Advertisement

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

  • Marijana Pavlović
  • Stefan Nikolić
  • Nevenka Gligorijević
  • Biljana Dojčinović
  • Sandra Aranđelović
  • Sanja Grgurić-ŠipkaEmail author
  • Siniša Radulović
Original Paper

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.

Graphical abstract

Keywords

Anticancer agents Ruthenium(II)–arene complexes DNA intercalating ligand Biological activity 

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

Notes

Acknowledgements

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

Supplementary material

775_2019_1647_MOESM1_ESM.pdf (943 kb)
Supplementary material 1 (PDF 943 kb)

References

  1. 1.
    Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK (2008) Dalton Trans 2:183–194CrossRefGoogle Scholar
  2. 2.
    Sledge G, Loehrer PJ, Roth BJ, Einhorn LH (1988) J Clin Oncol 6:1811–1814CrossRefGoogle Scholar
  3. 3.
    Florea A-M, Büsselberg D (2011) Cancers 3:1351–1371CrossRefGoogle Scholar
  4. 4.
    Liang X-J, Meng H, Wang Y, He H, Meng J, Lu J, Wang PC, Zhao Y, Gao X, Sun B (2010) Proc Natl Acad Sci USA 107:7449–7454CrossRefGoogle Scholar
  5. 5.
    Fong TT-H, Lok C-N, Chung CY-S, Fung Y-ME, Chow P-K, Wan P-K, Che C-M (2016) Angew Chem Int Ed 55:11935–11939CrossRefGoogle Scholar
  6. 6.
    Hu PC, Wang Y, Zhang Y, Song H, Gao FF, Lin HY, Wang ZH, Wei L, Yang F (2016) RSC Adv 6:29963–29976CrossRefGoogle Scholar
  7. 7.
    Rademaker-Lakhai JM, van den Bongard D, Pluim D, Beijnen JH, Schellens JH (2004) Clin Cancer Res 10:3717–3727CrossRefGoogle Scholar
  8. 8.
    Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) J Inorg Biochem 100:891–904CrossRefGoogle Scholar
  9. 9.
    Bytzek AK, Koellensperger G, Keppler BK, Hartinger CG (2016) J Inorg Biochem 160:250–255CrossRefGoogle Scholar
  10. 10.
    Murray BS, Babak MV, Hartinger CG, Dyson PJ (2016) Coord Chem Rev 306(part 1):86–114CrossRefGoogle Scholar
  11. 11.
    Dougan SJ, Sadler PJ (2007) Chimia 61:704–715CrossRefGoogle Scholar
  12. 12.
    Suss-Fink G (2010) Dalton Trans 39:1673–1688CrossRefGoogle Scholar
  13. 13.
    Morris RE, Aird RE, del Socorro Murdoch P, Chen H, Cummings J, Hughes ND, Parsons S, Parkin A, Boydand G, Jodrell DI (2001) J Med Chem 44:3616–3621CrossRefGoogle Scholar
  14. 14.
    Notaro A, Gasser G (2017) Chem Soc Rev 46:7317–7337CrossRefGoogle Scholar
  15. 15.
    Zeng L, Gupta P, Chen Y, Wang E, Ji L, Chao H, Chen ZS (2017) Chem Soc Rev 46:5771–5804CrossRefGoogle Scholar
  16. 16.
    Monro S, Colón KL, Yin H, Roque J, Konda P, Gujar S, Thummel RP, Lilge L, Cameron CG, McFarland SA (2018) Chem Rev.  https://doi.org/10.1021/acs.chemrev.8b00211 Google Scholar
  17. 17.
    Jakubaszek M, Goud B, Ferrari S, Gasser G (2018) Chem Commun 54:13040–13059CrossRefGoogle Scholar
  18. 18.
    Heinemann F, Karges J, Gasser G (2017) Acc Chem Res 50:2727–2736CrossRefGoogle Scholar
  19. 19.
    Song H, Kaiser JT, Barton JK (2012) Nat. Chem 4:615–620CrossRefGoogle Scholar
  20. 20.
    Kilah NL, Meggers E (2012) Aust J Chem 65:1325–1332CrossRefGoogle Scholar
  21. 21.
    Dwyer FP, Gyarfas EC, Rogers WP, Koch JH (1952) Nature 170:190CrossRefGoogle Scholar
  22. 22.
    Tan C, Wu S, Lai S, Wang M, Chen Y, Zhou L, Zhu Y, Lian W, Peng W, Ji L (2011) Dalton Trans 40:8611–8621CrossRefGoogle Scholar
  23. 23.
    Baroud AA, Mihajlović-Lalić LJE, Stanković D, Kajzerberger M, van Hecke K, Grgurić-Šipka S, Savić A (2017) J Serb Chem Soc 82(3):267–275Google Scholar
  24. 24.
    Jovanović K, Tanić M, Ivanović I, Gligorijević N, Dojčinović B, Radulović S (2016) J Inorg Biochem 163:362–373CrossRefGoogle Scholar
  25. 25.
    Jensen SB, Rodger SJ, Spicer MD (1998) J Organomet Chem 556:151–158CrossRefGoogle Scholar
