Advertisement

Molecular and Cellular Biochemistry

, Volume 345, Issue 1–2, pp 69–76 | Cite as

Chemical modification of ascorbic acid and evaluation of its lipophilic derivatives as inhibitors of secretory phospholipase A2 with anti-inflammatory activity

  • Riyaz Mohamed
  • K. K. Dharmappa
  • Shaista Tarannum
  • N. M. Jameel
  • S. A. Kannum
  • H. S. Ashrafulla
  • Lokanath Rai
  • Cletus JMD’ Souza
  • M. A. Shekhar
  • Bannikuppe S. Vishwanath
Article

Abstract

The halo 6-fatty acid esters of l-ascorbic acid 3a, 3b and 6-fatty acid esters of l-ascorbic acid 5ag were achieved from l-ascorbic acid 1. Compounds 3a, 3b and 5ag were evaluated for anti-oxidant, anti-lipid peroxidation, and secretory phospholipase A2 (sPLA2) inhibition in vitro, and sPLA2 induced mouse paw edema. All the derivatives retained their anti-oxidant property compared to ascorbic acid at 6 × 10−4M and are good inhibitors of lipid peroxidation at 1 mg ml−1 as evaluated by 2, 2-Diphenyl-1-picrylhydrazyl radical and thio-barbituric acid methods, respectively. Compounds 5e and 5f significantly inhibited purified group I sPLA2 from Naja naja and group II sPLA2 from Vipera russelli, human synovial fluid and human pleural fluid with IC50 value ranging from 64 ± 1.95 to 82 ± 1.3 and 48 ± 2.27 to 61 ± 2.23 μM, respectively. The compounds 5e and 5f also showed varying degree of potency in neutralizing indirect hemolytic activity of sPLA2 at 50 μM concentration, and sPLA2 induced mouse paw edema at the dose 3 mg/kg. Further docking studies also confirmed that compounds 5e and 5f have maximum interaction with increasing negative energy value. Single molecule possessing both anti-oxidant and anti-inflammatory activities is of great therapeutic significance in inflammatory disorders.

Keywords

6-fatty acid esters of l-ascorbic acid sPLA2 Anti-inflammatory activity Docking Anti-oxidant 

Notes

Acknowledgments

Author expresses his sincere gratitude to the Lady Tata Memorial Trust, Mumbai for financial assistance, and the University of Mysore, Mysore, for providing laboratory facilities. We extend our thanks to Dr. C R Nagendran, Professor (retired), Dept of Botany, University of Mysore for the needful help in english correction.

Supplementary material

11010_2010_561_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 40 kb)

