Sesquiterpene Lactones from Cynara cornigera: Acetyl Cholinesterase Inhibition and In Silico Ligand Docking

Abstract

Wild artichoke (Cynara cornigera), a thistle-like perennial belonging to the Asteraceae family, is native to the Mediterranean region, northwestern Africa, and the Canary Islands. While the pleasant, albeit bitter, taste of the leaves and flowers is attributed to the sesquiterpene lactones cynaropicrin and cynarin, a comprehensive phytochemical investigation still needs to be reported. In this study seven sesquiterpene lactones were isolated from an aqueous methanol plant extract, including a new halogenated metabolite (1), the naturally isolated compound sibthorpine (2), and five metabolites isolated for the first time from C. cornigera. Structures were established by spectroscopic methods, including HREIMS, ¹H, ¹³C, DEPT, ¹H-¹H COSY, HMQC, and HMBC-NMR experiments as well as by X-ray analysis. The isolated bioactive nutrients were analyzed for their antioxidant and metal chelating activity. Compound 1 exhibited a potent metal chelating activity as well as a high antioxidant capacity. Moreover, select compounds were effective as acetyl cholinesterase inhibitors presenting the possibility for such compounds to be examined for anti-neurodegenerative activity. A computational pharmacophore elucidation and docking study was performed to estimate the pharmacophoric features and binding conformation of isolated compounds in the acetyl cholinesterase active site.

Key words

Cynara cornigera - Asteraceae - sesquiterpene lactones - acetyl cholinesterase inhibition - in silico ligand docking

