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Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes

Authorized Users Only
2014
Authors
Savic, Aleksandar
Filipovic, Lana
Arandelovic, Sandra
Dojčinović, Biljana
Radulovic, Sinisa
Sabo, Tibor
Grgurić-Šipka, Sanja
Article (Published version)
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Abstract
Novel Pt(II) complexes of general formula [PtI2(L1-3)], (C1-C3): where L1-3 are isobutyl, n-pentyl and isopentyl esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid has been synthesized and characterized by elemental analysis, UV/Vis, IR, (H-1, C-13 and HSQC, Pt) NMR spectroscopy and ESI mass spectrometry. Spectroscopic data and computational studies have shown the usual square planar coordination geometry of synthesized complexes, with coordination of ligands via nitrogen donor atoms. The cytotoxic activity of novel ligands and corresponding complexes were investigated on a palette of different cells line. Complexes C1-C3 exhibited activity comparable to cisplatin, with IC50 values (04) ranging from 4.6 +/- 0.6 to 17.2 +/- 2, and showed the highest potential in HeLa, LS-174 and EA.hy.926 cells. Ligands L1-L3 exhibited two- to four-times less activity than corresponding complexes. Analysis of the mode of action in HeLa cells, by ICP-MS study, showed markedly highe...r intracellular accumulation and DNA binding affinity of C1-C3 versus cisplatin, after 4 h and 20 h post-treatment. Annexin-V-FITC assay, flow cytometry and fluorescence microscopy study demonstrated occurrence of cell death through both apoptotic and necrotic changes. Tested complexes, at corresponding IC50 concentrations, caused considerable "sub-G1" peak, without other substantial alterations of cell cycle, while only Cl induced higher level of phosphatidylserine externalization (11.7%), comparing to ligand L1 (4.9%) and cisplatin (8.4%). Structure-activity comparison indicated variations of C1-C3 cytotoxicity, related to the drug/ligand lipophilicity (C log P value), while intracellular platinum content and DNA platination increased on increase of length and branching of ester chain, in sequence: Cl (isobutyl) LT C2 (n-pentyl) LT C3 (isopentyl).

Keywords:
Apoptosis / Cancer / Platinum complexes / Amine ligands
Source:
European Journal of Medicinal Chemistry, 2014, 82, 372-384
Publisher:
  • Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
Funding / projects:
  • Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-172035)
  • 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: 10.1016/j.ejmech.2014.05.060