References

  1. 1.
    Burke JE, Dennis EA (2009) Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50 Suppl: S237–S242Google Scholar
  2. 2.
    Diaz BL, Arm JP (2003) Phospholipase A2. Prostaglandins Leukot Essent Fatty Acids 69:87–97CrossRefPubMedGoogle Scholar
  3. 3.
    Mathisen GH, Thorkildsen IH, Paulsen RE (2007) Secretory PLA2-IIA and ROS generation in peripheral mitochondria are critical for neuronal death. Brain Res 1153:43–51CrossRefPubMedGoogle Scholar
  4. 4.
    Kim C, Kim JY, Kim JH (2008) Cytosolic phospholipase A2, lipoxygenase metabolites, and reactive oxygen species. BMB Rep 41:555–559PubMedGoogle Scholar
  5. 5.
    Imai K, Aimoto T, Shima T, Nakashima T, Sato M, Kimura R (2000) Alteration in membrane fluidity of rat liver microsomes and of liposomes by protoporphyrin and its anti-lipid peroxidative effect. Biol Pharm Bull 23:415–419PubMedGoogle Scholar
  6. 6.
    Muralikrishna Adibhatla R, Hatcher JF (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med 40:376–387CrossRefPubMedGoogle Scholar
  7. 7.
    Blanc L, Barres C, Bette-Bobillo P, Vidal M (2007) Reticulocyte-secreted exosomes bind natural IgM antibodies: involvement of a ROS-activatable endosomal phospholipase iPLA2. Blood 110:3407–3416CrossRefPubMedGoogle Scholar
  8. 8.
    Miguel F, Augusto AC, Gurgueira SA (2009) Effect of acute vs chronic H2O2-induced oxidative stress on antioxidant enzyme activities. Free Radic Res 43:340–347CrossRefPubMedGoogle Scholar
  9. 9.
    Keller JN, Mattson MP (1998) Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. Rev Neurosci 9:105–116PubMedGoogle Scholar
  10. 10.
    Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T (1999) Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem 274:2234–2242CrossRefPubMedGoogle Scholar
  11. 11.
    Adibhatla RM, Hatcher JF (2008) Phospholipase A2, reactive oxygen species, and lipid peroxidation in CNS pathologies. BMB Rep 41:560–567PubMedGoogle Scholar
  12. 12.
    Chandra V, Jasti J, Kaur P, Dey S, Srinivasan A, Betzel Ch, Singh TP (2002) Design of specific peptide inhibitors of phospholipase A2: structure of a complex formed between Russell’s viper phospholipase A2 and a designed peptide Leu-Ala-Ile-Tyr-Ser (LAIYS). Acta Crystallogr D Biol Crystallogr 58(Pt 10 Pt 2):1813–1819CrossRefPubMedGoogle Scholar
  13. 13.
    Jameel NM, Frey BM, Frey FJ, Gowda TV, Vishwanath BS (2005) Inhibition of secretory phospholipase A2 enzyme by bilirubin: a new role as endogenous anti-inflammatory molecule. Mol Cell Biochem 276:219–225CrossRefPubMedGoogle Scholar
  14. 14.
    Fawzy AA, Vishwanath BS, Franson RC (1988) Inhibition of human non-pancreatic phospholipases A2 by retinoids and flavonoids. Mechanism of action. Agents Actions 25:394–400CrossRefPubMedGoogle Scholar
  15. 15.
    Jameel NM, Shekhar MA, Vishwanath BS (2006) Alpha-lipoic acid: an inhibitor of secretory phospholipase A2 with anti-inflammatory activity. Life Sci 80:146–153CrossRefPubMedGoogle Scholar
  16. 16.
    Mandl J, Szarka A, Bánhegyi G (2009) Vitamin C: update on physiology and pharmacology. Br J Pharmacol 157:1097–1110CrossRefPubMedGoogle Scholar
  17. 17.
    Song QX, Wei DZ, Zhou WY, Xu WQ, Yang SL (2004) Enzymatic synthesis and antioxidant properties of l-ascorbyl oleate and l-ascorbyl linoleate. Biotechnol Lett 26:1777–1780CrossRefPubMedGoogle Scholar
  18. 18.
    Nanda BL, Nataraju A, Rajesh R, Rangappa KS, Shekar MA, Vishwanath BS (2007) PLA2 mediated arachidonate free radicals: PLA2 inhibition and neutralization of free radicals by anti-oxidants—a new role as anti-inflammatory molecule. Curr Top Med Chem 7:765–777CrossRefPubMedGoogle Scholar
  19. 19.
    Takebayashi J, Tai A, Gohda E, Yamamoto I (2006) Characterization of the radical-scavenging reaction of 2-O-substituted ascorbic acid derivatives, AA-2G, AA-2P, and AA-2S: a kinetic and stoichiometric study. Biol Pharm Bull 29:766–771CrossRefPubMedGoogle Scholar
  20. 20.
    Fang Q, Naidu KA, Naidu KA, Zhao H, Sun M, Dan HC, Nasir A, Kaiser HE, Cheng JQ, Nicosia SV, Coppola D (2006) Ascorbyl stearate inhibits cell proliferation and tumor growth in human ovarian carcinoma cells by targeting the PI3K/AKT pathway. Anticancer Res 26:203–209PubMedGoogle Scholar
  21. 21.
