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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Anticholinesterase and Antioxidant Activities of Natural Abietane Diterpenoids with Molecular Docking Studies

Author(s): Gülaçtı Topçu*, Atilla Akdemir, Ufuk Kolak, Mehmet Öztürk, Mehmet Boğa, Fatemeh Bahadori and Seda Damla Hatipoğlu Çakmar

Volume 17, Issue 3, 2020

Page: [269 - 284] Pages: 16

DOI: 10.2174/1567205017666200424133534

Price: $65


Background: Alzheimer’s Disease (AD) is one of the most prevalent causes of dementia in the world, and no drugs available that can provide a complete cure. Cholinergic neurons of the cerebral cortex of AD patients are lost due to increased activity of cholinesterase enzymes.

Objective: Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are the two major classes of cholinesterases in the mammalian brain. The involvement of oxidative stress in the progression of AD is known. Thus, the objective of this study is to determine strong ChE inhibitors with anti-oxidant activity.

Methods: In this study, 41 abietane diterpenoids have been assayed for antioxidant and anticholinesterase (both for AChE and BuChE) properties in vitro, which were previously isolated from Salvia species, and structurally determined by spectroscopic methods, particularly intensive 1D- and 2DNMR and mass experiments. Molecular modeling studies were performed to rationalize the in vitro ChE inhibitory activity of several abietane diterpenoids compared with galantamine.

Results: Thirteen out of the tested 41 abietane diterpenoids exhibited at least 50% inhibition on either AChE or BuChE. The strongest inhibitory activity was obtained for Bractealine against BuChE (3.43 μM) and AChE (33.21 μM) while the most selective ligand was found to be Hypargenin E against BuChE enzyme (6.93 μM). A full correlation was not found between anticholinesterase and antioxidant activities. The results obtained from molecular modelling studies of Hypargenin E and Bractealine on AChE and BuChE were found to be in accordance with the in vitro anti-cholinesterase activity tests.

Conclusion: Abietane diterpenoids are promising molecules for the treatment of mild-moderate AD.

Keywords: Alzheimer’s Disease, cholinesterase inhibition, acetylcholinesterase, butyrylcholinesterase, antioxidant, docking studies, abietane diterpenoids, Salvia.

