TY  - CONF
AU  - Stanković, Nevena
AU  - Mladenović, Milan
AU  - Matić, Sanja
AU  - Stanić, Snežana
AU  - Mihailović, Mirjana
AU  - Mihailović, Vladimir
AU  - Katanić, Jelena
AU  - Boroja, Tatjana
AU  - Vuković, Nenad
PY  - 2015
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6144
AB  - Eight chroman-2,4-diones, namely 2a-h, were evaluated as in vivo genotoxic agents in Wistar rats livers and kidneys using the alkaline comet assay. Compounds 2a, (E)-3- (1-(2-aminoethylamino) ethylidene) chroman-2,4-dione,2b,(E)-3-( 1-(2-hydroxyethylamino) ethylidene) chroman-2,4-dione, and 2f, (3E,3'E) - 3,3'-( l, l '-(ethane-1,2-diylbis (azanediyl)) bis (ethan-1-yl-l-ylidene)) dichroman-2,4- dione showed no genotoxic potential and were tested as antigenotoxic agents by application prior to ethyl methanesulfonate (EMS), a proven mutagen. As antigentotoxics, compounds significantly diminished EMS-induced DNA damage in both organs. The reduction of liver DNA damage amounted 86.93% (2b), 77.23% (2f), and 64.52% (2a), respectively, while the reduction in kidney DNA damage was 89.52 (2b), 82.50% (2f) and 68.14% (2a). Since EMS produce harmful d-ethylguanine lesion which is incorporated in aberrant genotoxic G=T and T=G pairing after rat Topoisomerase Ila (rToplla) catalyzed ATP-dependent DNA strand breaks, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on enzyme level using molecular docking and molecular dynamics simulations. According to molecular docking studies, those compounds occupy the A TPase region proximal to rGlu86, catalytic amino acid involved in the hydrolysis of y-pbosphate group of ATP via water bridges. Molecular dynamics simulations showed that 2a, 2b, and 2f are a barrier for the formation of ATP-H20-rGlu86 bridge. Since compounds inhibit the hydrolysis of ATP, they prohibit the energy for the DNA double strand ligation, and therefore neutralize any possible damage that can arise after the formation of 06-ethylguanine harmful lesion. Consequently, compounds 2a, 2b, and 2f prevent EMS mutagenic and carcinogenic effects, and can be applied in the cancer treatment to control the rate of anticancer alkylation drugs.
PB  - Banja Luka: Prirodno-matematički fakultet
C3  - III simpozijum biologa i ekologa Republike Srpske (SBERS, 2015): Zbornik radova; 2015 Nov 12-14; Banja Luka, Republika Srpska
T1  - Newly discovered chroman-2,4-diones neutralize DNA alkylation damage in vivo on topIIa level: A story behind the molecular modeling approach
SP  - 118
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6144
ER  - 

@conference{
author = "Stanković, Nevena and Mladenović, Milan and Matić, Sanja and Stanić, Snežana and Mihailović, Mirjana and Mihailović, Vladimir and Katanić, Jelena and Boroja, Tatjana and Vuković, Nenad",
year = "2015",
abstract = "Eight chroman-2,4-diones, namely 2a-h, were evaluated as in vivo genotoxic agents in Wistar rats livers and kidneys using the alkaline comet assay. Compounds 2a, (E)-3- (1-(2-aminoethylamino) ethylidene) chroman-2,4-dione,2b,(E)-3-( 1-(2-hydroxyethylamino) ethylidene) chroman-2,4-dione, and 2f, (3E,3'E) - 3,3'-( l, l '-(ethane-1,2-diylbis (azanediyl)) bis (ethan-1-yl-l-ylidene)) dichroman-2,4- dione showed no genotoxic potential and were tested as antigenotoxic agents by application prior to ethyl methanesulfonate (EMS), a proven mutagen. As antigentotoxics, compounds significantly diminished EMS-induced DNA damage in both organs. The reduction of liver DNA damage amounted 86.93% (2b), 77.23% (2f), and 64.52% (2a), respectively, while the reduction in kidney DNA damage was 89.52 (2b), 82.50% (2f) and 68.14% (2a). Since EMS produce harmful d-ethylguanine lesion which is incorporated in aberrant genotoxic G=T and T=G pairing after rat Topoisomerase Ila (rToplla) catalyzed ATP-dependent DNA strand breaks, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on enzyme level using molecular docking and molecular dynamics simulations. According to molecular docking studies, those compounds occupy the A TPase region proximal to rGlu86, catalytic amino acid involved in the hydrolysis of y-pbosphate group of ATP via water bridges. Molecular dynamics simulations showed that 2a, 2b, and 2f are a barrier for the formation of ATP-H20-rGlu86 bridge. Since compounds inhibit the hydrolysis of ATP, they prohibit the energy for the DNA double strand ligation, and therefore neutralize any possible damage that can arise after the formation of 06-ethylguanine harmful lesion. Consequently, compounds 2a, 2b, and 2f prevent EMS mutagenic and carcinogenic effects, and can be applied in the cancer treatment to control the rate of anticancer alkylation drugs.",
publisher = "Banja Luka: Prirodno-matematički fakultet",
journal = "III simpozijum biologa i ekologa Republike Srpske (SBERS, 2015): Zbornik radova; 2015 Nov 12-14; Banja Luka, Republika Srpska",
title = "Newly discovered chroman-2,4-diones neutralize DNA alkylation damage in vivo on topIIa level: A story behind the molecular modeling approach",
pages = "118",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6144"
}

