Skip to main content
SpringerLink
Log in

Synthesis and evaluation of cyclic nitrone derivatives as potential anti-cancer agents

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

Abstract

Nitrones have been found to exhibit attractive biological values as immuno spin trapping agents. However, successful clinical cases of nitrone therapeutics are still lacking. Herein we report the synthesis and antiproliferative activity of a series of structurally diverse nitrone derivatives against a panel of 5 cancer cell lines, based on which indole- and pyrrole-fused were further evaluated by analogue preparation and in-vitro screening. Analogues with moderate to good potency were identified. This study shows the promise for further pursuit of nitrone-type small molecules in chemotherapy.

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
Scheme 1
Fig. 3
Scheme 2
Fig. 4

Similar content being viewed by others

References

  1. Grigorev́ IA, In nitrile oxides, nitrones, and nitronates in organic synthesis: novel strategies in synthesis. In: Feuer, H., editor; 2nd ed. Hoboken, NJ: John Wiley & Sons; 2008. p. 129−434

  2. Anderson LL. Diverse applications of nitrones for the synthesis of heterocyclic compounds. Asian J Org Chem. 2016;5:9–30. https://doi.org/10.1002/ajoc.201500211

    Article  CAS  Google Scholar 

  3. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis, Novel Strategies in Synthesis, 2nd Ed., Fuer H, (Ed), John Wiley & Sons, Inc., Hoboken, New Jersey, 2008

  4. Mason RP. Imaging free radicals in organelles, cells, tissue, and in vivo with immuno-spin trapping. Redox Bio. 2016;8:422–9. https://doi.org/10.1016/j.redox.2016.04.003

    Article  CAS  Google Scholar 

  5. Maples KR, Green AR, Floy RA. Nitrone-related therapeutics. CNS Drugs. 2004;18:1071–84. https://doi.org/10.2165/00023210-200418150-00003

    Article  CAS  PubMed  Google Scholar 

  6. Floyd RA, Kopke RD, Choi CH, Foster SB, Doblas S, Towner RA. Nitrones as therapeutics. Free Radic Bio Med. 2008;45:1361–74. https://doi.org/10.1016/j.freeradbiomed.2008.08.017

    Article  CAS  Google Scholar 

  7. Villamena FA, Das A, Nash KM. Potential implication of the chemical properties and bioactivity of nitrone spin traps for therapeutics. Future Med Chem. 2012;4:1171–207. https://doi.org/10.4155/fmc.12.74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Floyd RA, Castro Faria Neto HC, Zimmerman GA, Hensley K, Towner RA. Nitrone-based therapeutics for neurodegenerative diseases: their use alone or in combination with lanthionines. Free Radic Bio Med. 2013;62:145–56. https://doi.org/10.1016/j.freeradbiomed.2013.01.033

    Article  CAS  Google Scholar 

  9. Novelli GP, Angiolini P, Tani R, Consales G, Bordi L. Phenyl-t-butyl-nitrone is active against traumatic shock in rats. Free Radic Res Commun. 1986;1:321–7. https://doi.org/10.3109/10715768609080971

    Article  CAS  PubMed  Google Scholar 

  10. Novelli GP, Angiolini P, Livi P, Pathernostro E. Oxygen-derived free radicals in the pathogenesis of experimental shock. Resuscitation. 1989;18:195–205. https://doi.org/10.1016/0300-9572(89)90022-1

    Article  CAS  PubMed  Google Scholar 

  11. Zhao Z, Cheng M, Maples KR, Ma JY, Buchan AM. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res. 2001;909:46–50. https://doi.org/10.1016/S0006-8993(01)02618-X

    Article  CAS  PubMed  Google Scholar 

  12. Garteiser P, Doblas S, DVM YW, Saunders D, MS JH, HT(ASCP) ML, et al. Multiparametric assessment of the anti-glioma properties of OKN007 by magnetic resonance imaging. J Magn Reson Imaging. 2010;31:796–806. https://doi.org/10.1002/jmri.22106

    Article  PubMed  Google Scholar 

  13. He T, Doblas S, Saunders D, Casteel R, Lerner M, Ritchey JW, et al. Effects of PBN and OKN007 in rodent glioma models assessed by 1HMR spectroscopy. Free Radic Biol Med. 2011;51:490–502. https://doi.org/10.1016/j.freeradbiomed.2011.04.037