    Raymond CC, Paul AS, Carl hoseney R, Charles WD, Yun YL, Donold WL (1977) Synthesis of 6-fatty acid esters of l-ascorbic acid. J Am Oil Chem Soc 54:308–312CrossRefGoogle Scholar
  22. 22.
    Blois MS (1957) Antioxidant determination by the use of a stable free radical. Nature 181:1199–1200CrossRefGoogle Scholar
  23. 23.
    Halliwell B, Gutteridge JMC (1989) Free radicals in Biology and Medicine, 2nd edn. Clarendon Press, OxfordGoogle Scholar
  24. 24.
    Stefanski E, Pruzanski W, Sternby B, Vadas P (1986) Purification of a soluble phopsholipase A2 from synovial fluid in rheumatoid arthritis. J Biochem 100:1297–1303PubMedGoogle Scholar
  25. 25.
    Kasturi S, Gowda TV (1989) Purification and characterization of a major phopsholipase A2 from Russell’s viper (Vipera russelli) venom. Toxicon 27:229–237CrossRefPubMedGoogle Scholar
  26. 26.
    Rudrammaji LM, Gowda TV (1988) Purification and characterization of three acidic, cytotoxic phospholipase A2 from Indian cobra (Naja naja) venom. Toxicon 36:921–932CrossRefGoogle Scholar
  27. 27.
    Patriarca P, Beckerdite S, Elsbach P (1972) Phospholipases and phospholipid turnover in Escherichia coli spheroplasts. Biochim Biophys Acta 260:593–600PubMedGoogle Scholar
  28. 28.
    Vishwanath BS, Frey FJ, Bradbury MJ, Dallman MF, Frey BM (1993) Glucocorticoid deficiency increases phospholipase A2 activity in rats. J Clin Invest 92:1974–1980CrossRefPubMedGoogle Scholar
  29. 29.
    Boman HG, Kaletta U (1957) Chromatography of rattlesnake venom; a separation of three phosphodiesterases. Biochim Biophys Acta 24:619–631CrossRefPubMedGoogle Scholar
  30. 30.
    Yamakawa MM, Hokama NZ (1976) In: A. Ohsaka, K. Hayashi, Y Sawai (eds) Animal, Plant and microbial toxins, vol 1. Plenum press, New York, p 97Google Scholar
  31. 31.
    Vishwanath BS, Fawzy AA, Franson RC (1988) Edema-inducing activity of phospholipase A2 purified from human synovial fluid and inhibition by aristolochic acid. Inflammation 12:549–561CrossRefPubMedGoogle Scholar
  32. 32.
    Mustard D, Ritchie DW (2005) Docking essential dynamics eigenstructures. Proteins 60:269–274CrossRefPubMedGoogle Scholar
  33. 33.
    Laurie AT, Jackson RM (2005) Q-SiteFinder: an energy-based method for the prediction of protein–ligand binding sites. Bioinformatics 21:1908–1916CrossRefPubMedGoogle Scholar
  34. 34.
    Sun GY, Horrocks LA, Farooqui AA (2007) The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem 103:1–16CrossRefPubMedGoogle Scholar
  35. 35.
    Weber V, Coudert P, Rubat C, Duroux E, Leal F, Couquelet J (2000) Antioxidant properties of novel lipophilic ascorbic acid analogues. J Pharm Pharmacol 52:523–530CrossRefPubMedGoogle Scholar
  36. 36.
    Vishwanath BS, Kini RM, Gowda TV (1987) Characterization of three edema-inducing phospholipase A2 enzymes from habu (Trimeresurus flavoviridis) venom and their interaction with the alkaloid aristolochic acid. Toxicon 25:501–515CrossRefPubMedGoogle Scholar
  37. 37.
    Dharmappa KK, Mohamed R, Shivaprasad HV, Vishwanath BS (2010) Genistein, a potent inhibitor of secretory phospholipase A2: a new insight in down regulation of inflammation. Inflammopharmacol 18:25–31CrossRefGoogle Scholar
  38. 38.
    Virupakshaiah DBM, Chandrakanth K, Rachanagouda P, Prasad H (2007) Computer Aided Docking Studies on Antiviral Drugs for SARS. Proceedings of world academy of science, engineering and technology 24: 307–6884Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Riyaz Mohamed
    • 1
  • K. K. Dharmappa
    • 1
  • Shaista Tarannum
    • 1
  • N. M. Jameel
    • 2
  • S. A. Kannum
    • 3
  • H. S. Ashrafulla
    • 4
  • Lokanath Rai
    • 5
  • Cletus JMD’ Souza
    • 1
  • M. A. Shekhar
    • 2
    • 6
  • Bannikuppe S. Vishwanath
    • 1
  1. 1.Department of Studies in BiochemistryUniversity of MysoreMysoreIndia
  2. 2.Chowdaiah Medical Centre and Apoorva Diabetes Foundation, Centre for Diabetes Care and ResearchMysoreIndia
  3. 3.Department of ChemistryYuvarajas collegeMysoreIndia
  4. 4.Volvox TechnologiesHassanIndia
  5. 5.Department of Studies in ChemistryUniversity of MysoreMysoreIndia
  6. 6.Department of EndocrinologyMysore Medical College and Research InstituteMysoreIndia

Personalised recommendations