Skip to main content

Advertisement

SpringerLink
Log in

Anti-tumor activity of lipophilic imidazolium salts on select NSCLC cell lines

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-small-cell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Scheme 5
Fig. 10
Fig. 11
Scheme 6
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18

Similar content being viewed by others

Abbreviations

CCR2:

CC chemokine receptor 2

CCL2:

CC chemokine ligand 2

CCR5:

CC chemokine receptor 5

TLC:

Thin-layer chromatography

References

  • Bruker (1997) SMART (Version 5.625), SAINT (Version 6.22) and SHELXTL (Version 6.10)

  • Bruker (2007) APEX II. Bruker AXS Inc., Madison

    Google Scholar 

  • Duah E, Adapala RK, Al-Azzam N, Kondeti V, Gombedza F, Thodeti CK, Paruchuri S (2013) Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT2 and CysLT1 receptors. Sci Rep 3:3274. doi:10.1038/srep03274

    Article  PubMed Central  PubMed  Google Scholar 

  • Ellames GJ, Herbert JM (2010) A method for the preparation of [13C6]-labelled 2-substituted naphthalenes. J Label Compd Radiopharm 53:801–803

    Article  CAS  Google Scholar 

  • Garrison JC, Youngs WJ (2005) Ag(I) N-heterocyclic carbene complexes: synthesis, structure, and application. Chem Rev 105:3978–4008

    Article  CAS  PubMed  Google Scholar 

  • Garrison JC, Simons RS, Kofron WG, Tessier CA, Youngs WJ (2001a) Synthesis and structural characterization of a silver complex of a mixed-donor N-heterocyclic carbene linked cyclophane. Chem Commun 21:1780–1781

    Article  Google Scholar 

  • Garrison JC, Simons RS, Talley JM, Wesdemiotis C, Tessier CA, Youngs WJ (2001b) Synthesis and structural characterization of an imidazolium-linked cyclophane and the silver complex of an N-heterocyclic carbene-linked cyclophane. Organometallics 20:1276–1278

    Article  CAS  Google Scholar 

  • Gautier A, Cisnetti F (2012) Advances in metal-carbene complexes as potent anti-cancer agents. Metallomics 4:23–32

    Article  CAS  PubMed  Google Scholar 

  • Hindi KM, Siciliano TJ, Durmus S, Panzner MJ, Medvetz DA, Reddy DV, Hogue LA, Hovis CE, Hilliard JK, Mallet RJ, Tessier CA, Cannon CL, Youngs WJ (2008) Synthesis, stability, and antimicrobial studies of electronically tuned silver acetate N-heterocyclic carbenes. J Med Chem 51:1577–1583

    Article  CAS  PubMed  Google Scholar 

  • Hindi KM, Ditto AJ, Panzner MJ, Medvetz DA, Hovis CE, Han DS, Hilliard JK, Taylor JB, Yun YH, Cannon CL, Youngs WJ (2009a) The antimicrobial efficacy of sustained release silver-carbene complex-loaded l-tyrosine polyphosphate nanoparticles: characterization, in vitro and in vivo studies. Biomaterials 30:3771–3779

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hindi KM, Panzner MJ, Cannon CL, Youngs WJ (2009b) The medicinal applications of imidazolium carbene–metal complexes. Chem Rev 109:3859–3884

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kascatan-Nebioglu A, Melaiye A, Hindi KM, Durmus S, Panzner MJ, Hogue LA, Mallett RJ, Hovis CE, Coughenour M, Crosby SD, Milsted A, Ely DL, Tessier CA, Cannon CL, Youngs WJ (2006) Synthesis from caffeine of a mixed N-heterocyclic carbene–silver acetate complex active against resistant respiratory pathogens. J Med Chem 49:6811–6818

    Article  CAS  PubMed  Google Scholar 

  • Katano K, Kondo A, Safaei R, Holzer A, Samimi G, Mishima M, Kuo YM, Rochdi M, Howell SB (2002) Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. Cancer Res 62:6559–6565

