Synthesis and anticancer activity of N-9- and N-7- substituted 1,2,3 triazole analogues of 2,6-di-substituted purine

Abstract

A library of N-9- and N-7-substituted 1,2,3 triazole analogues were generated on the 2,6-di-substituted purine upon reaction with various substituted aromatic azides. The synthesised analogues were screened for in vitro cytotoxic activity against various human cancer cell lines like (HCT-1 (colon), THP-1 (leukaemia), IMR-32 (neuroblastoma) and A-549 (lung)). From the bioassay results, it was observed that even though most of the synthesized derivatives exhibited a good potency against various screened cancer cell lines, but few of the analogues like 9a, 9b and 9e were found to be the most potent analogues in the series, with compound 9a showing IC50 values of 0.08 and 0.4 μM against THP-1 and A-549 cell lines, respectively.

This is a preview of subscription content, access via your institution.

Fig. 1
Scheme 1
Fig. 2
Fig. 3

Abbreviations

Ph:

Phenyl ring

Ba:

Benzyl amine

T:

Triazole ring

Pu:

Purine ring

Ea:

Ethanol amine

Py:

Pyrolidine

Pi:

Piperidine

CH2Ba:

Methylene group attached to benzene ring of benzyl amine

CH2T:

Methylene group attached to Triazole ring

References

  1. De Clercq E (1997) Current and potential therapies for the treatment of herpes-virus infections. Clin Microbiol Rev 10:674–669

    Article  Google Scholar 

  2. Hansen SW, Skovsgaard T, Sorensen JB (1985) Treatment of small cell lung cancer with 6-mercaptopurine: A phase II study. Cancer Treat Rep 69:555

    CAS  PubMed  Google Scholar 

  3. Havlicek L, Hanus J, Vesely J, LeClerc S, Meijer L, Shaw G, Strnad M (1997) 8-Azapurines as new inhibitors of cyclin-dependent kinases. J Med Chem 40:408–412

    CAS  Article  Google Scholar 

  4. Jeannette CA, Christian EP, Álvaro CM, Ricardo AT, Mario F, Maria JT, Adam A, Margot P, Cristian OS (2015) Synthesis and pharmacophore modelling of 2,6,9-trisubstituted purine derivatives and their potential role as apoptosis-inducing agents in cancer cell lines. Molecules 20(4):6808–6826

    Article  Google Scholar 

  5. Kay NE (1981) Abnormal T cell subpopulation function in CLL: excessive suppressor and deficient helper activity with respect to B cell proliferation. Blood 57:418–420

    CAS  Article  Google Scholar 

  6. Legraverend M, Grierson DS (2006) The purines: potent and versatile small molecule inhibitors and modulators of key biological targets. Med Chem 14:3987–4006

    CAS  Article  Google Scholar 

  7. MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR (2005) Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res 65:5399–5407

    CAS  Article  Google Scholar 

  8. Marr JJ (1991) Purine analogs as chemotherapeutic agents in leishmaniasis and American trypanosomiasis. J Lab Clin Med 118:111–119

    CAS  PubMed  Google Scholar 

  9. Mary EL, Patrick EC, Satya N, Brian KL (2015) Cyclin-dependent kinase inhibitors as anticancer therapeutics. Mol Pharmacol 88:846–852

    Article  Google Scholar 

  10. Masson C (1983) Treatment of herpes with acyclovir. Presse Med 12:1399–1400

    CAS  PubMed  Google Scholar 

  11. McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM, MacKenzie M, Melville J, Stewart K, Wang S, Zhelev N, Zheleva D, Lane DP (2002) Int J Cancer 102:463–468

    CAS  Article  Google Scholar 

  12. Melroy J, Nair V (2005) The antiviral activity, mechanism of action, clinical significance and resistance of abacavir in the treatment of pediatric AIDS. Curr Pharm Des 11:3847–3852

    CAS  Article  Google Scholar 

  13. Munshi PN, Lubin M, Bertino JR (2014) 6-Thioguanine: a drug with unrealized potential for cancer therapy. Oncologist 19:760–765

    CAS  Article  Google Scholar 

  14. Nabhan C, Gartenhaus RB, Tallman MS (2004) Purine nucleoside analogues and combination therapies in B-cell chronic lymphocytic leukaemia: dawn of a new era. Leuk Res 28(5):429–442

    CAS  Article  Google Scholar 

  15. Panos F, Bruce CA, Michael LG (1996) Purine analogs for the treatment of low-grade lymph proliferative disorder. Oncologist 1(3):125–139

    Google Scholar 

  16. Perez OD, Chang YT, Rosania G, Sutherlin D, Schultz PG (2002) Inhibition and reversal of myogenic differentiation by purine-based microtubule assembly inhibitors. Chem Biol 9(4):475–483

    CAS  Article  Google Scholar 

  17. Quan DJ, Peters MG (2004) Antiviral therapy: nucleotide and nucleoside analogs. Clin Liver Dis 8(2):371–385

    Article  Google Scholar 

  18. Rosemeyer H (2004) The chemo diversity of purine as a constituent of natural products. Chem Biodivers 1:361–401

    CAS  Article  Google Scholar 

  19. Saman MV, Salim KY, Danter WR, Koropatnick J (2018) PLoS ONE 13(1):e0191766

    Article  Google Scholar 

  20. Siegel-Lakhai WS, Rodenstein DO, Beijnen JH, Gianella-Borradori A, Schellens JHM, Talbot DC (2005) Clinical trial designs. J Clin Oncol 23:2060–2060

  21. Vince R (1991) Synthesis and anti-HIV activity of carbovir and related carbocyclic nucleosides. Nucl Acids Symp Ser 25:193–194

    CAS  Google Scholar 

  22. Wang X, Wang L, Wu N, Ma X, Xu J (2015) Clinical efficacy of oral ganciclovir for prophylaxis and treatment of recurrent herpes simplex keratitis: corrigendum. Chin Med J 128:46–50

    CAS  Article  Google Scholar 

  23. WS Hsieh, R Soo, BK Peh, T Loh, D Dong, D Soh, LS Wong, S Green,J Chiao, CY Cui, YF Lai, SC Lee, B Mow, R Soong, M Salto-Tellez, BC Goh (2009) Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. Clin Cancer Res 15:1435–1442

    CAS  Article  Google Scholar 

  24. Welsch ME, Snyder SA, Stockwell BR (2010) Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol 2010(14):347–361

    Article  Google Scholar 

  25. Whittaker SR, Te Poele RH, Chan F, Linardopoulos S, Walton MI, Garrett MD, Workman P (2007) The cyclin-dependent kinase inhibitor seliciclib (R-roscovitine; CYC202) decreases the expression of mitotic control genes and prevents entry into mitosis. Cell Cycle 6:3114–3131

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank University of Pretoria for providing postdoctoral fellowship to JK.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jabeena Khazir.

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

44_2019_2456_MOESM1_ESM.pdf

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Khazir, J., Mir, B.A., Chashoo, G. et al. Synthesis and anticancer activity of N-9- and N-7- substituted 1,2,3 triazole analogues of 2,6-di-substituted purine. Med Chem Res 29, 33–45 (2020). https://doi.org/10.1007/s00044-019-02456-9

Download citation

Keywords

  • 2,6 Dichloropurine
  • Cycloaddition
  • 1,2,3 triazoles
  • anticancer