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A new derivative of acetylsalicylic acid and carnosine: synthesis, physical and chemical properties, biological activity

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Abstract

Purpose

The aim of this study was to create and assess biological activity of a new compound based on carnosine and acetylsalicylic acid (ASA) that will comprise antioxidant effect with antiplatelet activity, while simultaneously preventing side effects on the gastrointestinal tract.

Methods

Salicyl-carnosine (SC) was synthesized by condensation of ASA and carnosine. Antioxidant activity was determined by spectrophotometric and chemiluminescence methods. Antiplatelet activity was carried out by the light transmission-aggregometry method using the inductor ADP. Chronic gastric ulcer in rats was modeled using glacial acetic acid.

Results

Using SOD-like activity, iron-induced chemiluminescence, BaSO4-activated respiratory burst, and evaluation of red blood cell structure stabilization during oxidative damage induced by sodium hypochlorite, it was shown that SC possesses antioxidant activity analogous, or better, than that of carnosine. Antiplatelet activity of SC was evaluated in the blood of healthy individuals, and was also shown to be comparable to, or exceeding that of ASA. Also SC demonstrates high resistance to hydrolysis by tissue and serum carnosinases. Most importantly, it was shown that SC has protected the gastric mucosa against the formation of stomach ulcerative lesions and promoted their epithelization, therefore overcoming the undesirable inherent side effects of ASA.

Conclusions

SC preserves pharmacologically significant properties of ASA and carnosine while retaining an anti-ulcer activity and resistance to the carnosinase hydrolysis at the same time. These properties are particularly promising for the potential development of new anti-inflammatory and antithrombotic drugs.

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Abbreviations

ASA:

acetylsalicylic acid

CL:

chemiluminescence

COX:

cyclooxygenase

HPLC:

high performance liquid chromatography

HRMS:

high resolution mass spectrometry

LP:

lipoproteins

LPO:

lipid peroxidation

NBT:

nitroblue tetrazolium

NSAIDs:

non-steroidal anti-inflammatory drugs

ROS:

reactive oxygen species

SA:

Salicylic acid

SC:

salicyl-carnosine

SOD:

Cu/Zn-superoxide dismutase

TEA:

trimethylamine

TLC:

thin layer chromatography

TCA:

trichloroacetic acid

STC:

Trolox-L-carnosine

RTC:

(R)-Trolox-L-carnosine

References

  1. Vlot AC, Dempsey DA, Klessig DF. Salicylic acid, a multifaceted hormone to combat disease. Annu Rev Phytopathol. 2009;47:177–206. https://doi.org/10.1146/annurev.phyto.050908.135202.

    Article  CAS  PubMed  Google Scholar 

  2. Vane J. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–5.

    Article  CAS  Google Scholar 

  3. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101:1206–18. https://doi.org/10.1161/01.CIR.101.10.1206.

    Article  CAS  PubMed  Google Scholar 

  4. Ekinci D. Salicylic acid derivatives: synthesis, features and usage as therapeutic tools. Expert Opin Ther Pat. 2011;21:1831–41. https://doi.org/10.1517/13543776.2011.636354.

    Article  CAS  PubMed  Google Scholar 

  5. Mekaj YH, Daci FT, Mekaj AY. New insights into the mechanisms of action of aspirin and its use in the prevention and treatment of arterial and venous thromboembolism. Ther Clin Risk Manag. 2015;11:1449–56. https://doi.org/10.2147/TCRM.S92222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Domashenko MA, Maksimova MY, Tanashyan MM. Acetylsalicylic acid in the treatment and prevention of cerebrovascular diseases. RMJ Neurol Psychiatry. 2011;30:1930–6 Russian.

  7. Mitchell AG, Broadhead JF. Hydrolysis of solubilized aspirin. J Pharm Sci. 1967;56:1261–6.

    Article  CAS  Google Scholar 

  8. Rowland PM, Riegelman S, Harris PA, Sholkoff SD, Eyring EJ. Kinetics of acetylsalicylic acid disposition in man. Nature. 1967;215:413–4.

    Article  CAS  Google Scholar 

  9. Tanashyan MM, Domashenko MA, Raskurazhev AA. Aspirin resistance: clinical and molecular genetic evaluation techniques. Annals Clin Exp Neurol. 2016;10:41–6 Russian.

