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Strong in Vitro Cytotoxic Potential of New Ruthenium-Cymene Complexes

Authorized Users Only
2015
Authors
Nikolić, Stefan
Opsenica, Dejan
Filipović, Vuk
Dojčinović, Biljana
Arandelovic, Sandra
Radulovic, Singa
Grgurić-Šipka, Sanja
Article (Published version)
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Abstract
Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from [(eta(6)-p-cymene)RuCl2](2) and corresponding ligands. The structures of complexes were determined with elemental analysis and IR, ESIMS, H-1 and C-13{H-1} NMR, and 2D H-1-N-15 correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC50 in the range 11.03-56.45 mu M, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC50 = 11.03 +/- 1.39 mu M) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of t...he apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 mu g Ru/10 (6) cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 mu g Pt/10 (6) cells) and C2 (0.08 mu g Ru/10 (6) cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure-activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.

Source:
Organometallics, 2015, 34, 14, 3464-3473
Publisher:
  • American Chemical Society (ACS)
Funding / projects:
  • Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-172035)
  • The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
  • Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors (RS-41026)
  • Reinforcement of the Faculty of Chemistry, University of Belgrade, towards becoming a Center of Excellence in the region of WB for Molecular Biotechnology and Food research (EU-256716)

DOI: 10.1021/acs.organomet.5b00041

ISSN: 0276-7333

WoS: 000358821800004

Scopus: 2-s2.0-84938099772
[ Google Scholar ]
41
35
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/1618
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Nikolić, Stefan
AU  - Opsenica, Dejan
AU  - Filipović, Vuk
AU  - Dojčinović, Biljana
AU  - Arandelovic, Sandra
AU  - Radulovic, Singa
AU  - Grgurić-Šipka, Sanja
PY  - 2015
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1618
AB  - Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from [(eta(6)-p-cymene)RuCl2](2) and corresponding ligands. The structures of complexes were determined with elemental analysis and IR, ESIMS, H-1 and C-13{H-1} NMR, and 2D H-1-N-15 correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC50 in the range 11.03-56.45 mu M, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC50 = 11.03 +/- 1.39 mu M) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 mu g Ru/10 (6) cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 mu g Pt/10 (6) cells) and C2 (0.08 mu g Ru/10 (6) cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure-activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.
PB  - American Chemical Society (ACS)
T2  - Organometallics
T1  - Strong in Vitro Cytotoxic Potential of New Ruthenium-Cymene Complexes
VL  - 34
IS  - 14
SP  - 3464
EP  - 3473
DO  - 10.1021/acs.organomet.5b00041
ER  - 
@article{
author = "Nikolić, Stefan and Opsenica, Dejan and Filipović, Vuk and Dojčinović, Biljana and Arandelovic, Sandra and Radulovic, Singa and Grgurić-Šipka, Sanja",
year = "2015",
abstract = "Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from [(eta(6)-p-cymene)RuCl2](2) and corresponding ligands. The structures of complexes were determined with elemental analysis and IR, ESIMS, H-1 and C-13{H-1} NMR, and 2D H-1-N-15 correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC50 in the range 11.03-56.45 mu M, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC50 = 11.03 +/- 1.39 mu M) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 mu g Ru/10 (6) cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 mu g Pt/10 (6) cells) and C2 (0.08 mu g Ru/10 (6) cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure-activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.",
publisher = "American Chemical Society (ACS)",
journal = "Organometallics",
title = "Strong in Vitro Cytotoxic Potential of New Ruthenium-Cymene Complexes",
volume = "34",
number = "14",
pages = "3464-3473",
doi = "10.1021/acs.organomet.5b00041"
}
Nikolić, S., Opsenica, D., Filipović, V., Dojčinović, B., Arandelovic, S., Radulovic, S.,& Grgurić-Šipka, S.. (2015). Strong in Vitro Cytotoxic Potential of New Ruthenium-Cymene Complexes. in Organometallics
American Chemical Society (ACS)., 34(14), 3464-3473.
https://doi.org/10.1021/acs.organomet.5b00041
Nikolić S, Opsenica D, Filipović V, Dojčinović B, Arandelovic S, Radulovic S, Grgurić-Šipka S. Strong in Vitro Cytotoxic Potential of New Ruthenium-Cymene Complexes. in Organometallics. 2015;34(14):3464-3473.
doi:10.1021/acs.organomet.5b00041 .
Nikolić, Stefan, Opsenica, Dejan, Filipović, Vuk, Dojčinović, Biljana, Arandelovic, Sandra, Radulovic, Singa, Grgurić-Šipka, Sanja, "Strong in Vitro Cytotoxic Potential of New Ruthenium-Cymene Complexes" in Organometallics, 34, no. 14 (2015):3464-3473,
https://doi.org/10.1021/acs.organomet.5b00041 . .

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