Kenche VB, Barnham KJ. Alzheimer’s disease & metals: therapeutic opportunities. Br J Pharmacol 2011; 163(2): 211-9.
[] [PMID: 21232050]
Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer’s disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 1998; 51(1): S2-S17.
[] [PMID: 9674758]
Farooqui T, Farooqui AA. Aging: an important factor for the pathogenesis of neurodegenerative diseases. Mech Ageing Dev 2009; 130(4): 203-15.
[] [PMID: 19071157]
Giacobini E. Selective inhibitors of butyrylcholinesterase: a valid alternative for therapy of Alzheimer’s disease? Drugs Aging 2001; 18(12): 891-8.
[] [PMID: 11888344]
Siciliano R, Barone E, Calabrese V. Rispoli V, Allan Butterfield D,Mancuso C.Experimental research on nitric oxide and the therapy of Alzheimer disease: a challenging bridge. CNS Neurol Disord Drug Targets 2011; 10(7): 766-76.
Ballard CG. Advances in the treatment of Alzheimer’s disease: benefits of dual cholinesterase inhibition. Eur Neurol 2002; 47(1): 64-70.
[] [PMID: 11803198]
Greig NH, Lahiri DK, Sambamurti K. Butyrylcholinesterase: An important new target in Alzheimer’s disease therapy. Int Psychogeriatr 2002; 14(1): 77-91.
[] [PMID: 12636181]
Savelev S, Okello E, Perry NS, Wilkins RM, Perry EK. Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil. Pharmacol Biochem Behav 2003; 75(3): 661-8.
[] [PMID: 12895684]
Orhan I, Kartal M, Naz Q, Ejaz A, Yilmaz G, Kan Y, et al. Antioxidant and anticholinesterase evaluation of selected Turkish Salvia species. Food Chem 2007; 103(4): 1247-54.
Topcu G, Kusman T. Lamiaceae family plants as a potential anticholinesterase source in the treatment of Alzheimer’s disease. Bezmialem Science 2014; 2(1): 1-25.
Çulhaoğlu B, Yapar G, Dirmenci T, Topçu G. Bioactive constituents of Salvia chrysophylla Stapf. Nat Prod Res 2013; 27(4-5): 438-47.
[] [PMID: 23126495]
Perry NS, Houghton PJ, Sampson J, et al. In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer’s disease. J Pharm Pharmacol 2001; 53(10): 1347-56.
[] [PMID: 11697542]
Howes M-JR, Perry E. The role of phytochemicals in the treatment and prevention of dementia. Drugs Aging 2011; 28(6): 439-68.
[] [PMID: 21639405]
Topcu G, Turkmen Z, Schilling J, Kingston D, Pezzuto J, Ulubelen A. Cytotoxic activity of some Anatolian Salvia extracts and isolated abietane diterpenoids. Pharm Biol 2008; 46(3): 180-4.
Topçu G, Yücer R, Şenol H. Bioactive constituents of anatolian Salvia species Salvia Biotechnology. Springer 2017; pp. 31-132.
Akaberi M, Iranshahi M, Mehri S. Molecular signaling pathways behind the biological effects of Salvia species diterpenes in neuropharmacology and cardiology. Phytother Res 2016; 30(6): 878-93.
[] [PMID: 26988179]
Imanshahidi M, Hosseinzadeh H. The pharmacological effects of Salvia species on the central nervous system. Phytother Res 2006; 20(6): 427-37.
[] [PMID: 16619340]
Topçu G, Öztürk M, Kuşman T, Barla Demirkoz AA, Kolak U, Ulubelen A. Terpenoids, essential oil composition, fatty acid profile, and biological activities of Anatolian Salvia fruticosa Mill. Turk J Chem 2013; 37(4): 619-32.
Topcu G, Altiner EN, Gozcu S, et al. Studies on di- and triterpenoids from Salvia staminea with cytotoxic activity. Planta Med 2003; 69(5): 464-7.
[] [PMID: 12802732]
Ulubelen A, Oksüz S, Topcu G, Gören AC, Voelter W. Antibacterial diterpenes from the roots of Salvia blepharochlaena. J Nat Prod 2001; 64(4): 549-51.
[] [PMID: 11325249]
Ulubelen A, Topcu G. Diterpenoids from Salvia species and their pharmacological activities. Adv Nat Prod Chem 1994; pp. 363-81.
Wu Y-B, Ni Z-Y, Shi Q-W, et al. Constituents from Salvia species and their biological activities. Chem Rev 2012; 112(11): 5967-6026.
[] [PMID: 22967178]
Ulubelen A, Topcu G, Johansson CB. Norditerpenoids and diterpenoids from Salvia multicaulis with antituberculous activity. J Nat Prod 1997; 60(12): 1275-80.
[] [PMID: 9428161]
Sallam A, Mira A, Ashour A, Shimizu K. Acetylcholine esterase inhibitors and melanin synthesis inhibitors from Salvia officinalis. Phytomedicine 2016; 23(10): 1005-11.
[] [PMID: 27444345]
Chan H-H, Hwang T-L, Su C-R, Reddy MVB, Wu T-S. Anti-inflammatory, anticholinesterase and antioxidative constituents from the roots and the leaves of Salvia nipponica Miq. var. formosana. Phytomedicine 2011; 18(2-3): 148-50.
[] [PMID: 21115331]
Topcu G, Kolak U, Ozturk M, et al. Investigation of anticholinesterase activity of a series of Salvia extracts and the constituents of Salvia staminea. Nat Prod J 2013; 3(1): 3-9.
Howes M-JR, Houghton PJ. Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function. Pharmacol Biochem Behav 2003; 75(3): 513-27.
[] [PMID: 12895669]
Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr 2000; 71(2): 621S-9S.
[] [PMID: 10681270]
Kubínová R, Pořízková R, Navrátilová A, et al. Antimicrobial and enzyme inhibitory activities of the constituents of Plectranthus madagascariensis (Pers.) Benth. J Enzyme Inhib Med Chem 2014; 29(5): 749-52.
[] [PMID: 24506206]
Ulubelen A, Oksüz S, Kolak U, Bozok-Johansson C, Çelik C, Voelter W. Antibacterial diterpenes from the roots of Salvia viridis. Planta Med 2000; 66(5): 458-62.
[] [PMID: 10909268]
Ulubelen A, Topcu G, Tan N. Rearranged abietane diterpenes from Salvia candidissima. Phytochemistry 1992; 31(10): 3637-8.
