TY  - JOUR
AU  - Stanković, Dalibor
AU  - Ristić, Slavica M.
AU  - Vukadinović, Aleksandar
AU  - Mirković, Marija D.
AU  - Vladimirov, Sandra S.
AU  - Milanović, Zorana
AU  - Radović, Magdalena
AU  - Mijović, Milica
AU  - Stanković, Dalibor
AU  - Sabo, Tibor
AU  - Vranješ-Đurić, Sanja
AU  - Janković, Drina
PY  - 2019
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2894
AB  - It was reported that novel O,O′-diethyl-(S, S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl) propanoate dihydrochloride (DE-EDCP) displayed in vitro antiproliferative activity on several human and mouse cancer cell lines, which was comparable to that of the prototypical anticancer drug cisplatin. In order to reveal its toxicity profile, acute and repeated-dose toxicity studies were performed in Naval Medical Research Institute (NMRI) Han mice. The intravenous LD 50 values of DE-EDCP were found to be 95.3 and 101.3 mg/kg body weight in female and male mice, respectively. In the subacute toxicity study, DE-EDCP was administered intravenously at the doses of 15, 25, and 40 mg/kg/day for a period of 28 days. There were no adverse effects on general condition, growth, feed and water consumption, and hematological parameters. There was a significant increase in urea and alanine aminotransferase in female mice and aspartate aminotransferase and alkaline phosphatase in both genders in 40 mg/kg/day dose-treated group. The histopathological changes confined to the liver and kidney, but in other organs were not found. Satellite group revealed that changes in the kidney and liver were less pronounced, suggesting their reversibility. Interactions with DNA could also be of importance for understanding DE-EDCP toxic side effects. Hyperchromic effect obtained with ultraviolet–visible, suggested electrostatic interactions between DE-EDCP and calf thymus DNA. The toxicity testing of DE-EDCP was conducted to predict human outcomes.
PB  - SAGE PUBLICATIONS LTD
T2  - Human and Experimental Toxicology
T1  - Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP
VL  - 38
IS  - 4
SP  - 466
EP  - 481
DO  - 10.1177/0960327118819047
ER  - 

@article{
author = "Stanković, Dalibor and Ristić, Slavica M. and Vukadinović, Aleksandar and Mirković, Marija D. and Vladimirov, Sandra S. and Milanović, Zorana and Radović, Magdalena and Mijović, Milica and Stanković, Dalibor and Sabo, Tibor and Vranješ-Đurić, Sanja and Janković, Drina",
year = "2019",
abstract = "It was reported that novel O,O′-diethyl-(S, S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl) propanoate dihydrochloride (DE-EDCP) displayed in vitro antiproliferative activity on several human and mouse cancer cell lines, which was comparable to that of the prototypical anticancer drug cisplatin. In order to reveal its toxicity profile, acute and repeated-dose toxicity studies were performed in Naval Medical Research Institute (NMRI) Han mice. The intravenous LD 50 values of DE-EDCP were found to be 95.3 and 101.3 mg/kg body weight in female and male mice, respectively. In the subacute toxicity study, DE-EDCP was administered intravenously at the doses of 15, 25, and 40 mg/kg/day for a period of 28 days. There were no adverse effects on general condition, growth, feed and water consumption, and hematological parameters. There was a significant increase in urea and alanine aminotransferase in female mice and aspartate aminotransferase and alkaline phosphatase in both genders in 40 mg/kg/day dose-treated group. The histopathological changes confined to the liver and kidney, but in other organs were not found. Satellite group revealed that changes in the kidney and liver were less pronounced, suggesting their reversibility. Interactions with DNA could also be of importance for understanding DE-EDCP toxic side effects. Hyperchromic effect obtained with ultraviolet–visible, suggested electrostatic interactions between DE-EDCP and calf thymus DNA. The toxicity testing of DE-EDCP was conducted to predict human outcomes.",
publisher = "SAGE PUBLICATIONS LTD",
journal = "Human and Experimental Toxicology",
title = "Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP",
volume = "38",
number = "4",
pages = "466-481",
doi = "10.1177/0960327118819047"
}

