Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study
Само за регистроване кориснике
2019
Аутори
Joksimović, NenadPetronijević, Jelena
Janković, Nenad Ž.
Baskić, Dejan
Popović, Suzana Lj.
Todorović, Danijela V.
Matić, Sanja Lj.
Bogdanović, Goran A.
Vraneš, Milan
Tot, Aleksandar
Bugarčić, Zorica M.
Чланак у часопису (Објављена верзија)
,
© 2019 Elsevier Inc
Метаподаци
Приказ свих података о документуАпстракт
In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the... highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [K sv = (3.7 ± 0.1) and (3.4 ± 0.1) × 10 3 M −1 , respectively], an intercalative mode also confirmed through viscosity measurements. K a values, obtained as result of fluorescence titration of BSA with D13 and D15 [K a = (4.2 ± 0.2) and (2.6 ± 0.2) × 10 5 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region. © 2019 Elsevier Inc.
Кључне речи:
3-Hydroxy-3-pyrrolin-2-ones / Mechanisms of cytotoxic activity / Antitumor activity / DNA binding study / BSA binding study / Molecular dockingИзвор:
Bioorganic Chemistry, 2019, 88, 102954-Финансирање / пројекти:
- Испитивање механизма реакција комплекса јона прелазних метала са биолошки значајним молекулима (RS-172011)
Напомена:
- Peer-reviewed version of the article (Accepted Manuscript or postprint) available at: https://vinar.vin.bg.ac.rs/handle/123456789/8186
DOI: 10.1016/j.bioorg.2019.102954
ISSN: 0045-2068
PubMed: 31054428
WoS: 000475378400047
Scopus: 2-s2.0-85064921313
Колекције
Институција/група
VinčaTY - JOUR AU - Joksimović, Nenad AU - Petronijević, Jelena AU - Janković, Nenad Ž. AU - Baskić, Dejan AU - Popović, Suzana Lj. AU - Todorović, Danijela V. AU - Matić, Sanja Lj. AU - Bogdanović, Goran A. AU - Vraneš, Milan AU - Tot, Aleksandar AU - Bugarčić, Zorica M. PY - 2019 UR - https://vinar.vin.bg.ac.rs/handle/123456789/8173 AB - In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [K sv = (3.7 ± 0.1) and (3.4 ± 0.1) × 10 3 M −1 , respectively], an intercalative mode also confirmed through viscosity measurements. K a values, obtained as result of fluorescence titration of BSA with D13 and D15 [K a = (4.2 ± 0.2) and (2.6 ± 0.2) × 10 5 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region. © 2019 Elsevier Inc. T2 - Bioorganic Chemistry T1 - Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study VL - 88 SP - 102954 DO - 10.1016/j.bioorg.2019.102954 ER -
@article{ author = "Joksimović, Nenad and Petronijević, Jelena and Janković, Nenad Ž. and Baskić, Dejan and Popović, Suzana Lj. and Todorović, Danijela V. and Matić, Sanja Lj. and Bogdanović, Goran A. and Vraneš, Milan and Tot, Aleksandar and Bugarčić, Zorica M.", year = "2019", abstract = "In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [K sv = (3.7 ± 0.1) and (3.4 ± 0.1) × 10 3 M −1 , respectively], an intercalative mode also confirmed through viscosity measurements. K a values, obtained as result of fluorescence titration of BSA with D13 and D15 [K a = (4.2 ± 0.2) and (2.6 ± 0.2) × 10 5 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region. © 2019 Elsevier Inc.", journal = "Bioorganic Chemistry", title = "Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study", volume = "88", pages = "102954", doi = "10.1016/j.bioorg.2019.102954" }
Joksimović, N., Petronijević, J., Janković, N. Ž., Baskić, D., Popović, S. Lj., Todorović, D. V., Matić, S. Lj., Bogdanović, G. A., Vraneš, M., Tot, A.,& Bugarčić, Z. M.. (2019). Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study. in Bioorganic Chemistry, 88, 102954. https://doi.org/10.1016/j.bioorg.2019.102954
Joksimović N, Petronijević J, Janković NŽ, Baskić D, Popović SL, Todorović DV, Matić SL, Bogdanović GA, Vraneš M, Tot A, Bugarčić ZM. Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study. in Bioorganic Chemistry. 2019;88:102954. doi:10.1016/j.bioorg.2019.102954 .
Joksimović, Nenad, Petronijević, Jelena, Janković, Nenad Ž., Baskić, Dejan, Popović, Suzana Lj., Todorović, Danijela V., Matić, Sanja Lj., Bogdanović, Goran A., Vraneš, Milan, Tot, Aleksandar, Bugarčić, Zorica M., "Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study" in Bioorganic Chemistry, 88 (2019):102954, https://doi.org/10.1016/j.bioorg.2019.102954 . .