Advertisement

Synthesis and Characterization of a Series of Orthogonally Protected l-Carnosine Derivatives

  • Mohammad H. El-Dakdouki
  • Nadine Daouk
  • Hiba Abdallah
Article

Abstract

l-Carnosine (β-alanyl-l-histidine) is an endogenous dipeptide that has been recognized for its broad spectrum of beneficial biological activities. However, the therapeutic utility of molecule has been hampered by its instability in human plasma (half-life in human serum < 5 min) due to the presence of carnosinase enzyme that catalyzes its hydrolysis into the respective individual amino acids. While a large number of carnosine derivatives have been synthesized to optimize its overall pharmacokinetic profile, reports that provide molecular evidence as to how the dipeptide interacts with its biological target are scarce. Therefore, many questions are yet to be answered concerning the pharmacophoric regions in carnosine and its significance to the molecule’s diverse biological activities. In this study, we set out to construct a small library of carnosine analogues that can be used in assessing the influence of the various functional groups of the dipeptide on its important biological properties. Orthogonal protection/deprotection of selected functional groups led to the exposure of amino group at the N-terminus, the carboxyl group at the C-terminus, and the imidazole ring of histidine. To examine the significance of the imidazole group in preventing the aggregation of the β-amyloid plaques, histidine was replaced by phenylalanine and a series of β-Ala-Phe analogues was generated. To study the influence of the length of the carbon chain in β-Ala on the β-amyloid aggregation, a series of Gly-His analogues was synthesized. A series of Gly-Phe was also constructed and will be used as negative control in future β-amyloid plaque assembly experiments. The synthesized carnosine derivatives were characterized by NMR (proton, carbon, and 1H–1H COSY), and mass spectroscopy.

Keywords

l-Carnosine Orthogonal deprotection β-Alanine Histidine Peptides 

Notes

Acknowledgements

We are grateful for Dr. Kamal Bouhadir from the American University of Beirut for helping in NMR experiments.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human and Animal Rights

The article does not contain any studies with human or animal subjects performed by any of the authors.

Informed Consent

The authors declare that there is no informed consent in the article.

Supplementary material

10989_2018_9680_MOESM1_ESM.docx (4.4 mb)
Supplementary material 1 (DOCX 4536 KB)