Stanković, N., Mladenović, M., Matić, S., Stanić, S., Mihailović, M., Mihailović, V., Katanić, J., Boroja, T.,& Vuković, N.. (2015). Newly discovered chroman-2,4-diones neutralize DNA alkylation damage in vivo on topIIa level: A story behind the molecular modeling approach. in III simpozijum biologa i ekologa Republike Srpske (SBERS, 2015): Zbornik radova; 2015 Nov 12-14; Banja Luka, Republika Srpska
Banja Luka: Prirodno-matematički fakultet., 118.
https://hdl.handle.net/21.15107/rcub_ibiss_6144

Stanković N, Mladenović M, Matić S, Stanić S, Mihailović M, Mihailović V, Katanić J, Boroja T, Vuković N. Newly discovered chroman-2,4-diones neutralize DNA alkylation damage in vivo on topIIa level: A story behind the molecular modeling approach. in III simpozijum biologa i ekologa Republike Srpske (SBERS, 2015): Zbornik radova; 2015 Nov 12-14; Banja Luka, Republika Srpska. 2015;:118.
https://hdl.handle.net/21.15107/rcub_ibiss_6144 .

Stanković, Nevena, Mladenović, Milan, Matić, Sanja, Stanić, Snežana, Mihailović, Mirjana, Mihailović, Vladimir, Katanić, Jelena, Boroja, Tatjana, Vuković, Nenad, "Newly discovered chroman-2,4-diones neutralize DNA alkylation damage in vivo on topIIa level: A story behind the molecular modeling approach" in III simpozijum biologa i ekologa Republike Srpske (SBERS, 2015): Zbornik radova; 2015 Nov 12-14; Banja Luka, Republika Srpska (2015):118,
https://hdl.handle.net/21.15107/rcub_ibiss_6144 .

TY  - JOUR
AU  - Stanković, Nevena
AU  - Mladenović, Milan
AU  - Matić, Sanja
AU  - Stanić, Snežana
AU  - Stanković, Vesna
AU  - Mihailović, Mirjana
AU  - Mihailović, Vladimir
AU  - Katanić, Jelena
AU  - Boroja, Tatjana
AU  - Vuković, Nenad
AU  - Sukdolak, Slobodan
PY  - 2015
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2004
AB  - Two chroman-2,4-dione derivatives, namely 2a and 2f, were tested as in
   vivo anticoagulants by seven days of continuous per os application to
   adult male Wistar rats in a concentration of 20 mg/kg of body weight.
   Derivatives were selected from a group of six previously
   intraperitoneally applied compounds on the basis of presenting
   remarkable activity in a concentration of 2 mg/kg of body weight. The
   derivatives 2a and 2f are VKORC1 inhibitors, and comparison of the
   absorption spectra, association, and dissociation constants suggested
   that the compounds will be bound to serum albumin in the same manner as
   warfarin is, leading to transfer towards the molecular target VKORC1.
   After oral administration, the compounds proved to be anticoagulants
   comparable with warfarin, inasmuch as the measured prothrombin times for
   2a and 2f were 56.63 and 60.08 s, respectively. The INR values of 2a and
   2f ranged from 2.6 to 2.8, recommending them as useful therapeutics in
   the treatment of patients suffering from thromboembolic events and
   atrial fibrillation. The high percentage of binding and high binding
   affinity of 2a and 2f towards serum albumin reduced the risk of induced
   internal bleeding. Several kinds of toxicity studies were performed to
   investigate whether or not 2a and 2f can cause pathological changes in
   the liver, kidneys, and DNA. The catalytic activity of serum enzymes,
   concentration and catalytic activity of liver and kidney oxidative
   stress markers and enzymes, respectively, as well as the observed
   hepatic and renal morphological changes indicated that the compounds in
   relation to warfarin induced irrelevant hepatic toxicity, no increment
   of necrosis, and inconsiderable oxidative damage in the liver and
   kidneys. Estimation of DNA damage using the comet assay confirmed that
   2a and 2f caused no clinically significant genotoxicity. The higher
   activity and lower toxicity of 2f recommended this compound as a better
   drug candidate than 2a. (C) 2014 Elsevier Ireland Ltd. All rights
   reserved.
PB  - Elsevier
T2  - Chemico-Biological Interactions
T1  - Serum albumin binding analysis and toxicological screening of novel
 chroman-2,4-diones as oral anticoagulants
VL  - 227
DO  - 10.1016/j.cbi.2014.12.005
SP  - 18
EP  - 31
ER  - 

