Skip to main content
SpringerLink
Log in

Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study

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

Abstract

The compounds reducing tumor cell viability and disrupting DNA topoisomerase reactions have been widely used in anticancer drug development. Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is a potent intercalating agent that interferes with nucleic acid processing through interaction with DNA topoisomerase II. Although ellipticine is a well-characterized compound, it is not a widely-accepted drug due to the adverse effects detected upon administration. We have previously reported two novel ellipticine derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2) as potent compounds targeting DNA topoisomerase II. This study covers an extended synthesis, characterization, and activity data for five new salts of N-methyl 5-demetyl ellipticine (Z-1, Z-2, Z-4, Z-5 and Z-6) having several organic halides and their effects on human topoisomerase II enzymes. Moreover, combined in silico studies were conducted for better understanding of modes of action of studied molecules at the binding pocket of target. Our results showed that three of the derivatives (Z-1, Z-2, and Z-6) have considerable effect on the catalytic activity of human topoisomerase II implying the influence of alkyl groups added to the parental structure of ellipticine.

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
Fig. 2
Fig. 3 
Fig. 4

Similar content being viewed by others

References

  • Ashley RE, Osheroff N (2014) Natural products as topoisomerase II poisons: effects of thymoquinone on DNA cleavage mediated by human topoisomerase IIα. Chem Res Toxicol 27:787–793

    Article  CAS  Google Scholar 

  • Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413

    Article  CAS  Google Scholar 

  • Chikamori K, Grozav AG, Kozuki T, Grabowski D, Ganapathi R, Ganapathi MK (2010) DNA topoisomerase II enzymes as molecular targets for cancer chemotherapy. Curr Cancer Drug Tar 10:758–777

    Article  CAS  Google Scholar 

  • Coban G, Zencir S, Zupkó I, Réthy B, Gunes HS, Topcu Z (2008) Synthesis and biological activity evaluation of 1H-benzimidazoles via mammalian DNA topoisomerase I and cytostaticity assays. Eur J Med Chem 44:2280–2285

    Article  Google Scholar 

  • Deane FM, O’Sullivan EC, Maguire AR, Gilbert J, Sakoff JA, McCluskey A, McCarthy FO (2013) Synthesis and evaluation of novel ellipticines as potential anti-cancer agents. Org Biomol Chem 1:1334–1344

    Article  Google Scholar 

  • Delgado JL, Hsieh CM, Chan NL, Hiasa H (2018) Topoisomerases as anticancer targets. Biochem J 475:373–398

    Article  CAS  Google Scholar 

  • Desmond molecular dynamics system, D.E.S.R., New York, NY, 2017.

  • Fosse P, Rene B, Charra M, Paoletti C, Saucier J (1992) Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives structure–activity relationship. Mol Pharm 42:590–595

    CAS  Google Scholar 

  • Friesner R, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749

    Article  CAS  Google Scholar 

  • Garbett NC, Graves DE (2004) Extending nature’s leads: the anticancer agent ellipticine. Curr Med Chem Anticancer Agents 4:149–172

    Article  CAS  Google Scholar 

  • Gul HI, Cizmecioglu M, Zencir S, Gul M, Canturk P, Atalay M, Topcu Z (2009) Cytotoxic activity of 4’-hydroxychalcone derivatives against Jurkat cells and their effects on mammalian DNA topoisomerase I. J Enzym Inhib Med Chem 24:804–807

    Article  CAS  Google Scholar 

  • Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31:1695–1697

    Article  CAS  Google Scholar 

  • Iacopetta D, Rosano C, Puoci F, Parisi OI, Saturnino C, Caruso A et al. (2017) Multifaceted properties of 1,4dimethylcarbazoles: focus on trimethoxybenzamide and trimethoxyphenylurea derivatives as novel human topoisomerase II inhibitors. Eur J Pharm Sci 96:263–272

    Article  CAS  Google Scholar 

  • Ketron AC, Osheroff N (2014) Phytochemicals as anticancer and chemopreventive topoisomerase II poisons. Phytochem Rev 13:19–35

    Article  CAS  Google Scholar 

  • Kuo PL, Hsu YL, Chang CH, Lin CC (2005) The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. Cancer Lett 223:293–301

    Article  CAS  Google Scholar 

  • Lichota A, Gwozdzinski K (2018) Anticancer activity of natural compounds from plant and marine environment. Int J Mol Sci 19:1–38

    Article  Google Scholar 

  • Martyna GJ (1994) Remarks on “Constant-temperature molecular dynamics with momentum conservation”. Phys Rev E 50:3234–3236

    Article  CAS  Google Scholar 

  • McClendon AK, Osheroff N (2007) DNA topoisomerase II, genotoxicity, and cancer. Mutat Res 623:83–97