Stanković, D., Ristić, S. M., Vukadinović, A., Mirković, M. D., Vladimirov, S. S., Milanović, Z., Radović, M., Mijović, M., Stanković, D., Sabo, T., Vranješ-Đurić, S.,& Janković, D.. (2019). Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP. in Human and Experimental Toxicology
SAGE PUBLICATIONS LTD., 38(4), 466-481.
https://doi.org/10.1177/0960327118819047

Stanković D, Ristić SM, Vukadinović A, Mirković MD, Vladimirov SS, Milanović Z, Radović M, Mijović M, Stanković D, Sabo T, Vranješ-Đurić S, Janković D. Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP. in Human and Experimental Toxicology. 2019;38(4):466-481.
doi:10.1177/0960327118819047 .

Stanković, Dalibor, Ristić, Slavica M., Vukadinović, Aleksandar, Mirković, Marija D., Vladimirov, Sandra S., Milanović, Zorana, Radović, Magdalena, Mijović, Milica, Stanković, Dalibor, Sabo, Tibor, Vranješ-Đurić, Sanja, Janković, Drina, "Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP" in Human and Experimental Toxicology, 38, no. 4 (2019):466-481,
https://doi.org/10.1177/0960327118819047 . .

TY  - JOUR
AU  - Isaković, Anđelka M.
AU  - Petričević, Saša
AU  - Ristić, Slavica M.
AU  - Popadić, Dušan
AU  - Kravić-Stevović, Tamara
AU  - Zogović, Nevena
AU  - Poljarević, Jelena
AU  - Živanović-Radnić, Tatjana
AU  - Sabo, Tibor
AU  - Isaković, Aleksandra J.
AU  - Marković, Ivanka
AU  - Trajković, Vladimir S.
AU  - Misirlić-Denčić, Sonja
PY  - 2018
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2086
AB  - Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O, O-diethyl-(S, S)-ethylenediamineN, N'di-2-(3-cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays. Apoptosis and autophagy were investigated using flow cytometry, fluorescence and electron microscopy, and western blotting. In vivo antitumor potential was assessed in subcutaneous mouse melanoma model after 14 days of treatment with EE. Tumor mass and volume were measured, and RT-PCR was used for investigating the expression of autophagy-related, proapoptotic, and antiapoptotic molecules in tumor tissue. Investigated organic compound exerts significant cytotoxic effect against B16 cells. EE induced apoptosis, as confirmed by phosphatidyl serine externalisation, caspase activation, and ultrastructural features typical for apoptosis seen on fluorescence and electron microscopes. The apoptotic mechanism included prompt disruption of mitochondrial membrane potential and oxidative stress. No autophagy was observed. Antimelanoma action and apoptosis induction were confirmed in vivo, as EE decreased mass and volume of tumors, and increased expression of several proapoptotic genes. EE possesses significant antimelanoma action and causes caspasedependent apoptosis mediated by mitochondrial damage and reactive oxygen species production. Decrease in tumor growth and increase in expression of proapoptotic genes in tumor tissue suggest that EE warrants further investigation as a candidate agent in treating melanoma. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.
PB  - Lippincott Williams & Wilkins, Philadelphia
T2  - Melanoma Research
T1  - In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid
VL  - 28
IS  - 1
SP  - 8
EP  - 20
DO  - 10.1097/CMR.0000000000000409
ER  - 