  10. Shi X, Ding M, Dong Z, Chen F, Ye J, Wang S, et al. Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Mol Cell Biochem. 1999;199:93–102.

    Article  CAS  Google Scholar 

  11. Aruoma OI, Halliwell B. The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs. Xenobiotica. 1988;18:459–70. https://doi.org/10.3109/00498258809041682.

    Article  CAS  PubMed  Google Scholar 

  12. Baltazar MT, Dinis-Oliveira RJ, Duarte JA, Bastos ML, Carvalho F. Antioxidant properties and associated mechanisms of salicylates. Curr Med Chem. 2011;18:3252–64. https://doi.org/10.2174/092986711796391552.

    Article  CAS  PubMed  Google Scholar 

  13. Berezhnoy DS, Stvolinsky SL, Lopachev AV, Devyatov AA, Lopacheva OM, Kulikova OI, et al. Carnosine as an effective neuroprotector in brain pathology and potential neuromodulator in normal conditions. Amino Acids. 2019;51(1):139–50. https://doi.org/10.1007/s00726-018-2667-7.

    Article  CAS  PubMed  Google Scholar 

  14. Boldyrev AA, Aldini G, Derave W. Physiology and pathophysiology of Carnosine. Physiol Rev. 2013;93:1803–45. https://doi.org/10.1152/physrev.00039.2012.

    Article  CAS  PubMed  Google Scholar 

  15. Trubitsina IE, Shabanova ME, Chikunova BZ, Shavratsky VK, Formazyuk VB, Sergienko VI, et al. Characteristics of antiulcer activity of carnosine. Patol Fiziol Eksp Ter. 1997;4:17–20 Russian.

    Google Scholar 

  16. Wolos A, Piekarska K. Carnosinase in the kidney and liver. Int J Biochem. 1975;6:723–6.

  17. Stvolinsky SL, Antonova NA, Kulikova OI, Lopachev AV, Abaimov DA, Al-Baidani I, et al. Lipoilcarnosine: synthesis, study of physico-chemical and antioxidant properties, biological activity. Biomed Khim. 2018;64(3):268–75. https://doi.org/10.18097/PBMC20186403268 Russian.

    Article  CAS  PubMed  Google Scholar 

  18. Stvolinsky SL, Bulygina ER, Fedorova TN, Meguro K, Sato T, Tyulina OV, et al. Biological activity of novel synthetic derivatives of carnosine. Cell Mol Neurobiol. 2010;30(3):395–404. https://doi.org/10.1007/s10571-009-9462-7.

    Article  CAS  PubMed  Google Scholar 

  19. Dubois VD, Bastawrous A. N-acetylcarnosine (NAC) drops for age-related cataract. Cochrane Database Syst Rev. 2017;28;2:CD009493. https://doi.org/10.1002/14651858.CD009493.pub2.

  20. Tanashyan MM, Fedorova TN, Stvolinskij SL, Andreeva LA, Nagaev IY, Migulin VA, Shabalina AA, Trubitsyna IE, Lopachev AV, Kulikova OI, Abaimov DA. Agent possessing antiaggregant, cytoprotective and antioxidant activity. RU 2694061 C1.

  21. Gulyaeva NV. Superoxide-scavenging activity of carnosine in the presence of copper and zinc ions. Biokhimiia. 1987;52(7):1216–20.

    CAS  Google Scholar 

  22. Fedorova TN, Us KS, Ostrovskaya RU. Estimation of the antioxidant effect of the Nootropic dipeptide Noopept on the model of Fe2+-induced Chemiluminescence of lipoproteins of human serum in vitro. Neurochem J. 2007;1:260–3.

    Article  Google Scholar 

  23. Vladimirov YA. Studies of the antioxidant activity by measuring chemiluminescence kinetics. in Proceedings of the International Symposium on Natural Antioxidants: Molecular Mechanism and Health Effects / Ed. Packer L., Traber M.G., Xin W. AOCS Press: Champaing., Illinois, 1996:125–144.

  24. Pegova A, Abe H, Boldyrev A. Hydrolysis of carnosine and related compounds by mammalian carnosinases. Comp Biochem Physiol. Part B. Biochem Mol Biol. 2000;127:443–6.

    Article  CAS  Google Scholar 

  25. Boldyrev A, Abe H, Stvolinsky S, Tyulina O. Effects of carnosine and related compounds on generation of free oxygen species: a comparative study. Comp Biochem Physiol B Biochem Mol Biol. 1995;112(3):481–5.