    Article  CAS  Google Scholar 

  • Metacore/Metadrug platform, Clarivate Analytics (2019) https://portal.genego.com/

  • Miller CM, O’Sullivan EC, Devine KJ, McCarthy. CM (2012) Synthesis and biological evaluation of novel isoellipticine derivatives and salt. Org Biomol Chem 10:7912–7921

    Article  CAS  Google Scholar 

  • Moody DL, Dyba M, Kosakowska-Cholody T, Tarasova NI, Michejda CJ (2007) Synthesis and biological activity of 5-aza-ellipticine derivatives. Bioorg Med Chem Lett 17:2380–2384

    Article  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  Google Scholar 

  • Rouëssé J, Spielmann M, Turpin F, Le Chevalier T, Azab M, Mondésir JM (1993) Phase II study of elliptinium acetate salvage treatment of advanced breast cancer. Eur J Cancer 29:856–859

    Article  Google Scholar 

  • Senarisoy M, Canturk P, Zencir S, Baran Y, Topcu Z (2013) Gossypol interferes with both type I and type II topoisomerase activities without generating strand breaks. Cell Biochem Biophys 66:199–204

    Article  CAS  Google Scholar 

  • Thompson D, Miller C, McCarthy FO (2008) Computer simulations reveal a novel nucleotide-type binding orientation for ellipticine-based anticancer c-kit kinase inhibitors. Biochemistry 47:10333–10344

    Article  CAS  Google Scholar 

  • Topcu Z (2001) DNA topoisomerases as targets for anticancer drugs. J Clin Pharm Ther 26:405–416

    Article  CAS  Google Scholar 

  • Topcu Z, Ozturk B, Kucukoglu O, Kilic E (2008) Inhibition of mammalian type I DNA topoisomerase by Helichrysum pamphylicum is correlated with the total antioxidant capacities of its individual flavonoids. Z Naturforsch C 63:69–74

    Article  CAS  Google Scholar 

  • Vann KR, Ekiz G, Zencir S, Bedir E, Topcu Z, Osheroff N (2016a) Effects of secondary metabolites from the fungus Septofusidium berolinense on DNA cleavage mediated by human topoisomerase IIα. Chem Res Toxicol 29:415–420

    Article  CAS  Google Scholar 

  • Vann KR, Ergun Y, Zencir S, Oncuoglu S, Osheroff N, Topcu Z (2016b) Inhibition of human DNA topoisomerase IIα by two novel ellipticine derivatives. Bioorg Med Chem Lett 26:1809–1812

    Article  CAS  Google Scholar 

  • Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein-ligand docking using GOLD. Proteins 52:609–623

    Article  CAS  Google Scholar 

  • Wang JC (1971) Interaction between DNA and an Escherichia coli protein omega. J Mol Biol 55:523–533

    Article  CAS  Google Scholar 

  • Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM (2012) The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J Mol Biol 424:109–124

    Article  CAS  Google Scholar 

  • Zupkó I, Molnár J, Réthy B, Minorics R, Frank E, Wölfling J et al. (2014) Anticancer and multidrug resistance-reversal effects of solanidine analogs synthetized from pregnadienolone acetate. Molecules 17:2061–2076

    Article  Google Scholar 

Download references

Acknowledgements

This study is supported by the grant of TUBITAK 115Z349 (PI; ZT).

Author contributions

MK, enzyme assays; VA, synthesis and characterization of test compounds; AK and IZ, mammalian cell viability assays; MZ and KS, in silico analyses; SD, in silico analyses and editing manuscript; HO, consultation and data analyses; YE, designing experiments, synthesis and characterization of test compounds, interpretation of data; SZ, designing experiments, enzyme assays, editing the manuscript; ZT, designed the project, enzyme assays, interpretation of data and writing manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Izmir, 35100, Turkey

    M. Kuskucu & Z. Topcu

  2. Department of Chemistry, Faculty of Science, Dokuz Eylul University, Izmir, 35160, Turkey

    V. Akyildiz & Y. Ergün

  3. Institute of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, 6720, Hungary

    Á. Kulmány & I. Zupko

  4. Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, 20070, Turkey

    S. Zencir

  5. Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, 34734, Turkey

    S. Durdagi, M. Zaka & K. Sahin

  6. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, Izmir, 35100, Turkey

    H. Orhan

Authors
  1. M. Kuskucu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Akyildiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Á. Kulmány
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Ergün
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Zencir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I. Zupko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Durdagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Zaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Sahin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H. Orhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Z. Topcu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z. Topcu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kuskucu, M., Akyildiz, V., Kulmány, Á. et al. Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study. Med Chem Res 29, 189–198 (2020). https://doi.org/10.1007/s00044-019-02472-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-019-02472-9

Keywords

Search

Navigation