Amino Acids

, Volume 47, Issue 5, pp 1007–1013 | Cite as

Synthesis and in vitro antitumor activity of new octapeptide analogs of somatostatin containing unnatural amino acids

  • Svetlana Ts. Staykova
  • Diana W. Wesselinova
  • Lyubomir T. Vezenkov
  • Emilia D. Naydenova
Original Article
First Online:
Received:
Accepted:

Abstract

Some modified octapeptide analogs of somatostatin with the following structure D-Phe-c(Cys-Phe-D-Trp-Xxx-Yyy-Cys)-Thr-NH2, where Xxx is Lys or Orn and Yyy is Aib (α-aminoisobutyric acid), Ac5c (1-aminocyclopentanecarboxylic acid) or Ac6c (1-aminocyclohexane carboxylic acid) have been synthesized. The peptides were prepared by standard Fmoc—solid phase peptide chemistry method. The direct disulphide bond formation has been employed on the solid phase by Tl(CF3CO2)3. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29 (human colorectal cancer cell line), MDA-MB-23 (human breast cancer cell line), Hep-G2 (human hepatocellular carcinoma cell line), HeLa (cervical cancer cell line) and normal human diploid cell line Lep-3. The new peptides exhibited different concentration-dependent antiproliferative effect against the tumor cell lines after 24 h treatment. The compounds were most effective to the HT-29 tumor cells. The compound 4C (Orn5, Aib6) demonstrated the most pronounced antiproliferative effects on HT-29 cells with the IC50 = 0.0199 μM.

Keywords

Somatostatin analog SPPS Unnatural amino acids Cytotoxic 
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Notes

Acknowledgments

We gratefully acknowledge the financial support by University of Chemical Technology and Metallurgy—contract 11331.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. Appetecchia M, Baldelli R (2010) Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. J Exp Clin Cancer Res 29:1–19. doi: 10.1186/1756-9966-29-19 CrossRefGoogle Scholar
  2. Barrie R, Woltering EA, Hajarizadeh H et al (1993) Inhibition of angiogenesis by somatostatin and somatostatin-like compoundsis structurally dependent. J Surg Res 55:446–450CrossRefPubMedGoogle Scholar
  3. Cai R-Z, Szoke B, Lu R et al (1986) Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Natl Acad Sci USA 83(6):1896–1900CrossRefPubMedCentralPubMedGoogle Scholar
  4. Coy D, Murphy WA (1997) Linear somatostatin analogs. US Patent, Patent Number 5633263, 27 May 1997. http://www.lens.org/images/patent/US/5633263/A/US_5633263_A.pdf
  5. Dinnendahl V, Fricke U (2010) Arzneistoff-Profile. Govi Pharmazeutischer Verlag. Eschborn, 8 (23)Google Scholar
  6. Haberfeld H (2009) Austria-codex. 2009/2010 ed. Österreichischer Apothekerverlag, ViennaGoogle Scholar
  7. Horvath A, Vadasz Z, Szende B et al (1998) Systematic structure-activity relationship studies of the antitumor peptide TT-232. Peptides: pp 494–495Google Scholar
  8. Karle IL, Balaram P (1990) Structural characteristics of alpha-helical peptide molecules containing Aib residues. Biochemistry 29(29):6747–6756CrossRefPubMedGoogle Scholar
  9. Kazmierski WM, Ferguson RD, Lipkowski AW, Huby VJ (1995) A topographical model of μ-opioid and brain somatostatin receptor selective ligands NMR and molecular dynamics studies. Int J Pept Protein Res 46(3–4):265–278PubMedGoogle Scholar
  10. Murphy WA, Heiman ML, Lance VA, Mezo I, Coy DH (1985) Octapeptide analogs of somatostatin exhibiting greatly enhanced in vivo and in vitro inhibition of growth hormone secretion in the rat. Biochem Biophys Res Commun 132(3):922–928CrossRefPubMedGoogle Scholar
  11. Pollak M (1997) The potential role of somatostatin analogues in breast cancer treatment. Yale J of Biol Med 70(5–6):535–539Google Scholar
  12. Pollak MN, Shally AV (1998) Mechanisms of antineoplastic action of somatostatin analogs. Proc Soc Exp Biol Med 217(2):143–152CrossRefPubMedGoogle Scholar
  13. Prasad S, Rao RB, Balaram P (1995) Contrasting solution conformations of peptides containing alpha, alpha-dialkylated residues with linear and cyclic side chains. Biopolymers 35(1):11–20CrossRefPubMedGoogle Scholar
  14. Prasad S, Mathur A, Sharma R, Gupta N, Ahuja R, Jaggi M, Sindh TA, Mukherjee R (2006) Octapeptide analogs of somatostatin containing dialkylated dmino acids with potent anticancer activity. Int J Pept Res Ther 12(2):179–185CrossRefGoogle Scholar
  15. Pyronnet S, Bousquet C, Najib S, Azar R, Laklai H, Susini C (2008) Antitumor effect of somatostatin. Mol Cell Endocrinol 286(1–2):230–237. doi: 10.1016/j.mce.2008.02.002 CrossRefPubMedGoogle Scholar
  16. Reubi JC, Waster B, Schaer JC, Laissue JA (2001) Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 28:836–846CrossRefPubMedGoogle Scholar
  17. Shimon I (2003) Somatostatin receptors in pituitary and development of somatostatin receptor subtype-selective analogs. Endocrine 20(3):265–269CrossRefPubMedGoogle Scholar
  18. Staykova S, Naydenova E, Wesselinova D, Kalistratova A, Vezenkov L (2012a) Synthesis and in vitro study of the anticancer activity of new analogs of octreotide. Prot Pept Lett 19(12):1257–1262CrossRefGoogle Scholar
  19. Staykova S, Naydenova E, Wesselinova D, Vezenkov L (2012) Synthesis and anticancer activity of new analogs of Vapreotide and RC-121. Peptides 2012, Proceeding of the 32th European Peptide Symposium, 474–475Google Scholar
  20. Strosberg J, Kvols L (2010) Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol 16(24):2963–2970CrossRefPubMedCentralPubMedGoogle Scholar
  21. Susini C, Buscail L (2006) Rationale for the use of somatostatin analogs as antitumor agents. Ann Onc 17:1733–1742CrossRefGoogle Scholar
  22. Veber DF, Holly FW, Nutt RF, Bergstrand SJ et al (1979) Highly active cyclic and bicyclic somatostatin analogues of reduced ring size. Nature 280:512–514CrossRefPubMedGoogle Scholar
  23. Veber DF, Freidinger RM, Perlow DS, Paleveda WJ, Holly FW et al (1981) A potent cyclic hexapeptide analogue of somatostatin. Nature 292:55–58CrossRefPubMedGoogle Scholar
  24. Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2(12):999–1017CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Svetlana Ts. Staykova
    • 1
  • Diana W. Wesselinova
    • 2
  • Lyubomir T. Vezenkov
    • 3
  • Emilia D. Naydenova
    • 3
  1. 1.Institute of Molecular Biology “Roumen Tsanev”Bulgarian Academy of SciencesSofiaBulgaria
  2. 2.Institute of Experimental Morphology, Pathology and Anthropology with MuzeumBulgarian Academy of SciencesSofiaBulgaria
  3. 3.Department of Organic ChemistryUniversity of Chemical Technology and MetallurgySofiaBulgaria

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