    Article  CAS  Google Scholar 

  26. Prokopieva VD, Bohan NA, Johnson P, Abe H, Boldyrev AA. Effects of carnosine and related compounds on the stability and morphology of erythrocytes from alcoholics. Alcohol Alcohol. 2000;35:44–8.

    Article  CAS  Google Scholar 

  27. Tanashyan MM, Spavronskaya LR, Shabalina AA, Abaimov DA, Raskurazhev AA. Platelet aggregation characteristics and pharmacokinetics of salicylic and acetylsalicylic acids in patients with cerebrovascular disorders. Eksp Klin Farmakol. 2017;80:48–51.

    CAS  Google Scholar 

  28. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1961;194:927–9.

    Article  Google Scholar 

  29. Okabe S, Roth JL, Pfeiffer CJ. A method for experimental, penetrating gastric and duodenal ulcers in rats. Observations on normal healing. Am J Dig Dis. 1971;16:277–84.

    Article  CAS  Google Scholar 

  30. Cao G, Alessio HM, Cutler RG. Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med. 1993;14(3):303–11.

    Article  CAS  Google Scholar 

  31. Fee JA, Peisach J, Mims WB. Superoxide dismutase. Examination of the metal binding sites by electron spin echo spectroscopy. J Biol Chem. 1981;25;256(4):1910–4.

    CAS  PubMed  Google Scholar 

  32. Kataoka M, Tonooka K, Ando T, Imai K, Aimoto T. Hydroxyl radical scavenging activity of nonsteroidal anti-inflammatory drugs. Free Radic Res. 1997;27(4):419–27.

    Article  CAS  Google Scholar 

  33. Durak I, Karaayvaz M, Cimen MY, Avci A, Cimen OB, Büyükkoçak S, et al. Aspirin impairs antioxidant system and causes peroxidation in human erythrocytes and Guinea pig myocardial tissue. Hum Exp Toxicol. 2001;20(1):34–7.

    Article  CAS  Google Scholar 

  34. Kohen R, Misgav R, Ginsburg I. The SOD like activity of copper:carnosine, copper:anserine and copper:homocarnosine complexes. Free Radic Res Commun. 1991;12–13 Pt 1:179–85.

  35. Joshi R, Kumar S, Unnikrishnan M, Mukherjee T. Free radical scavenging reactions of sulfasalazine, 5-aminosalicylic acid and sulfapyridine: mechanistic aspects and antioxidant activity. Free Radic Res. 2005;39(11):1163–72.

    Article  CAS  Google Scholar 

  36. Couto D, Ribeiro D, Freitas M, Gomes A, Lima JL, Fernandes E. Scavenging of reactive oxygen and nitrogen species by the prodrug sulfasalazine and its metabolites 5-aminosalicylic acid and sulfapyridine. Redox Rep. 2010;15(6):259–67. https://doi.org/10.1179/135100010X12826446921707.

    Article  CAS  PubMed  Google Scholar 

  37. Badwey JA, Karnovsky ML. Active oxygen species and the functions of phagocytic leukocytes. Annu Rev Biochem. 1980;49:695–726.

    Article  CAS  Google Scholar 

  38. Black HS. Role of reactive oxygen species in inflammatory process. In: Hensbyand C., Lowe NJ, editors. Non-steroidal Anti-inflammatory Drugs: Pharmacology and the Skin. Basel: Karger;1989. Vol. 2, p. 1–20.

  39. Pattison DI and Davies MJ. Evidence for rapid inter- and intramolecular chlorine transfer reactions of histamine and carnosine chloramines: Implications for the prevention of hypochlorous acid-mediated damage. Biochemistry. 2006;4;45(26):8152–8162.

  40. Benbarek H, Ayad A, Deby-Dupont G, Boukraa L, Serteyn D. Modulatory effects of non-steroidal anti-inflammatory drugs on the luminol and lucigenin amplified chemiluminescence of equine neutrophils. Vet Res Commun. 2012;36(1):29–33.

    Article  CAS  Google Scholar 

  41. Stvolinsky SL, Sousa Pontesh E, Sergienko VI. Boldyrev AA Immunomodulatory effects of carnosine in vitro and in vivo. Biol Membr. 1996;13(3):299–306 Russian.

