New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity
Само за регистроване кориснике
2018
Аутори
Radisavljević, SnežanaBratsos, Ioannis
Scheurer, Andreas
Korzekwa, Jana
Masnikosa, Romana
Tot, Aleksandar
Gligorijević, Nevenka N.
Radulović, Siniša S.
Rilak Simović, Ana
Чланак у часопису (Објављена верзија)
,
© 2018 The Royal Society of Chemistry
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Приказ свих података о документуАпстракт
With the aim of assessing whether Au(iii) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(iii) complexes of the general formula [Au(N-N'-N)Cl]Cl-2, where N-N'-N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me-2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1-3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5-monophosphate (5-GMP)) and... calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5-GMP and CT DNA, which can be explained by the steric hindrance and sigma-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (Delta H-not equal > 0, Delta S-not equal < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1-3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1-3 bound to CT DNA with moderate binding affinity (K-b = 1.6-5.7 x 10(3) M-1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1-3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 mu M. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival.
Извор:
Dalton Transactions, 2018, 47, 38, 13696-13712Финансирање / пројекти:
- Испитивање механизма реакција комплекса јона прелазних метала са биолошки значајним молекулима (RS-MESTD-Basic Research (BR or ON)-172011)
- Фармакодинамска и фармакогеномска испитивања новијих лекова у лечењу солидних тумора (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41026)
DOI: 10.1039/C8DT02903B
ISSN: 1477-9226; 1477-9234
PubMed: 30209465
WoS: 000446199500047
Scopus: 2-s2.0-85054049994
Колекције
Институција/група
VinčaTY - JOUR AU - Radisavljević, Snežana AU - Bratsos, Ioannis AU - Scheurer, Andreas AU - Korzekwa, Jana AU - Masnikosa, Romana AU - Tot, Aleksandar AU - Gligorijević, Nevenka N. AU - Radulović, Siniša S. AU - Rilak Simović, Ana PY - 2018 UR - http://xlink.rsc.org/?DOI=C8DT02903B UR - https://vinar.vin.bg.ac.rs/handle/123456789/7894 AB - With the aim of assessing whether Au(iii) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(iii) complexes of the general formula [Au(N-N'-N)Cl]Cl-2, where N-N'-N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me-2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1-3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5-monophosphate (5-GMP)) and calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5-GMP and CT DNA, which can be explained by the steric hindrance and sigma-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (Delta H-not equal > 0, Delta S-not equal < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1-3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1-3 bound to CT DNA with moderate binding affinity (K-b = 1.6-5.7 x 10(3) M-1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1-3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 mu M. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival. T2 - Dalton Transactions T1 - New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity VL - 47 IS - 38 SP - 13696 EP - 13712 DO - 10.1039/C8DT02903B ER -
@article{ author = "Radisavljević, Snežana and Bratsos, Ioannis and Scheurer, Andreas and Korzekwa, Jana and Masnikosa, Romana and Tot, Aleksandar and Gligorijević, Nevenka N. and Radulović, Siniša S. and Rilak Simović, Ana", year = "2018", abstract = "With the aim of assessing whether Au(iii) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(iii) complexes of the general formula [Au(N-N'-N)Cl]Cl-2, where N-N'-N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me-2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1-3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5-monophosphate (5-GMP)) and calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5-GMP and CT DNA, which can be explained by the steric hindrance and sigma-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (Delta H-not equal > 0, Delta S-not equal < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1-3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1-3 bound to CT DNA with moderate binding affinity (K-b = 1.6-5.7 x 10(3) M-1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1-3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 mu M. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival.", journal = "Dalton Transactions", title = "New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity", volume = "47", number = "38", pages = "13696-13712", doi = "10.1039/C8DT02903B" }
Radisavljević, S., Bratsos, I., Scheurer, A., Korzekwa, J., Masnikosa, R., Tot, A., Gligorijević, N. N., Radulović, S. S.,& Rilak Simović, A.. (2018). New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity. in Dalton Transactions, 47(38), 13696-13712. https://doi.org/10.1039/C8DT02903B
Radisavljević S, Bratsos I, Scheurer A, Korzekwa J, Masnikosa R, Tot A, Gligorijević NN, Radulović SS, Rilak Simović A. New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity. in Dalton Transactions. 2018;47(38):13696-13712. doi:10.1039/C8DT02903B .
Radisavljević, Snežana, Bratsos, Ioannis, Scheurer, Andreas, Korzekwa, Jana, Masnikosa, Romana, Tot, Aleksandar, Gligorijević, Nevenka N., Radulović, Siniša S., Rilak Simović, Ana, "New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity" in Dalton Transactions, 47, no. 38 (2018):13696-13712, https://doi.org/10.1039/C8DT02903B . .