  26. 26.
    Gillard RD, Hill REE, Maskill R (1970) J Chem Soc A 1447–1451Google Scholar
  27. 27.
    Supino R (1995) Humana Press 43:137–149Google Scholar
  28. 28.
    Strober W (2001) Curr Protoc Immunol Appendix 3B:1–2Google Scholar
  29. 29.
    Ormerod MG (1994) Oxford University Press, Oxford, 119–125Google Scholar
  30. 30.
    Spector DL, Goldman RD, Leinwand LA (1998) Cold Spring Harbor Laboratory Press, 1Google Scholar
  31. 31.
    van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP (1998) Cytometry 31:1–9CrossRefGoogle Scholar
  32. 32.
    Ott I, Biot C, Hartinger C (2014) Wiley, New York, 63–97Google Scholar
  33. 33.
    Selby M, Delosh R, Laudeman J, Ogle C, Reinhart R, Silvers T, Lawrence S, Kinders R, Parchment R, Teicher BA, Evans DM (2017) SLAS Discov. 22(5):473–483Google Scholar
  34. 34.
    Sarangapani S, Patil A, Ngeow YK, Elsa Mohan R, Asundi A, Lang MJ (2018) Integr Biol 10(5):313–324CrossRefGoogle Scholar
  35. 35.
    Patra M, Joshi T, Pierroz V, Ingram K, Kaiser M, Ferrari S, Spingler B, Keiser J, Gasser G (2013) Chem Eur J 19:14768–14772CrossRefGoogle Scholar
  36. 36.
    Yan YK, Melchart M, Habtemariam A, Sadler PJ (2005) Chem Commun 4764–4776Google Scholar
  37. 37.
    Nikolić S, Rangasamy L, Gligorijević N, Aranđelović S, Radulović S, Gasser G, Grgurić-Šipka S (2016) J Inorg Biochem 160:156–165CrossRefGoogle Scholar
  38. 38.
    Valladolid J, Hortigüela C, Busto N, Espino G, Rodríguez AM, Leal JM, Jalón FA, Manzano BR, Carbayo A, García B (2014) Dalton Trans 43:2629–2645CrossRefGoogle Scholar
  39. 39.
    Kepp O, Galluzzi L, Lipinski M, Yuanand J, Kroemer G (2011) Nat Rev Drug Discov 10:221–237CrossRefGoogle Scholar
  40. 40.
    Berridge MV, Tan AS (1993) Arch Biochem Biophys 303(2):474–482CrossRefGoogle Scholar
  41. 41.
    Wang D, Lippard S (2005) Nat Rev Drug Discov 4:307–320CrossRefGoogle Scholar
  42. 42.
    Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Cell Death Differ 16:3–11CrossRefGoogle Scholar
  43. 43.
    Sun X, Shi B, Zheng H, Min L, Yang J, Li X, Liao X, Huang W, Zhang M, Xu S, Zhu Z, Cui H, Liu X (2018) Cell Death Dis 9:260CrossRefGoogle Scholar
  44. 44.
    Radisavljević S, Bratsos I, Scheurer A, Korzekwa J, Masnikosa R, Tot A, Gligorijević N, Radulović S, Rilak Simović A (2018) Dalton Trans 47(38):13696–13712CrossRefGoogle Scholar
  45. 45.
    Sancho-Martínez SM, Prieto-García L, Prieto M, López-Novoa JM, López-Hernández FJ (2012) Pharmacol Therapeut 136:35–55CrossRefGoogle Scholar
  46. 46.
    Corazao-Rozas P, Guerreschi P, André F, Gabert PE, Lancel S, Dekiouk S, Fontaine D, Tardivel M, Savina A, Quesnel B, Mortier L, Marchetti P, Kluza J (2016) Oncotarget 7(26):39473–39485CrossRefGoogle Scholar
  47. 47.
    Hong SK, Starenki D, Wu PK, Park JI (2017) Cancer Biol Ther 18(2):106–114CrossRefGoogle Scholar
  48. 48.
    Acland M, Mittal P, Lokman NA, Klingler-Hoffmann M, Oehler MK, Hoffmann P (2018) Proteomics Clin Appl 12(3):1–13CrossRefGoogle Scholar

Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  • Marijana Pavlović
    • 1
  • Stefan Nikolić
    • 2
  • Nevenka Gligorijević
    • 1
  • Biljana Dojčinović
    • 3
  • Sandra Aranđelović
    • 1
  • Sanja Grgurić-Šipka
    • 4
    Email author
  • Siniša Radulović
    • 1
  1. 1.Institute for Oncology and Radiology of SerbiaDepartment of Experimental OncologyBelgradeSerbia
  2. 2.Innovation Center of the Faculty of ChemistryUniversity of BelgradeBelgradeSerbia
  3. 3.Institute of Chemistry, Technology and Metallurgy, Centre of Chemistry, University of BelgradeBelgradeSerbia
  4. 4.Faculty of ChemistryUniversity of BelgradeBelgradeSerbia

Personalised recommendations