth the attention concerning related drug discovery initiatives.
C3  - Planta Medica
T1  - Specific role of oxidized species in the bioactivity of two
 antioxidants: apigenin and 20-hydroxyecdysone
IS  - 16
VL  - 81
DO  - 10.1055/s-0035-1565306
ER  - 

@conference{
author = "Danko, B. and Csabi, J. and Hsieh, T. J. and Wang, H. C. and Vidaković, Melita and Trouillas, P. and Toth, G. and Hunyadi, A.",
year = "2015",
abstract = "Antioxidants are generally considered as „double-edged swords”: various health benefits are attributed to them since they can decrease oxidative stress caused by reactive oxygen species (ROS), but they can also increase it by directly or indirectly contributing to the formation of ROS [1]. On the other hand, a necessarily existing third face of antioxidants is generally overlooked, namely the specific bioactivities of their oxidized metabolites that are formed after scavenging ROS, and, as such, that must represent amounts proportional to the oxidative stress.

In the present work, a phenolic (apigenin; Ap) and a non-phenolic (20-hydroxyecdysone; 20E) antioxidant was studied for the biological importance of their oxidized metabolites. Protoapigenone (Pa), a p-quinol B-ring containing protoflavone known for its strong anticancer properties [2] was obtained from Ap upon oxidation with PIFA. In silico studies revealed the favorable formation of Pa from Ap when scavenging OH radicals, which was confirmed by HPLC-DAD when subjecting Ap to Fenton-reaction. Moreover, incubation with GSH yielded Ap from Pa, revealing an Ap-Pa redox cycle of outmost biomedical interest. 20E was subjected to base-catalyzed auto-oxidation, yielding B-ring modified derivatives including calonysterone and its desmotrope pair. In vitro activity of the compounds was tested on the phosphorylation of Akt (playing an important role in cell survival/apoptosis), and much stronger activities than that of 20E were observed. All major metabolites were detected from the Fenton-reaction of 20E.

Based on these examples, our results demonstrate that oxidized metabolites, forming when antioxidants scavenge ROS, can play specific role in the bioactivity of these compounds, and that such metabolites worth the attention concerning related drug discovery initiatives.",
journal = "Planta Medica",
title = "Specific role of oxidized species in the bioactivity of two
 antioxidants: apigenin and 20-hydroxyecdysone",
number = "16",
volume = "81",
doi = "10.1055/s-0035-1565306"
}

Danko, B., Csabi, J., Hsieh, T. J., Wang, H. C., Vidaković, M., Trouillas, P., Toth, G.,& Hunyadi, A.. (2015). Specific role of oxidized species in the bioactivity of two
 antioxidants: apigenin and 20-hydroxyecdysone. in Planta Medica, 81(16).
https://doi.org/10.1055/s-0035-1565306

Danko B, Csabi J, Hsieh TJ, Wang HC, Vidaković M, Trouillas P, Toth G, Hunyadi A. Specific role of oxidized species in the bioactivity of two
 antioxidants: apigenin and 20-hydroxyecdysone. in Planta Medica. 2015;81(16).
doi:10.1055/s-0035-1565306 .

Danko, B., Csabi, J., Hsieh, T. J., Wang, H. C., Vidaković, Melita, Trouillas, P., Toth, G., Hunyadi, A., "Specific role of oxidized species in the bioactivity of two
 antioxidants: apigenin and 20-hydroxyecdysone" in Planta Medica, 81, no. 16 (2015),
https://doi.org/10.1055/s-0035-1565306 . .