@article{
author = "Stanković, Nevena and Mladenović, Milan and Matić, Sanja and Stanić, Snežana and Stanković, Vesna and Mihailović, Mirjana and Mihailović, Vladimir and Katanić, Jelena and Boroja, Tatjana and Vuković, Nenad and Sukdolak, Slobodan",
year = "2015",
abstract = "Two chroman-2,4-dione derivatives, namely 2a and 2f, were tested as in
   vivo anticoagulants by seven days of continuous per os application to
   adult male Wistar rats in a concentration of 20 mg/kg of body weight.
   Derivatives were selected from a group of six previously
   intraperitoneally applied compounds on the basis of presenting
   remarkable activity in a concentration of 2 mg/kg of body weight. The
   derivatives 2a and 2f are VKORC1 inhibitors, and comparison of the
   absorption spectra, association, and dissociation constants suggested
   that the compounds will be bound to serum albumin in the same manner as
   warfarin is, leading to transfer towards the molecular target VKORC1.
   After oral administration, the compounds proved to be anticoagulants
   comparable with warfarin, inasmuch as the measured prothrombin times for
   2a and 2f were 56.63 and 60.08 s, respectively. The INR values of 2a and
   2f ranged from 2.6 to 2.8, recommending them as useful therapeutics in
   the treatment of patients suffering from thromboembolic events and
   atrial fibrillation. The high percentage of binding and high binding
   affinity of 2a and 2f towards serum albumin reduced the risk of induced
   internal bleeding. Several kinds of toxicity studies were performed to
   investigate whether or not 2a and 2f can cause pathological changes in
   the liver, kidneys, and DNA. The catalytic activity of serum enzymes,
   concentration and catalytic activity of liver and kidney oxidative
   stress markers and enzymes, respectively, as well as the observed
   hepatic and renal morphological changes indicated that the compounds in
   relation to warfarin induced irrelevant hepatic toxicity, no increment
   of necrosis, and inconsiderable oxidative damage in the liver and
   kidneys. Estimation of DNA damage using the comet assay confirmed that
   2a and 2f caused no clinically significant genotoxicity. The higher
   activity and lower toxicity of 2f recommended this compound as a better
   drug candidate than 2a. (C) 2014 Elsevier Ireland Ltd. All rights
   reserved.",
publisher = "Elsevier",
journal = "Chemico-Biological Interactions",
title = "Serum albumin binding analysis and toxicological screening of novel
 chroman-2,4-diones as oral anticoagulants",
volume = "227",
doi = "10.1016/j.cbi.2014.12.005",
pages = "18-31"
}

Stanković, N., Mladenović, M., Matić, S., Stanić, S., Stanković, V., Mihailović, M., Mihailović, V., Katanić, J., Boroja, T., Vuković, N.,& Sukdolak, S.. (2015). Serum albumin binding analysis and toxicological screening of novel
 chroman-2,4-diones as oral anticoagulants. in Chemico-Biological Interactions
Elsevier., 227, 18-31.
https://doi.org/10.1016/j.cbi.2014.12.005

Stanković N, Mladenović M, Matić S, Stanić S, Stanković V, Mihailović M, Mihailović V, Katanić J, Boroja T, Vuković N, Sukdolak S. Serum albumin binding analysis and toxicological screening of novel
 chroman-2,4-diones as oral anticoagulants. in Chemico-Biological Interactions. 2015;227:18-31.
doi:10.1016/j.cbi.2014.12.005 .

Stanković, Nevena, Mladenović, Milan, Matić, Sanja, Stanić, Snežana, Stanković, Vesna, Mihailović, Mirjana, Mihailović, Vladimir, Katanić, Jelena, Boroja, Tatjana, Vuković, Nenad, Sukdolak, Slobodan, "Serum albumin binding analysis and toxicological screening of novel
 chroman-2,4-diones as oral anticoagulants" in Chemico-Biological Interactions, 227 (2015):18-31,
https://doi.org/10.1016/j.cbi.2014.12.005 . .