    Google Scholar 

  42. Fedorova TN, Belyaev MS, Trunova OA, Gnezditsky VV, Maximova MY, Boldyrev AA. Neuropeptide carnosine increases stability of lipoproteins and red blood cells as well as efficiency of immune competent system in patients with chronic discirculatory encephalopathy. Biochem (Moscow) Suppl Ser A. 2009;3:62–5. https://doi.org/10.1134/S1990747809010085.

    Article  Google Scholar 

  43. Yeung J, Li W, Holinstat M. Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol Rev. 2018;70(3):526–48. https://doi.org/10.1124/pr.117.014530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nikitenko NI, Shavratskiĭ VK, Boldyrev AA, Suslina ZA, Ionova VG. Effect of carnosine and its derivatives on ADP-induced human platelet aggregation. Biomed Khim. 1995;41(1):41–3 Russian.

  45. Ukawa H, Yamakuni H, Kato S, Takeuchi K. Effects of cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs on mucosal ulcerogenic and healing responses of the stomach. Dig Dis Sci. 1998;43:2003–11.

    Article  CAS  Google Scholar 

  46. Zhen XE, Zong M, Gao SN, Cao YG, Jiang L, Chen SX, Wang K, Sun SQ, Peng HS, Bai YH, Li S. Preparation and characterization of a novel aspirin derivative with anti-thrombotic and gastric mucosal protection properties. PLoS One. 2014;3;9(6):e98513. doi: https://doi.org/10.1371/journal.pone.0098513.

  47. Naito Y, Yoshikawa T, Yagi N, et al. Effects of polaprezinc on lipid peroxidation, neutrophil accumulation, and TNF-alpha expression in rats with aspirin-induced gastric mucosal injury. Dig Dis Sci. 2001;46(4):845–51.

    Article  CAS  Google Scholar 

  48. Yoshikawa T, Naito Y, Tanigawa T, Yoneta T, Yasuda M, Ueda S, et al. Effect of zinc-carnosine chelate compound (Z-103), a novel antioxidant, on acute gastric mucosal injury induced by ischemia-reperfusion in rats. Free Radic Res Commun. 1991;14(4):289–96.

    Article  CAS  Google Scholar 

  49. Ueda K, Ueyama T, Oka M, et al. Polaprezinc (zinc L-carnosine) is a potent inducer of anti-oxidative stress enzyme, heme oxygenase (HO)-1—a new mechanism of gastric mucosal protection. J Pharmacol Sci. 2009;110(3):285–94. https://doi.org/10.1254/jphs.09056fp.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang Q, Feng L. Protective effect of polaprezinc on acute gastric mucosal injury in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2019;28;44(1):22–27. https://doi.org/10.11817/j.issn.1672-7347.2019.01.004.

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Acknowledgments

This work was supported by state assignment of Research Center of Neurology.

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Authors and Affiliations

  1. Laboratory of Clinical and Experimental neurochemistry, Research Center of Neurology, Volokolamskoe shosse, 80, Moscow, Russian Federation, 125367

    Olga I. Kulikova, Sergey L. Stvolinsky, Olga M. Lopacheva, Ksenia N. Kulichenkova, Alexander V. Lopachev & Tatiana N. Fedorova

  2. N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Leninsky Prospect, 47, Moscow, Russian Federation, 119991

    Vasily A. Migulin

  3. Department of Chemistry of Physiologically Active Substances, Institute of Molecular Genetics of the Russian Academy of Sciences, Kurchatov Square 2, Moscow, Russian Federation, 123182

    Ludmila A. Andreeva & Igor Yu. Nagaev

  4. Moscow Clinical Scientific Center after A.S. Loginov of the Moscow Healthcare Department, Shosse Enthusiasts, 86, Moscow, Russian Federation, 111125

    Irina E. Trubitsina

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  1. Olga I. Kulikova
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  2. Sergey L. Stvolinsky
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  3. Vasily A. Migulin
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Correspondence to Olga I. Kulikova.

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Kulikova, O.I., Stvolinsky, S.L., Migulin, V.A. et al. A new derivative of acetylsalicylic acid and carnosine: synthesis, physical and chemical properties, biological activity. DARU J Pharm Sci 28, 119–130 (2020). https://doi.org/10.1007/s40199-019-00323-x

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