• Logo
  • SBMUJournals

Design, Synthesis and Evaluation of Linear and Cyclic Peptide Analogues of Carnosine as Anticancer Agents

Mohammad Hassan Houshdar Tehrani, Abdolhamid Bamoniri, Mohammadreza Gholibeikian, Maryam Khosravi
17

Views

PDF

Abstract

Aim

Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide widely and abundantly distributed in the muscle and nervous tissues of animal species. Carnosine contains several beneficial biological properties such as antiglycating and antioxidant activities. It also contains antineoplastic effects in human cell culture as well as in animal experiments, however, the clear molecular basis of this activity has not been known yet. In the present study, in order to further examine structural basis of Carnosine for the anticancer activity, some linear and cyclic Carnosine peptide analogues were synthesized and their cytotoxicity were examined.

Material and Methods

 Linear and cyclic Carnosine peptide analogues were synthesized with appropriate protected amino acids and reagents using solid-phase peptide synthesis strategy, and anti-neoplastic activity of the synthesized compounds were examined on cancer cell lines of HepG2 (Human Liver Cancer Cell Line) and HT-29 (Human Colorectal Adenocarcinoma Cell Line) using MTT assay and flow cytometry analysis. Safety profile of the synthesized Carnosine analogues was also examined using skin fibroblast cells.

Results

 Our results showed that Carnosine analogues were toxic against HepG2 and HT-29 cell lines with a mean IC50 value 12.7 µg/mL. Flow cytometry analysis showed that such toxic activity could be, at least partly, through apoptosis induction.

Conclusion

 According to our experiments, in overall, compound 3b can be a good candidate for the further development of safe anticancer agents. On the other hand, cyclic peptides analogues of Carnosine, 1c and 2c, considering the properties of toxicity activities good enough on cancerous cell lines along with high safety profiles on normal skin cells, could be candidates for further works on finding anticancer agents with peptide structure giving better physicochemical properties for oral administration.   

Keywords: Carnosine analogues, Anticancer agents, Solid-phase peptide synthesis, MTT assay, Flow cytometry analysis.


References

Gulewitsch W and Amiradžibi S (1900) Ueber das carnosin, eine neue organische base des fleischextractes. Ber Dtsch Chem Ges 33: 1902-3.

Bauer K (2013) Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain. Neurochem Res 30: 1339–1345.

Wu JW, Liu KN, How SC, Chen WA, Lai CM, Liu HS, Hu CJ and Wang SS (2013) Carnosine’s effect on amyloid fibril formation and induced cytotoxicity oflysozyme. PLoS One 8: e81982.

Sale C, Saunders B and Harris RC (2010) Effect of beta-alanine supplementation on muscle carnosine concentrations and exercise performance. Amino Acids 39: 321-33.

Snyder SH (1980) Brain peptides as neurotransmitters. Science 209: 976-83.

Brown CE (1981) Interactions among carnosine, anserine, ophidine and copper in biochemical adaptation. J Theor Biol 88: 245-56.

Hipkiss AR, Michaelis J and Syrris P (1955) Non‐enzymatic glycosylation of the dipeptide l‐carnosine, a potential anti‐protein‐cross‐linking agent. FEBS Lett 371: 81-5.

Shendikova EN, Mel’sitova IV and Yurkova IL (2016) Effect of Histidine Containing Dipeptides on the Free Radical Fragmentation of Biologically Active Phospho Derivatives of Glycerol. High Energ Chem 50: 249-253.

Guitto A, Calderan A and Ruzza P (2005) Carnosine and carnosine-related antioxidants: a review. Curr Med Chem 12: 2293–2315.

Aldini G, Facino RF and Beretta G (2005) Carnosine and related dipeptides asquenchers of reactive carbonyl species: from structural studies to therapeutic perspectives. Biofactors 24: 77–87.

Hipkiss AR (2009) Carnosine and its possible roles in nutrition and health. Adv Food Nutr Res 57: 87–154.

Boldyrev AA, Aldini G, Derave W (2013) Physiology and pathophysiology of carnosine. Physiol Rev 93: 1803–1845.

Kang JH, Kim KS, Choi SY, Kwon HY, Won MH and Kang TC (2002) Carnosine and related dipeptides protect human ceruloplasmin against peroxyl radicalmediated modification. Mol Cells 13: 498e502.

Holliday R and McFarland G (1996) Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine. Br J Cancer 73: 966.

Horii Y, Shen J, Fujisaki Y, Yoshida K and Nagai K (2012) Effects of Lcarnosine on splenic sympathetic nerve activity and tumor proliferation. Neurosci Lett 510:1–5.

Renner C, Zemitzsch N, Fuchs B, Geiger KD, Hermes M, Hengstler J, Gebhardt R, Meixensberger J and Gaunitz F (2010) Carnosine retards tumor growth in vivo in an NIH3T3-HER2/neu mouse model. Mol Cancer 9:2.

Gaunitz F and Hipkiss AR (2012) Carnosine and cancer—a perspective. Amino Acids 43:135–142.

Gaunitz F and Hipkiss AR (2014) Inhibition of tumour cell growth by carnosine: some possible mechanisms. Amino Acids 46:327–337.

Houshdar Tehrani MH, Bamoniri AH, Gholibeikian MR (2018) The toxicity study of synthesized inverse carnosine peptide analogues on HepG2 and HT-29 cells. Iran J Basic Med Sci 21:39-46.

Pourahmad J, Amirmostofian M, Kobarfard F and Shahraki J (2009) Biological reactive intermediates that mediate dacarbazine cytotoxicity. Cancer Chemother Pharmacol 65: 89-96.

Rothman DM, Vazquez ME, Vogel EM and Imperiali B (2003) Caged phospho-amino acid building blocks for solid-phase peptide synthesis. J Org Chem 68: 6795-8.

Riccardi C and Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1: 1458-61.

Wang F, Yu L, Monopoli MP, Sandin P, Mahon E and Salvati A (2013) The biomolecular corona is retained during nanoparticle uptake and protects the cells from the damage induced by cationic nanoparticles until degraded in the lysosomes. Nanomedicine 9: 1159-68.




DOI: https://doi.org/10.22037/ipa.v1i3.22920

Refbacks

  • There are currently no refbacks.