    CAS  PubMed  Google Scholar 

  • Kondeti V, Duah E, Al-Azzam N, Thodeti CK, Boyce JA, Paruchuri S (2013) Differential regulation of cysteinyl leukotriene receptor signaling by protein kinase C in human mast cells. PLoS One 15 8(8):e71536 PMID:23977066

    Article  CAS  Google Scholar 

  • Landsdown AB (2002) Silver I: its antibacterial properties and mechanism of action. J Wound Care 11:125–130

    Article  Google Scholar 

  • Landsdown AB (2004) A Review of the use of silver in wound care: facts and fallacies. Br J Nurs 13:S6–S19

    Article  Google Scholar 

  • Lansdown AB, Williams A (2004) How safe is silver in wound care. J Wound Care 13:131–136

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Hindi K, Watts KM, Taylor JB, Zhang K, Li Z, Hunstad DA, Cannon CL, Youngs WJ, Wooley KL (2010) Shell crosslinked nanoparticles carrying silver antimicrobials as therapeutics. Chem Commun 46:121–123

    Article  CAS  Google Scholar 

  • Lin JC, Huang RT, Lee CS, Bhattacharyya A, Hwang WS, Lin IJ (2009) Coinage metal—N-heterocyclic carbene complexes. Chem Rev 109:3561–3598

    Article  CAS  PubMed  Google Scholar 

  • Malhotra SV, Kumar V (2010) A profile of the in vitro anti-tumor activity of imidazolium-based ionic liquids. Bioorg Med Chem Lett 20:581–585

    Article  CAS  PubMed  Google Scholar 

  • Markova AA, Plyavnik NV, Tatarskii VV Jr, Shtil AA, Serebrennikova GA (2010) Novel alkyl cationic glycerolipids with a heterocyclic polar domain induce disturbances of the cell cycle and the death of human leukemia cells. Russ J Bioorg Chem 36(4):532–534

    Article  CAS  Google Scholar 

  • Medvetz DA, Hindi KM, Panzner MJ, Ditto AJ, Yun YH, Youngs WJ (2008) Anti-cancer activity of Ag(I) N-heterocyclic carbene complexes derived from 4,5-dichloro-1H-imidazole. Metal Based Drugs 2008:384010

    Article  PubMed Central  PubMed  Google Scholar 

  • Oehinger L, Rubbiani R, Ott I (2013) N-heterocyclic carbene metal complexes in medicinal chemistry. Dalton Trans 42:3269–3284

    Article  Google Scholar 

  • Ornelas-Megiatto C, Shah PN, Wich PR, Cohen JL, Tagaev JA, Smolen JA, Wright BD, Panzner MJ, Youngs WJ, Frechet JMJ, Cannon CL (2012) Aerosolized antimicrobial agents based on degradable dextran nanoparticles loaded with silver carbene complexes. Mol Pharm 9(11):3012–3022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Panzner MJ, Deeraksa A, Smith A, Wright BD, Hindi KM, Kascatan-Nebioglu A, Torres AG, Judy BM, Hovis CE, Hilliard JK, Mallett RJ, Cope E, Estes DM, Cannon CL, Leid JG, Youngs WJ (2009) Synthesis and in vitro efficacy studies of silver carbene complexes on biosafety level 3 bacteria. Eur J Inorg Chem 13:1739–1745

    Article  Google Scholar 

  • Riduan SN, Zhang Y (2013) Imidazolium salts and their polymeric materials for biological applications. Chem Soc Rev 42:9055–9070

    Article  CAS  PubMed  Google Scholar 

  • Russel AD, Path FR, Hugo WB (1994) Antimicrobial activity and action of silver. Prog Med Chem 31:351–370

    Article  Google Scholar 

  • Sheldrick GM (2008) A short history of SHELX. Acta Cryst A64:112

    Article  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2012) Cancer statistic. CA Cancer J Clin 54:8–29