References

  1. Aldini G, Carini M, Beretta G, Bradamante S, Maffei Facino R (2002) Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? Biochem. Biophys Res Commun 298:699–706CrossRefGoogle Scholar
  2. Bauer K (2005) Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain. Neurochemical Res 30:1339–1345CrossRefGoogle Scholar
  3. Bellia F, Amorini AM, La Mendola D, Vecchio G, Tavazzi B, Giardina B et al (2008) New glycosidic derivatives of histidine-containing dipeptides with antioxidant properties and resistant to carnosinase activity. Eur J Med Chem 43:373–380Google Scholar
  4. Bellia F, Vecchio G, Rizzarelli E (2012) Carnosine derivatives: new multifunctional drug-like molecules. Amino Acids 43:153–163CrossRefPubMedGoogle Scholar
  5. Bellia F, Oliveri V, Rizzarelli E, Vecchio G (2013) New derivative of carnosine for nanoparticle assemblies. Eur J Med Chem 70:225–232CrossRefPubMedGoogle Scholar
  6. Bertinaria M, Rolando B, Giorgis A, Montanaro G, Gasco A, Daniel PG et al (2011) Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents. J Med Chem 54:611–621CrossRefPubMedGoogle Scholar
  7. Bertinaria M, Rolando B, Giorgis M, Montanaro G, Marini E, Collino M et al (2012) Carnosine analogues containing NO-donor substructures: synthesis, physico-chemical characterization and preliminary pharmacological profile. Eur J Med Chem 54:103–112CrossRefPubMedGoogle Scholar
  8. Boldyrev AA (2000) Problems and perspectives in studying the biological role of carnosine. Biochemistry 65:751–756PubMedGoogle Scholar
  9. Boldyrev AA, Gallant SC, Sukhich GT (1999) Carnosine: the protective, anti-aging peptide. Mol Asp Med 19:581–587Google Scholar
  10. Castelletto V, Cheng G, Greenland BW, Hamley IW, Harris PJ (2011) Tuning the self-assembly of the bioactive dipeptide L-carnosine by incorporation of a bulky aromatic substituent. Langmuir 27:2980–2988CrossRefPubMedGoogle Scholar
  11. Craik DJ, Fairlie DP, Liras S, Price D (2013) The future of peptide-based drugs. Chem Biol Drug Design 81:136–147CrossRefGoogle Scholar
  12. Durmus Z, Kavas H, Baykal A, Sozeri H (2011) Synthesis and characterization of L-carnosine coated iron oxide nanoparticles. J Alloys Compd 509:2555–2561CrossRefGoogle Scholar
  13. Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20:122–128CrossRefPubMedGoogle Scholar
  14. Guiotto A, Calderan A, Ruzza P, Borin G (2005) Carnosine and carnosine-related antioxidants: a review. Curr Med Chem 12:2293–2315CrossRefPubMedGoogle Scholar
  15. Hamley IW (2007) Peptide fibrillization. Angew Chem Int Ed 46:8128–8147CrossRefGoogle Scholar
  16. Hipkiss AR (2009) Carnosine and its possible roles in nutrition and health. Adv. Food Nutr Res 57:87–154CrossRefGoogle Scholar
  17. Hipkiss RA, Cartwright PC, Bromley C, Gross SR, Bill RM (2013) Carnosine: can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential. Chem Cent J 7:38–46CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hobart LJ, Seibel I, Yeargans GS, Seidler NW (2004) Anti-crosslinking properties of carnosine: significance of histidine. Life Sci 75:1379–1389CrossRefPubMedGoogle Scholar
  19. Iacobini C, Menini S, Fantauzzi CB, Pesce CM, Giaccari A, Salomone E et al (2017) FL-926-16, a novel bioavailable carnosinase-resistant carnosine derivative, prevents onset and stops progression of diabetic nephropathy in db/db mice. Br J Pharmacol.  https://doi.org/10.1111/bph.14070 PubMedGoogle Scholar
  20. Krpetić Z, Guerrini L, Larmour IA, Reglinski J, Faulds K, Graham D (2012) Importance of nanoparticle size in colorimetric and SERS-based multimodal trace detection of Ni(II) ions with functional gold nanoparticles. Small 8:707–714CrossRefPubMedGoogle Scholar
  21. Lanza V, Bellia F, D’Agata R, Grasso G, Rizzarelli E, Vecchio G (2011) New glycoside derivatives of carnosine and analogs resistant to carnosinase hydrolysis: synthesis and characterization of their copper(II) complexes. J Inorg Biochem 105:181–188CrossRefPubMedGoogle Scholar
  22. Li H, Chen J, Huang H, Feng J-J, Wang A-J, Shao L-X (2016) Green and facile synthesis of L-carnosine protected fluorescent gold nanoclusters for cellular imaging. Sens Actuators B 223:40–44CrossRefGoogle Scholar
  23. Mahapatra RD, Dey J, Weiss RG (2017) L-Carnosine-derived Fmoc-tripeptides forming pH-sensitive and proteolytically stable supramolecular hydrogels. Langmuir 33:12989–12999CrossRefPubMedGoogle Scholar
  24. Malkar VV, Mukherjee T, Kapoor S (2015) Carnosine induced formation of silver nanochains: a radiolytic study. Radiat Phys Chem 107:54–58CrossRefGoogle Scholar
  25. Orioli M, Vistoli G, Regazzoni L, Pedretti A, Lapolla A, Rossoni G et al (2011) Design, synthesis, ADME properties, and pharmacological activities of beta-alanyl-D-histidine (D-carnosine) prodrugs with improved bioavailability. ChemMedChem 6:1269–1282CrossRefPubMedGoogle Scholar
  26. Pegova A, Abe H, Boldyrev A (2000) Hydrolysis of carnosine and related compounds by mammalian carnosinases. Comp Biochem Physiol B 127:443–446CrossRefPubMedGoogle Scholar
  27. Saada MC, Montero JL, Vullo D, Scozzafava A, Winum JY, Supuran CT (2011) Carbonic anhydrase activators: gold nanoparticles coated with derivatized histamine, histidine, and carnosine show enhanced activatory effects on several mammalian isoforms. J Med Chem 54:1170–1177CrossRefPubMedGoogle Scholar
  28. Sachdeva S (2017) Peptides as ‘Drugs’: the journey so far. Int J Pept Res Ther 23:49–60CrossRefGoogle Scholar
  29. Teufel M, Saudek V, Ledig JP, Bernhardt A, Boularand S et al (2003) Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J Biol Chem 278:6521–6531CrossRefPubMedGoogle Scholar
  30. Unno H, Yamashita T, Ujita S, Okumura N, Otani H, Okumura A et al (2008) Structural basis for substrate recognition and hydrolysis by mouse carnosinase CN2. J Biol Chem 283:27289–27299CrossRefPubMedGoogle Scholar
  31. Vistoli G, Orioli M, Pedretti A, Regazzoni L, Canevotti R, Negrisoli G at al (2009) Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species. ChemMedChem 4:967–975CrossRefPubMedGoogle Scholar
  32. Vistoli G, Colzani M, Mazzolari A, Maddis DD, Grazioso G, Pedretti A, Carini M, Aldini G (2016) Future Med Chem 8:1721–1737CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of ChemistryBeirut Arab UniversityBeirutLebanon

Personalised recommendations