ISSN: 0223-5234

PubMed: 24927057

WoS: 000339039100035

Scopus: 2-s2.0-84902328846
[ Google Scholar ]
30
25
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/1593
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Savic, Aleksandar
AU  - Filipovic, Lana
AU  - Arandelovic, Sandra
AU  - Dojčinović, Biljana
AU  - Radulovic, Sinisa
AU  - Sabo, Tibor
AU  - Grgurić-Šipka, Sanja
PY  - 2014
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1593
AB  - Novel Pt(II) complexes of general formula [PtI2(L1-3)], (C1-C3): where L1-3 are isobutyl, n-pentyl and isopentyl esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid has been synthesized and characterized by elemental analysis, UV/Vis, IR, (H-1, C-13 and HSQC, Pt) NMR spectroscopy and ESI mass spectrometry. Spectroscopic data and computational studies have shown the usual square planar coordination geometry of synthesized complexes, with coordination of ligands via nitrogen donor atoms. The cytotoxic activity of novel ligands and corresponding complexes were investigated on a palette of different cells line. Complexes C1-C3 exhibited activity comparable to cisplatin, with IC50 values (04) ranging from 4.6 +/- 0.6 to 17.2 +/- 2, and showed the highest potential in HeLa, LS-174 and EA.hy.926 cells. Ligands L1-L3 exhibited two- to four-times less activity than corresponding complexes. Analysis of the mode of action in HeLa cells, by ICP-MS study, showed markedly higher intracellular accumulation and DNA binding affinity of C1-C3 versus cisplatin, after 4 h and 20 h post-treatment. Annexin-V-FITC assay, flow cytometry and fluorescence microscopy study demonstrated occurrence of cell death through both apoptotic and necrotic changes. Tested complexes, at corresponding IC50 concentrations, caused considerable "sub-G1" peak, without other substantial alterations of cell cycle, while only Cl induced higher level of phosphatidylserine externalization (11.7%), comparing to ligand L1 (4.9%) and cisplatin (8.4%). Structure-activity comparison indicated variations of C1-C3 cytotoxicity, related to the drug/ligand lipophilicity (C log P value), while intracellular platinum content and DNA platination increased on increase of length and branching of ester chain, in sequence: Cl (isobutyl)  LT  C2 (n-pentyl)  LT  C3 (isopentyl).
PB  - Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
T2  - European Journal of Medicinal Chemistry
T1  - Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes
VL  - 82
SP  - 372
EP  - 384
DO  - 10.1016/j.ejmech.2014.05.060
ER  - 
@article{
author = "Savic, Aleksandar and Filipovic, Lana and Arandelovic, Sandra and Dojčinović, Biljana and Radulovic, Sinisa and Sabo, Tibor and Grgurić-Šipka, Sanja",
year = "2014",
abstract = "Novel Pt(II) complexes of general formula [PtI2(L1-3)], (C1-C3): where L1-3 are isobutyl, n-pentyl and isopentyl esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid has been synthesized and characterized by elemental analysis, UV/Vis, IR, (H-1, C-13 and HSQC, Pt) NMR spectroscopy and ESI mass spectrometry. Spectroscopic data and computational studies have shown the usual square planar coordination geometry of synthesized complexes, with coordination of ligands via nitrogen donor atoms. The cytotoxic activity of novel ligands and corresponding complexes were investigated on a palette of different cells line. Complexes C1-C3 exhibited activity comparable to cisplatin, with IC50 values (04) ranging from 4.6 +/- 0.6 to 17.2 +/- 2, and showed the highest potential in HeLa, LS-174 and EA.hy.926 cells. Ligands L1-L3 exhibited two- to four-times less activity than corresponding complexes. Analysis of the mode of action in HeLa cells, by ICP-MS study, showed markedly higher intracellular accumulation and DNA binding affinity of C1-C3 versus cisplatin, after 4 h and 20 h post-treatment. Annexin-V-FITC assay, flow cytometry and fluorescence microscopy study demonstrated occurrence of cell death through both apoptotic and necrotic changes. Tested complexes, at corresponding IC50 concentrations, caused considerable "sub-G1" peak, without other substantial alterations of cell cycle, while only Cl induced higher level of phosphatidylserine externalization (11.7%), comparing to ligand L1 (4.9%) and cisplatin (8.4%). Structure-activity comparison indicated variations of C1-C3 cytotoxicity, related to the drug/ligand lipophilicity (C log P value), while intracellular platinum content and DNA platination increased on increase of length and branching of ester chain, in sequence: Cl (isobutyl)  LT  C2 (n-pentyl)  LT  C3 (isopentyl).",
publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Paris",
journal = "European Journal of Medicinal Chemistry",
title = "Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes",
volume = "82",
pages = "372-384",
doi = "10.1016/j.ejmech.2014.05.060"
}
Savic, A., Filipovic, L., Arandelovic, S., Dojčinović, B., Radulovic, S., Sabo, T.,& Grgurić-Šipka, S.. (2014). Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes. in European Journal of Medicinal Chemistry
Elsevier France-Editions Scientifiques Medicales Elsevier, Paris., 82, 372-384.
https://doi.org/10.1016/j.ejmech.2014.05.060
Savic A, Filipovic L, Arandelovic S, Dojčinović B, Radulovic S, Sabo T, Grgurić-Šipka S. Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes. in European Journal of Medicinal Chemistry. 2014;82:372-384.
doi:10.1016/j.ejmech.2014.05.060 .
Savic, Aleksandar, Filipovic, Lana, Arandelovic, Sandra, Dojčinović, Biljana, Radulovic, Sinisa, Sabo, Tibor, Grgurić-Šipka, Sanja, "Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes" in European Journal of Medicinal Chemistry, 82 (2014):372-384,
https://doi.org/10.1016/j.ejmech.2014.05.060 . .

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