    Article  CAS  PubMed  Google Scholar 

  14. Floyd RA, Towner RA, He T, Hensley K, Maples KR. Translational research involving oxidative stress and diseases of aging. Free Radic Biol Med. 2011;51:931–41. https://doi.org/10.1016/j.freeradbiomed.2011.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakae D, Kishida H, Enami T, Konishi Y, Hensley KL, Floyd RA. et al. Effects of phenyl N-tert-butyl nitrone and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined diet. Cancer Sci. 2003;94:26–31. https://doi.org/10.1111/j.1349-7006.2003.tb01347.x

    Article  CAS  PubMed  Google Scholar 

  16. Doblas S, Saunders D, Kshirsager P, Pye Q, Oblander J, Gordon B. et al. Phenyl-tert-butyl-nitrone induces tumor regression and decreases angiogenesis in a C6 rat glioma model. Free Radic Biol Med. 2008;44:63–72. https://doi.org/10.1016/j.freeradbiomed.2007.09.006

    Article  CAS  PubMed  Google Scholar 

  17. Tabatabaie T, Graham KL, Vasquez AM, Floyd RA, Kotake Y. Inhibition of the cytokine-mediated inducible nitric oxide synthase expression in rat insulinoma cells by phenyl N-tert-butylnitrone. Nitric Oxide. 2000;4:157–67. https://doi.org/10.1006/niox.2000.0281

    Article  CAS  PubMed  Google Scholar 

  18. Matés JM, Sánchez-Jiménez FM. Role of reactive oxygen species in apoptosis: implications for cancer therapy. Int J Biochem Cell Bio. 2000;32:157–70. https://doi.org/10.1016/S1357-2725(99)00088-6

    Article  Google Scholar 

  19. Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and varius chromic conditions. J Carcinog. 2006;5:14. https://doi.org/10.1186/1477-3163-5-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sullivan LB, Chandel NS. Mitochondrial reactive oxygen species and cancer. Cancer Metab. 2014;2:17. https://doi.org/10.1186/2049-3002-2-17

    Article  PubMed  PubMed Central  Google Scholar 

  21. Schumaker PT. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell. 2006;10:175–6. https://doi.org/10.1016/j.ccr.2006.08.015

    Article  CAS  Google Scholar 

  22. Kumari S, Badana AK, MM G, SS G, Malla RR. Reactive oxygen species: a key constitutent in cancer survival. Biomark Insights. 2018;13:1177271918755391. https://doi.org/10.1177/1177271918755391

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li ZY, Zhao JB, Sun BZ, Zhou TT, Liu S, Liu. et al. Asymmetric nitrone synthesis via ligand-enabled copper-catalyzed cope-type hydroamination of cyclopropene with oxime. J Am Chem Soc. 2017;139:11702–5. https://doi.org/10.1021/jacs.7b06523

    Article  CAS  PubMed  Google Scholar 

  24. Zhang MR, Liu S, Li H, Guo YJ, Li N, Guan MH. et al. Copper-Catalyzed Cope-Type Hydroamination of Non-activated Olefins toward Cyclic Nitrones: Scope, Mechanism, and Enantioselective Process Development. Chem Eur J. 2019;25:12620–7. https://doi.org/10.1002/chem.201902683

    Article  CAS  PubMed  Google Scholar 

  25. Liu MZ, Zhou TT, Zhang MR, Zhao JB, Zhang Q. Palladium (II)-Catalyzed cope-type hydroamination: efficient access to five and six-membered cyclic nitrones. Asian J Org Chem. 2019;8:1363–71. https://doi.org/10.1002/ajoc.201900367

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to National Natural Science Foundation of China (21871045), the natural science foundation of Jilin Province (20190201070JC) and Changchun University of Technology for generous financial support.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biology, Jilin Provincial Key Laboratory of Carbon Fiber Development and Application, Changchun University of Technology, Changchun, China

    Wei Zhou, Dongyan Ju, Yuhui Ao, Yu Liu & Jinbo Zhao

Authors
  1. Wei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongyan Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuhui Ao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinbo Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yuhui Ao, Yu Liu or Jinbo Zhao.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

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

Zhou, W., Ju, D., Ao, Y. et al. Synthesis and evaluation of cyclic nitrone derivatives as potential anti-cancer agents. Med Chem Res 30, 1309–1316 (2021). https://doi.org/10.1007/s00044-021-02729-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02729-2

Keywords

Search

Navigation