@article{
author = "Isaković, Anđelka M. and Petričević, Saša and Ristić, Slavica M. and Popadić, Dušan and Kravić-Stevović, Tamara and Zogović, Nevena and Poljarević, Jelena and Živanović-Radnić, Tatjana and Sabo, Tibor and Isaković, Aleksandra J. and Marković, Ivanka and Trajković, Vladimir S. and Misirlić-Denčić, Sonja",
year = "2018",
abstract = "Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O, O-diethyl-(S, S)-ethylenediamineN, N'di-2-(3-cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays. Apoptosis and autophagy were investigated using flow cytometry, fluorescence and electron microscopy, and western blotting. In vivo antitumor potential was assessed in subcutaneous mouse melanoma model after 14 days of treatment with EE. Tumor mass and volume were measured, and RT-PCR was used for investigating the expression of autophagy-related, proapoptotic, and antiapoptotic molecules in tumor tissue. Investigated organic compound exerts significant cytotoxic effect against B16 cells. EE induced apoptosis, as confirmed by phosphatidyl serine externalisation, caspase activation, and ultrastructural features typical for apoptosis seen on fluorescence and electron microscopes. The apoptotic mechanism included prompt disruption of mitochondrial membrane potential and oxidative stress. No autophagy was observed. Antimelanoma action and apoptosis induction were confirmed in vivo, as EE decreased mass and volume of tumors, and increased expression of several proapoptotic genes. EE possesses significant antimelanoma action and causes caspasedependent apoptosis mediated by mitochondrial damage and reactive oxygen species production. Decrease in tumor growth and increase in expression of proapoptotic genes in tumor tissue suggest that EE warrants further investigation as a candidate agent in treating melanoma. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.",
publisher = "Lippincott Williams & Wilkins, Philadelphia",
journal = "Melanoma Research",
title = "In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid",
volume = "28",
number = "1",
pages = "8-20",
doi = "10.1097/CMR.0000000000000409"
}

Isaković, A. M., Petričević, S., Ristić, S. M., Popadić, D., Kravić-Stevović, T., Zogović, N., Poljarević, J., Živanović-Radnić, T., Sabo, T., Isaković, A. J., Marković, I., Trajković, V. S.,& Misirlić-Denčić, S.. (2018). In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid. in Melanoma Research
Lippincott Williams & Wilkins, Philadelphia., 28(1), 8-20.
https://doi.org/10.1097/CMR.0000000000000409

Isaković AM, Petričević S, Ristić SM, Popadić D, Kravić-Stevović T, Zogović N, Poljarević J, Živanović-Radnić T, Sabo T, Isaković AJ, Marković I, Trajković VS, Misirlić-Denčić S. In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid. in Melanoma Research. 2018;28(1):8-20.
doi:10.1097/CMR.0000000000000409 .

Isaković, Anđelka M., Petričević, Saša, Ristić, Slavica M., Popadić, Dušan, Kravić-Stevović, Tamara, Zogović, Nevena, Poljarević, Jelena, Živanović-Radnić, Tatjana, Sabo, Tibor, Isaković, Aleksandra J., Marković, Ivanka, Trajković, Vladimir S., Misirlić-Denčić, Sonja, "In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid" in Melanoma Research, 28, no. 1 (2018):8-20,
https://doi.org/10.1097/CMR.0000000000000409 . .

TY  - JOUR
AU  - Tubić, Biljana K.
AU  - Marković, Bojan D.
AU  - Vladimirov, Sandra S.
AU  - Ristić, Slavica M.
AU  - Ivković, Branka
AU  - Savić, Miroslav M.
AU  - Poljarević, Jelena
AU  - Sabo, Tibor
PY  - 2017
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2459
AB  - A series of new (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate esters has shown cytotoxic activity towards human leukemic cell lines. The aim of this study was to develop and validate a bioanalytical method for quantification of (S,S)-O,O-diethyl-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate dihydrochlorides (DE-EDCP) and its metabolite, substituted propanoic acid (EDCP), in mouse serum by ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Structural analog, derivative of 1,3-propanediamine, was used as an internal standard (IS). Sample preparation employed protein precipitation by acetonitrile and subsequent centrifugation. Optimal UHPLC separation conditions were set to achieve simultaneous determination of both compounds in a short run time of 6 min. Additionally, the selected reaction monitoring (SRM) mode developed in this method allowed a highly sensitive, accurate, and precise identification of compounds of interest. The lower limit of quantitation (LOQ) was 1.3 ng mL(-1) for DE-EDCP and 0.3 mu g mL(-1) for EDCP. The calibration curves were linear over the concentration range of 1.3-26.7 ng mL(-1) and 0.3-6.7 mu g mL(-1) for DE-EDCP and EDCP, respectively. Precision (%CV) and accuracy (% RE) for DE-EDCP and EDCP ranged from 3.5% to 16.0% and from 1.8% to 14.4%, respectively. The validation process was performed in accordance with the regulatory guidance/guideline, and all of the obtained results met the established acceptance criteria. The newly developed and validated UHPLC-MS/MS method is rapid, sensitive, and selective, and it can be successfully applied to drug monitoring in nonclinical studies.
PB  - Akademiai Kiado Rt, Budapest
T2  - Acta Chromatographica
T1  - Highly Sensitive UHPLC-MS/MS Method for Quantification of Ethylenediamine-N,N '-di-2-(3-cyclohexyl) Propanoic Acid Derivatives in Mouse Serum
VL  - 29
IS  - 2
SP  - 235
EP  - 252
DO  - 10.1556/1326.2017.29.2.7
ER  - 