Ulubelen A, Miski M, Mabry T. A new diterpene acid from Salvia tomentosa. J Nat Prod 1981; 44(1): 119-24.
Kolak U, Kabouche A, Oztürk M, Kabouche Z, Topçu G, Ulubelen A. Antioxidant diterpenoids from the roots of Salvia barrelieri. Phytochem Anal 2009; 20(4): 320-7.
[] [PMID: 19402189]
Ulubelen A, Öksüz S, Kolak U, Tan N, Bozok-Johansson C, Çelik C, et al. Diterpenoids from the roots of Salvia bracteata. Phytochemistry 1999; 52(8): 1455-9.
Ulubelen A, Topcu G, Tan N. Diterpenoids from Salvia candidissima. Tetrahedron Lett 1992; 33(47): 7241-4.
Ulubelen A. Euphraticol and euphracal, two new diterpenes from Salvia euphratica. J Nat Prod 1989; 52(6): 1313-5.
Ulubelen A. Cardioactive and antibacterial terpenoids from some Salvia species. Phytochemistry 2003; 64(2): 395-9.
[] [PMID: 12943755]
Kabouche A, Kabouche Z, Öztürk M, Kolak U, Topçu G. Antioxidant abietane diterpenoids from Salvia barrelieri. Food Chem 2007; 102(4): 1281-7.
Ulubelen A, Evren N, Tuzlaci E, Johansson C. Diterpenoids from the roots of Salvia hypargeia. J Nat Prod 1988; 51(6): 1178-83.
[] [PMID: 3236010]
Ulubelen A. Two new diterpenoids from Salvia longipedicellata. Planta Med 1990; 56(3): 329-30.
[] [PMID: 17221431]
Ulubelen A, Topcu G, Sönmez U, Eris C. Terpenoids from Salvia nemorosa. Phytochemistry 1994; 35(4): 1065-7.
Ulubelon A, Tuzlaci E. New diterpenes from Salvia pachystachys. J Nat Prod 1990; 53(6): 1597-9.
Ulubelen A, Topcu G. Abietane diterpenoids from Salvia pomifera. Phytochemistry 1992; 31(11): 3949-51.
Topçu G, Ulubelen A. Terpenoids from Salvia kronenburgii. J Nat Prod 1999; 62(12): 1605-8.
Topcu G, Ulubelen A. Abietane and rearranged abietane diterpenes from Salvia montbretii. J Nat Prod 1996; 59(8): 734-7.
Ulubelen A, Tan N, Topcu G. Terpenoids from Salvia candidissima subsp. candidissima. Phytochemistry 1997; 45(6): 1221-3.
Ulubelen A, Sönmez U, Topcu G. Diterpenoids from the roots of Salvia sclarea. Phytochemistry 1997; 44(7): 1297-9.
Topcu G, Eriş C, Ulubelen A. Rearranged abietane diterpenes from Salvia limbata. Phytochemistry 1996; 41(4): 1143-7.
Topçu G, Kolak U, Balci K, Ulubelen A. Structure elucidation of a new rearranged abietane diterpene from a biologically active plant, Salvia eriophora. Nat Prod Commun 2(10): 981-986 (2007).
Ulubelen A, Birman H, Oksüz S, et al. Cardioactive diterpenes from the roots of Salvia eriophora. Planta Med 2002; 68(9): 818-21.
[] [PMID: 12357394]
Ulubelen A, Topçu G, Sönmez U, Choudhary MI. Abietane diterpenes from Salvia napifolia. Phytochemistry 1995; 40(3): 861-4.
Ulubelen A, Topçu G, Chai H-B, Pezzuto JM. Cytotoxic activity of diterpenoids isolated from Salvia hypargeia. Pharm Biol 1999; 37(2): 148-51.
Ulubelen A. New diterpenoids from the roots of Salvia triloba. Planta Med 1990; 56(1): 82-3.
[] [PMID: 17221372]
Ulubelen A, Topcu G, Chen S, Cai P, Snyder JK. A new abietane diterpene from Salvia wiedemannii Boiss. J Org Chem 1991; 56(26): 7354-6.
Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activityBiochem Pharmacol 1961; 7(2): 88IN191-9095.
Miller H. A simplified method for the evaluation of antioxidants. J Am Oil Chem Soc 1971; 48(2): 91-1.
Blois MS. Antioxidant determinations by the use of a stable free radical. Nature 1958; 181(4617): 1199-200.
Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 1999; 26(9-10): 1231-7.
[] [PMID: 10381194]
Nishikimi M, Appaji N, Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 1972; 46(2): 849-54.
[] [PMID: 4400444]
Labute P. Protonate3D: assignment of ionization states and hydrogen coordinates to macromolecular structures. Proteins 2009; 75(1): 187-205.
[] [PMID: 18814299]
Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997; 267(3): 727-48.
[] [PMID: 9126849]
Phillips JC, Braun R, Wang W, et al. Scalable molecular dynamics with NAMD. J Comput Chem 2005; 26(16): 1781-802.
[] [PMID: 16222654]
Güzel-Akdemir Ö, Angeli A, Demir K, Supuran CT, Akdemir A. Novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group acting as human carbonic anhydrase IX inhibitors. J Enzyme Inhib Med Chem 2018; 33(1): 1299-308.
[] [PMID: 30249139]
Topcu G, Ulubelen A, Tam TC-M, Tao-Che C. Sesterterpenes and other constituents of Salvia yosgadensis. Phytochemistry 1996; 42(4): 1089-92.
Topçu G. Bioactive triterpenoids from Salvia species. J Nat Prod 2006; 69(3): 482-7.
[] [PMID: 16562861]
Öztekin N, Başkan S, Evrim Kepekçi S, Erim FB, Topçu G. Isolation and analysis of bioactive diterpenoids in Salvia species (Salvia chionantha and Salvia kronenburgiii) by micellar electrokinetic capillary chromatography. J Pharm Biomed Anal 2010; 51(2): 439-42.
[] [PMID: 19446421]
D’Ascenzio M, Carradori S, Secci D, et al. Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies. Bioorg Med Chem 2014; 22(15): 3982-8.
[] [PMID: 25027802]
Akdemir A, De Monte C, Carradori S, Supuran CT. Computational investigation of the selectivity of salen and tetrahydrosalen compounds towards the tumor-associated hCA XII isozyme. J Enzyme Inhib Med Chem 2015; 30(1): 114-8.
[] [PMID: 24666302]
Wang X, Morris-Natschke SL, Lee KH. New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev 2007; 27(1): 133-48.
[] [PMID: 16888751]

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