• References

• 1 Maros T, Rácz G, Katonai B, Kovács VV. Wirkungen der Cynara scolymus-Extrakte auf die Regeneration der Rattenleber, 1. Arzneimittelforschung 1966; 16: 127
• 2 Kraft K. Artichoke leaf extract – Recent findings reflecting effects on lipid metabolism, liver and gastrointestinal tracts. Phytomedicine 1997; 4: 369-378
• 3 Pittler MH, Ernst E. Artichoke leaf extract for serum cholesterol reduction. Perfusion 1998; 11: 338-340
• 4 Newall CA, Anderson LA, Philipson JD. Herbal medicine – a guide for health-care professionals. London: The Pharmaceutical Press; 1996: 36-37
• 5 Walker AF, Middleton RW, Petrowicz O. Artichoke leaves reduce symptoms of irritable bowel syndrome in a post-markting surveillance study. Phytother Res 2001; 15: 58
• 6 Englisch W, Beckers C, Unkauf M, Ruepp M, Zinserling V. Efficacy of artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittelforschung 2000; 50: 260
• 7 Kirchhoff R, Beckers CH, Kirchhoff GM, Trinezek-Gärtner H, Petrowicz O, Reimann HJ. Increase in choleresis by means of artichoke extract. Phytomedicine 1994; 1: 107-115
• 8 Perez-Garcia F, Adzet T, Canigueral S. Activity of artichoke leaf extract on reactive oxygen species in human leukocytes. Free Radic Res 2000; 33: 661
• 9 Fusco D, Colloca G, Lo Monaco MR, Cesari M. Effects of antioxidant supplementation on the ageing process. Clin Interv Aging 2007; 2: 377-387
• 10 Nie K, Yu JC, Fu Y, Cheng HY, Chen FY, Qu Y, Han JX. Agerelated decrease in constructive activation of Akt/PKB in SAMP10 hippocampus. Biochem Biophys Res Commun 2009; 378: 103-107
• 11 Felder CC, Bymaster FP, Ward J, DeLapp N. Therapeutic opportunities for muscarinic receptors in the central nervous system. J Med Chem 2000; 43: 4333-4353
• 12 Giacobini E. Invited review: cholinesterase inhibitors for Alzheimerʼs disease therapy: from tacrine to future applications. Neurochem Int 1998; 32: 413-419
• 13 Krall WJ, Sramek JJ, Cutler NR. Cholinesterase inhibitors: a therapeutic strategy for Alzheimer disease. Ann Pharmacother 1999; 33: 441-450
• 14 Rollinger JM, Mocka P, Zidorn C, Ellmerer EP, Langer T, Stuppner H. Application of the in combo screening approach for the discovery of non-alkaloid acetylcholinesterase inhibitors from Cichorium intybus . Curr Drug Discov Technol 2005; 2: 185-193
• 15 Elsayed SM, Nazif NM, Hassan RA, Hassanein HD, Elkholy YM, Gomaa NS, Shahat AA. Chemical and biological constituents from the leaf extracts of the wild artichoke (Cynara cornigera). Int J Pharm Pharm Sci 2012; 5: 396-400
• 16 Reis LV, Tavares MR, Brito Palma FMS, Marcelo MJ. Sesquiterpene lactones from Cynara humilis . Phytochemistry 1992; 31: 1285-1287
• 17 Omar AA, Sarg TM, Khafagy SM, Ibrahim YE, Grenz M. Guaianolides from Cynara sibthorpiana . Phytochemistry 1984; 23: 2381-2382
• 18 Barbetti P, Fardella G, Chiappini I, Scarcia V, Candiani AF. New cytotoxic selenoderivatives of guaianolides. Eur J Med Chem 1989; 24: 299-306
• 19 Rustaiyan A, Niknejad A, Zdero C, Bohlman F. A guaianolide from Centaurea behen . Phytochemistry 1981; 20: 2427-2429
• 20 Shimoda H, Ninomiya L, Nishida N, Yoshino T, Morikawa T, Matsuda H, Yoshikawa M. Anti-hyperlipidemic sesquiterpenes and new sesquiterpene glycosides from the leaves of artichoke (Cynara scolymus L.): structure requirement and mode of action. Bioorg Med Chem Lett 2003; 13: 223-228
• 21 Miyase T, Ueno A, Noro T, Kuroyanagi M, Fukushima S. Studies on sesquiterpene glycosides from Crepis japonica Benth. Chem Pharm Bull 1985; 33: 4451-4456
• 22 Gonzalez AG, Bermejo J, Breton JL, Betancor C. Amberboin, a new sesquiterpene lactone from Amberboa lippii D.C. An Quim 1967; 63: 965-966
• 23 Zdero C, Bohlmann F, Wasshausen DC, Mungal MG. Glaucolides from Old World Vernonia species. Phytochemistry 1991; 30: 4025-4028
• 24 Marco JA, Sanz JF, Albiach R, Rustaiyan A, Habibi Z. Bisabolene derivatives and sesquiterpene lactones from Cousinia species. Phytochemistry 1993; 32: 395-400
• 25 Singhal AK, Chowodhury PK, Sharma RP, Baruah JN, Herz W. Guaianolides from Tricholepis glaberrima. Phytochemistry 1982; 21: 462-463
• 26 Sepsova V, Karasova JZ, Korabecny J, Dolezal R, Zemek F, Bennion BJ, Kuca K. Oximes: inhibitors of human recombinant acetylcholinesterase. A structure-activity relationship (SAR) study. Int J Mol Sci 2013; 14: 16882-16900
• 27 Axelsen PH, Harel M, Silman I, Sussman JL. Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-ray crystallography. Protein Sci 1994; 3: 188-197
• 28 Chen D, Pan YF, Li CJ, Xie YF, Jiang YR. Virtual screening of acetylcholinesterase inhibitors. In: Mutasem T, editor Virtual screening. Shanghai: InTech; 2012: 83-91
• 29 Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A 1993; 90: 9031-9035
• 30 Schmidt TJ. Toxic activities of sesquiterpene lactones: structural and biochemical aspects. Curr Org Chem 1999; 3: 577-608
• 31 Ingkaninan K, Temkitthawon P, Chuenchom K, Yuyaem T, Thongnoi W. Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J Ethnopharmacol 2003; 89: 261-264
• 32 Yamaguchi T, Takamura H, Matoba T, Terao J. HPLC method for evaluation of the free radical-scavenging activity of foods by using 1,1,-diphenyl-2-picrylhydrazyl. Biosci Biotechnol Biochem 1998; 62: 1201-1204
• 33 Oktay M, Gülçin I, Küfrevioğlu ÖI. Determination of in vitro antioxidant activity of fennel (Foeniculum vulgare) seed extracts. Lebensm Wiss Technol 2003; 36: 263-271
• 34 Oyaizu M. Studies on products of browning reaction. Antioxidative activities of products of browning reaction prepared from glucosamine. JPN J Nut Diet 1986; 44: 307-331
• 35 Gulcin I, Buyukokuroglu ME, Kufrevioglu OI. Metal chelating and hydrogen peroxide scavenging effects of melatonin. J Pineal Res 2003; 34: 278-281
• 36 Miller NJ, Rice-Evans CA. The relative contributions of ascorbic acid and phenolic antioxidants to the total antioxidant activity of orange and apple fruit juices and blackcurrant drink. Food Chem 1997; 60: 331-337
• 37 Dinis TC, Madeira VM, Almeida LM. Action of phenolic derivatives (acetaminophen, salicylate, and 5-aminosalicylate) as inhibitors of membrane lipid peroxidation and as peroxyl radical scavengers. Arch Biochem Biophys 1994; 315: 161-169