@article{
author = "Tubić, Biljana K. and Marković, Bojan D. and Vladimirov, Sandra S. and Ristić, Slavica M. and Ivković, Branka and Savić, Miroslav M. and Poljarević, Jelena and Sabo, Tibor",
year = "2017",
abstract = "A series of new (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate esters has shown cytotoxic activity towards human leukemic cell lines. The aim of this study was to develop and validate a bioanalytical method for quantification of (S,S)-O,O-diethyl-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate dihydrochlorides (DE-EDCP) and its metabolite, substituted propanoic acid (EDCP), in mouse serum by ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Structural analog, derivative of 1,3-propanediamine, was used as an internal standard (IS). Sample preparation employed protein precipitation by acetonitrile and subsequent centrifugation. Optimal UHPLC separation conditions were set to achieve simultaneous determination of both compounds in a short run time of 6 min. Additionally, the selected reaction monitoring (SRM) mode developed in this method allowed a highly sensitive, accurate, and precise identification of compounds of interest. The lower limit of quantitation (LOQ) was 1.3 ng mL(-1) for DE-EDCP and 0.3 mu g mL(-1) for EDCP. The calibration curves were linear over the concentration range of 1.3-26.7 ng mL(-1) and 0.3-6.7 mu g mL(-1) for DE-EDCP and EDCP, respectively. Precision (%CV) and accuracy (% RE) for DE-EDCP and EDCP ranged from 3.5% to 16.0% and from 1.8% to 14.4%, respectively. The validation process was performed in accordance with the regulatory guidance/guideline, and all of the obtained results met the established acceptance criteria. The newly developed and validated UHPLC-MS/MS method is rapid, sensitive, and selective, and it can be successfully applied to drug monitoring in nonclinical studies.",
publisher = "Akademiai Kiado Rt, Budapest",
journal = "Acta Chromatographica",
title = "Highly Sensitive UHPLC-MS/MS Method for Quantification of Ethylenediamine-N,N '-di-2-(3-cyclohexyl) Propanoic Acid Derivatives in Mouse Serum",
volume = "29",
number = "2",
pages = "235-252",
doi = "10.1556/1326.2017.29.2.7"
}

Tubić, B. K., Marković, B. D., Vladimirov, S. S., Ristić, S. M., Ivković, B., Savić, M. M., Poljarević, J.,& Sabo, T.. (2017). Highly Sensitive UHPLC-MS/MS Method for Quantification of Ethylenediamine-N,N '-di-2-(3-cyclohexyl) Propanoic Acid Derivatives in Mouse Serum. in Acta Chromatographica
Akademiai Kiado Rt, Budapest., 29(2), 235-252.
https://doi.org/10.1556/1326.2017.29.2.7

Tubić BK, Marković BD, Vladimirov SS, Ristić SM, Ivković B, Savić MM, Poljarević J, Sabo T. Highly Sensitive UHPLC-MS/MS Method for Quantification of Ethylenediamine-N,N '-di-2-(3-cyclohexyl) Propanoic Acid Derivatives in Mouse Serum. in Acta Chromatographica. 2017;29(2):235-252.
doi:10.1556/1326.2017.29.2.7 .

Tubić, Biljana K., Marković, Bojan D., Vladimirov, Sandra S., Ristić, Slavica M., Ivković, Branka, Savić, Miroslav M., Poljarević, Jelena, Sabo, Tibor, "Highly Sensitive UHPLC-MS/MS Method for Quantification of Ethylenediamine-N,N '-di-2-(3-cyclohexyl) Propanoic Acid Derivatives in Mouse Serum" in Acta Chromatographica, 29, no. 2 (2017):235-252,
https://doi.org/10.1556/1326.2017.29.2.7 . .