    Google Scholar 

  • Tolcher W, Mita A, Lewis LD, Garrett CR, Till E, Daud AI, Patnaik A, Papadopoulos K, Takimoto C, Bartels P, Keating A, Antonia S (2008) Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J Clin Oncol 26:5198–5203

    Article  CAS  PubMed  Google Scholar 

  • Van Engeland M, Nieland L, Ramaekers F, Schutte B, Reutelingsperger C (1998) Annexin V affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:1–9

    Article  PubMed  Google Scholar 

  • Wright BD, Shah PN, McDonald LJ, Shaeffer ML, Wagers PO, Panzner MJ, Smolen J, Tagaev J, Tessier CA, Cannon CL, Youngs WJ (2012) Synthesis, characterization, and antimicrobial activity of silver carbene complexes derived from 4,5,6,7-tetrachlorobenzimidazole against antibiotic resistant bacteria. Dalton Trans 41:6500–6506

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334(2):115–124

    Article  PubMed  Google Scholar 

  • Youngs WJ, Hindi K, Medvetz D (2012a) Metal complexes incorporated within biodegradable nanoparticles and their use in treating cancer. US Patent 8,282,944, filed May 28, 2009, issued October 9, 2012

  • Youngs WJ, Knapp AR, Wagers PO, Tessier CA (2012b) Nanoparticle encapsulated silver carbene complexes and their antimicrobial and anti-cancer properties: a perspective. Dalton Trans 41:327–336

    Article  CAS  PubMed  Google Scholar 

  • Youngs W, Panzner M, Deblock M, Tessier C, Wright B, Wagers P, Robishaw N (2012c) Preparation of azolium and purinium salts as anti-cancer and antimicrobial agents. PCT Int Appl, WO 2012149523 A1 20121101

Download references

Acknowledgments

This project has been funded by The University of Akron, the Akron Research Commercialization Corporation, and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01-DK082546). We thank the National Science Foundation (NSF) for providing funds for the purchase of the NMR instruments (Nos. CHE-0341701 and DMR-0414599), mass spectrometers (CHE-0821313 and CHE-1012636), and X-ray diffractometers (CHE-0116041 and CHE-0840446) used in this work.

Author information

Author notes

  1. Brian D. Wright

    Present address: Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, St. Louis, MO, 63110, USA

  2. Michael C. Deblock

    Present address: Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

Authors and Affiliations

  1. Department of Chemistry, The University of Akron, Akron, OH, 44325-3601, USA

    Brian D. Wright, Michael C. Deblock, Patrick O. Wagers, Ernest Duah, Nikki K. Robishaw, Kerri L. Shelton, Marie R. Southerland, Michael A. DeBord, Kortney M. Kersten, Lucas J. McDonald, Jason A. Stiel, Matthew J. Panzner, Claire A. Tessier, Sailaja Paruchuri & Wiley J. Youngs

Authors
  1. Brian D. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael C. Deblock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick O. Wagers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ernest Duah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nikki K. Robishaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kerri L. Shelton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marie R. Southerland
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael A. DeBord
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kortney M. Kersten
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lucas J. McDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jason A. Stiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Matthew J. Panzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Claire A. Tessier
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Sailaja Paruchuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Wiley J. Youngs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wiley J. Youngs.

Additional information

Brian D. Wright, Michael C. Deblock, and Patrick O. Wagers have contributed equally to the manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material. Contained within are 1H and 13C NMR spectra for compounds 7, 8, 12, 13, and 23.

Supplementary material 1 (DOCX 763 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wright, B.D., Deblock, M.C., Wagers, P.O. et al. Anti-tumor activity of lipophilic imidazolium salts on select NSCLC cell lines. Med Chem Res 24, 2838–2861 (2015). https://doi.org/10.1007/s00044-015-1330-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-015-1330-z

Keywords

Search

Navigation