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New organoruthenium compounds with pyrido[2′,3′:5,6]pyrazino[2,3-f][1, 10]phenanthroline: synthesis, characterization, cytotoxicity, and investigation of mechanism of action

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Abstract

Three new ruthenium(II)-arene complexes with pyrido[2′,3′:5,6]pyrazino[2,3-f][1, 10]phenanthroline (ppf) of general formula: C1 ([(ƞ6-benzene)Ru(ppf)Cl]PF6, C2 ([(ƞ6-toluene)Ru(ppf)Cl]PF6) and C3 ([(ƞ6-p-cymene)Ru(ppf)Cl]PF6) have been synthesized. The structures of complexes were determined by elemental analysis, IR, ESI–MS, as well as with 1H and 13C NMR spectroscopy. Cytotoxic activity has been evaluated in three different human neoplastic cell lines (A549, A375, LS 174T) and in one human non-tumor cell line (MRC-5), by the MTT assay. Complexes C1–C3 showed IC50 values in the micromolar range below 100 µM. Complex C3, carrying ƞ6-p-cymene as the arene ligand, exhibited cytoselective activity toward human malignant melanoma A375 cells (IC50 = 15.8 ± 2.7 µM), and has been selected for further analyses of its biological effects. Drug-accumulation study performed in the A375 cells disclosed that C3 possess lower ability of entering the cells compared to cisplatin and distributes approximately equally in the cytosol and membrane/organelle fraction of cells. Investigations in the 3D model of A375 cells, disclosed different effects of the complex C3 and cisplatin on growth of multicellular tumor spheroids (MCTSs). While the size of cisplatin-treated MCTSs decreased with time, MCTSs treated with C3 continued to growth. Differences in structural organization and biological activity of this type of ruthenium(II)-arene complexes versus cisplatin in A375 malignant melanoma cells pointed out their different modes of action, and necessity for further biological studies and optimizations for potential applications.

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Abbreviations

NAMI-A:

[ImH][trans-RuCl4(DMSO)(Im)]

KP1019:

[transtetrachlorobis-(1H-indazole)ruthenate(III)]

KP1339:

Sodium [transtetrachlorobis-(1H-indazole)ruthenate(III)]

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

RNA:

Ribonucleic acid

PDT:

Photodynamic therapy

A549:

Human lung adenocarcinoma cells

A375:

Human malignant melanoma cells

LS 174T:

Human colorectal adenocarcinoma cells

MRC-5:

Non-tumor human lung fibroblast cells

ICP-MS:

Inductively coupled plasma mass spectrometry

RPMI 1640:

Roswell Park Memorial Institute nutrient medium (1640)

FCS:

Fetal calf serum

HEPES:

4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

MTT:

3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide dye

SDS:

Sodium dodecyl sulfate

PI:

Propidium iodide

PBS:

Phosphate-buffered saline

RNaseA:

Ribonuclease A

FACS:

Fluorescence-activated cell sorting

AO:

Acridine orange

EtBr:

Ethidium bromide

FITC:

Fluorescein isothiocyanate

MCTS:

Multicellular tumor spheroid

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Acknowledgements

Ministry of Education, Science and Technological Development of the Republic of Serbia, Grant numbers 172035 and III 41026.

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Author notes

  1. Marijana Pavlović and Stefan Nikolić contributed equally to this work.

Authors and Affiliations

  1. Institute for Oncology and Radiology of Serbia, Department of Experimental Oncology, Belgrade, Serbia

    Marijana Pavlović, Nevenka Gligorijević, Sandra Aranđelović & Siniša Radulović

  2. Innovation Center of the Faculty of Chemistry, University of Belgrade, Belgrade, Serbia

    Stefan Nikolić

  3. Institute of Chemistry, Technology and Metallurgy, Centre of Chemistry, University of Belgrade, Belgrade, Serbia

    Biljana Dojčinović

  4. Faculty of Chemistry, University of Belgrade, Belgrade, Serbia

    Sanja Grgurić-Šipka

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  1. Marijana Pavlović
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Correspondence to Sanja Grgurić-Šipka.

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Pavlović, M., Nikolić, S., Gligorijević, N. et al. New organoruthenium compounds with pyrido[2′,3′:5,6]pyrazino[2,3-f][1, 10]phenanthroline: synthesis, characterization, cytotoxicity, and investigation of mechanism of action. J Biol Inorg Chem 24, 297–310 (2019). https://doi.org/10.1007/s00775-019-01647-4

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