Journal of Chemical Biology

, Volume 7, Issue 3, pp 85–91 | Cite as

Synthesis and investigation of new Hesperadin analogues antitumor effects on HeLa cells

  • Fereshteh ShamsipourEmail author
  • Saeeideh Hosseinzadeh
  • Seyed Shahriar Arab
  • Sedigheh Vafaei
  • Samira Farid
  • Mahmood Jeddi-Tehrani
  • Saeed Balalaie
Original Article


Hesperadin is one of the indolinones that was designed against the ATP-binding site of Aurora kinase. This molecule inhibits Aurora B kinase by phosphorylation of histone H3. In this study, new derivatives of Hesperadin containing an amide group in their structures were synthesized through sequential Ugi/palladium-catalyzed approach and in vitro antitumor activity of new compounds were evaluated by cell proliferation assay. The results show that compounds 6f, 6i, 6l, and 6o were dose-dependently inhibited in different concentrations, and IC50 values were between 35 and 43 nM. It seems that lipophilic substitution on the indolinone core with the ability to form additional hydrogen bond might lead to increased stability of structure and activity of new Hesperadin analogues.


Aurora kinase Hesperadin Antitumor effects Analogues 



The authors are grateful to Miss Sedigheh Mirzaei, for carrying out the statistical analyses.


  1. 1.
    Adams RR, Maiato H, Earnshaw WC, Carmena M (2001) Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. J Cell Biol 153(4):865–880CrossRefGoogle Scholar
  2. 2.
    Bararjanian M, Hosseinzadeh S, Balalaie S, Bijanzadeh HR (2011) Palladium catalyzed stereoselective synthesis of 3-(anilinoarylmethylene)-2-oxindoles as Hesperadin analogoues. Tetrahedron 67(14):2644–2650CrossRefGoogle Scholar
  3. 3.
    Boss DS, Beijnen JH, Schellens JH (2009) Clinical experience with aurora kinase inhibitors: a review. Oncologist 14(8):780–793. doi: 10.1634/theoncologist.2009-0019 CrossRefGoogle Scholar
  4. 4.
    Carmena M, Earnshaw WC (2003) The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4(11):842–854. doi: 10.1038/nrm1245 CrossRefGoogle Scholar
  5. 5.
    Carvajal RD, Tse A, Schwartz GK (2006) Aurora kinases: new targets for cancer therapy. Clin Cancer Res Off J Am Assoc Cancer Res 12(23):6869–6875. doi: 10.1158/1078-0432.CCR-06-1405 CrossRefGoogle Scholar
  6. 6.
    Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS (2003) Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161(2):267–280CrossRefGoogle Scholar
  7. 7.
    Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5(1):1–10. doi: 10.1158/1541-7786.MCR-06-0208 CrossRefGoogle Scholar
  8. 8.
    Giet R, Petretti C, Prigent C (2005) Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 15(5):241–250. doi: 10.1016/j.tcb.2005.03.004 CrossRefGoogle Scholar
  9. 9.
    Goodsell DS, Morris GM, Olson AJ (1996) Automated docking of flexible ligands: applications of AutoDock. J Mol Recognit 9:1–5Google Scholar
  10. 10.
    Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM (2004) VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10(3):262–267. doi: 10.1038/nm1003 CrossRefGoogle Scholar
  11. 11.
    Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, Heckel A, van Meel J, Rieder CL, Peters JM (2003) The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 161(2):281–294. doi: 10.1083/jcb.200208092 CrossRefGoogle Scholar
  12. 12.
    Hontz AE, Li SA, Lingle WL, Negron V, Bruzek A, Salisbury JL, Li JJ (2007) Aurora a and B overexpression and centrosome amplification in early estrogen-induced tumor foci in the Syrian hamster kidney: implications for chromosomal instability, aneuploidy, and neoplasia. Cancer Res 67(7):2957–2963. doi: 10.1158/0008-5472.CAN-06-3296 CrossRefGoogle Scholar
  13. 13.
    Keen N, Taylor S (2009) Mitotic drivers–inhibitors of the Aurora B Kinase. Cancer Metastasis Rev 28(1–2):185–195. doi: 10.1007/s10555-009-9184-9 CrossRefGoogle Scholar
  14. 14.
    Kitzen JJ, de Jonge MJ, Verweij J (2010) Aurora kinase inhibitors. Crit Rev Oncol Hematol 73(2):99–110. doi: 10.1016/j.critrevonc.2009.03.009 CrossRefGoogle Scholar
  15. 15.
    Ladygina NG, Latsis RV, Yen T (2005) Effect of the pharmacological agent hesperadin on breast and prostate tumor cultured cells. Biomed Khim 51(2):170–176Google Scholar
  16. 16.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 19:1639–1662Google Scholar
  17. 17.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 16:2785–2791Google Scholar
  18. 18.
    Ota T, Suto S, Katayama H, Han Z-B, Suzuki F, Maeda M, Tanino M, Terada Y, Tatsuka M (2002) Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res 62(18):5168–5177Google Scholar
  19. 19.
    Pollard JR, Mortimore M (2009) Discovery and development of aurora kinase inhibitors as anticancer agents. J Med Chem 52(9):2629–2651. doi: 10.1021/jm8012129 CrossRefGoogle Scholar
  20. 20.
    Sausville EA (2004) Aurora kinases dawn as cancer drug targets. Nat Med 10(3):234–235CrossRefGoogle Scholar
  21. 21.
    Sessa F, Mapelli M, Ciferri C, Tarricone C, Areces LB, Schneider TR, Stukenberg PT, Musacchio A (2005) Mechanism of Aurora B activation by INCENP and inhibition by hesperadin. Mol Cell 18(3):379–391. doi: 10.1016/j.molcel.2005.03.031 CrossRefGoogle Scholar
  22. 22.
    The Electronic Protocol Book. A Quick and Practical Guide for Biologists. Available at
  23. 23.
    Vader G, Medema RH, Lens SM (2006) The chromosomal passenger complex: guiding Aurora-B through mitosis. J Cell Biol 173(6):833–837CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Fereshteh Shamsipour
    • 1
    Email author
  • Saeeideh Hosseinzadeh
    • 2
  • Seyed Shahriar Arab
    • 3
  • Sedigheh Vafaei
    • 1
  • Samira Farid
    • 1
  • Mahmood Jeddi-Tehrani
    • 1
  • Saeed Balalaie
    • 2
  1. 1.Monoclonal Antibody Research CenterAvicenna Research Institute, ACECRTehranIran
  2. 2.Peptide Chemistry Research CenterK. N. Toosi University of TechnologyTehranIran
  3. 3.Department of Biophysics, School of Biological SciencesTarbiat Modares UniversityTehranIran

Personalised recommendations