Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands
Autori
Nikolić, StefanRangasamy, Loganathan
Gligorijević, Nevenka
Aranđelović, Sandra
Radulović, Siniša
Gasser, Gilles
Grgurić-Šipka, Sanja
Članak u časopisu (Recenzirana verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Three new ruthenium(II)-arene complexes, namely [(eta(6)-p-cymene)Ru(Me(2)dppz)Cl]PF6 (1), [(eta(6)-benzene)Ru(Me(2)dppz)Cl]PF6 (2) and [(eta(6)-p-cymene)Ru(aip)Cl]PF6 (3) (Me(2)dppz = 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip = 2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying eta(6)-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeL...a cells. This event is followed by the accumulation of the sub-G1 DNA content after 48 h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me(2)dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin. (C) 2016 Elsevier Inc. All rights reserved.
Ključne reči:
Anticancer agents / Bioorganometallic chemistry / DNA intercalating ligand / Medicinal inorganic chemistry / Ruthenium(II)-arene complexIzvor:
Journal of Inorganic Biochemistry, 2016, 160, 156-165Izdavač:
- Elsevier Science Inc, New York
Finansiranje / projekti:
- Racionalni dizajn i sinteza biološki aktivnih i koordinacionih jedinjenja i funkcionalnih materijala, relevantnih u (bio)nanotehnologiji (RS-MESTD-Basic Research (BR or ON)-172035)
- Farmakodinamska i farmakogenomska ispitivanja novijih lekova u lečenju solidnih tumora (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41026)
- Swiss Government Excellence Scholarship for Postdoctoral Researcher [2014.0942/India/OP]
- Novartis Jubilee Foundation
- University of Zurich
- Stiftung fur wissenschaftliche Forschung of the University of Zurich
- Swiss National Science Foundation (SNSF) [PP00P2_133568, PP00P2_157545]
- COST Action [CM1105]
- UBS Promedica Stiftung
Napomena:
- This is peer-reviewed version of the following article: Nikolic, S.; Rangasamy, L.; Gligorijevic, N.; Arandelovic, S.; Radulovic, S.; Gasser, G.; Grguric-Sipka, S. Synthesis, Characterization and Biological Evaluation of Novel Ru(II)-Arene Complexes Containing Intercalating Ligands. J. Inorg. Biochem. 2016, 160, 156–165. https://doi.org/10.1016/j.jinorgbio.2016.01.005
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3639
DOI: 10.1016/j.jinorgbio.2016.01.005
ISSN: 0162-0134
PubMed: 26818702
WoS: 000378965200018
Scopus: 2-s2.0-84955164794
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Nikolić, Stefan AU - Rangasamy, Loganathan AU - Gligorijević, Nevenka AU - Aranđelović, Sandra AU - Radulović, Siniša AU - Gasser, Gilles AU - Grgurić-Šipka, Sanja PY - 2016 UR - https://cherry.chem.bg.ac.rs/handle/123456789/3638 AB - Three new ruthenium(II)-arene complexes, namely [(eta(6)-p-cymene)Ru(Me(2)dppz)Cl]PF6 (1), [(eta(6)-benzene)Ru(Me(2)dppz)Cl]PF6 (2) and [(eta(6)-p-cymene)Ru(aip)Cl]PF6 (3) (Me(2)dppz = 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip = 2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying eta(6)-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48 h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me(2)dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin. (C) 2016 Elsevier Inc. All rights reserved. PB - Elsevier Science Inc, New York T2 - Journal of Inorganic Biochemistry T1 - Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands VL - 160 SP - 156 EP - 165 DO - 10.1016/j.jinorgbio.2016.01.005 ER -
@article{ author = "Nikolić, Stefan and Rangasamy, Loganathan and Gligorijević, Nevenka and Aranđelović, Sandra and Radulović, Siniša and Gasser, Gilles and Grgurić-Šipka, Sanja", year = "2016", abstract = "Three new ruthenium(II)-arene complexes, namely [(eta(6)-p-cymene)Ru(Me(2)dppz)Cl]PF6 (1), [(eta(6)-benzene)Ru(Me(2)dppz)Cl]PF6 (2) and [(eta(6)-p-cymene)Ru(aip)Cl]PF6 (3) (Me(2)dppz = 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip = 2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying eta(6)-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48 h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me(2)dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin. (C) 2016 Elsevier Inc. All rights reserved.", publisher = "Elsevier Science Inc, New York", journal = "Journal of Inorganic Biochemistry", title = "Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands", volume = "160", pages = "156-165", doi = "10.1016/j.jinorgbio.2016.01.005" }
Nikolić, S., Rangasamy, L., Gligorijević, N., Aranđelović, S., Radulović, S., Gasser, G.,& Grgurić-Šipka, S.. (2016). Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands. in Journal of Inorganic Biochemistry Elsevier Science Inc, New York., 160, 156-165. https://doi.org/10.1016/j.jinorgbio.2016.01.005
Nikolić S, Rangasamy L, Gligorijević N, Aranđelović S, Radulović S, Gasser G, Grgurić-Šipka S. Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands. in Journal of Inorganic Biochemistry. 2016;160:156-165. doi:10.1016/j.jinorgbio.2016.01.005 .
Nikolić, Stefan, Rangasamy, Loganathan, Gligorijević, Nevenka, Aranđelović, Sandra, Radulović, Siniša, Gasser, Gilles, Grgurić-Šipka, Sanja, "Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands" in Journal of Inorganic Biochemistry, 160 (2016):156-165, https://doi.org/10.1016/j.jinorgbio.2016.01.005 . .