Evaluation of Acetylcholinesterase and Prolyl Oligopeptidase Inhibition of Novel Amino acid-functionalized Stigmasterol and Ursolic Acid Derivatives

Author(s): Nalin Seixas, Ionara I. Dalcol*, Bruno Ravanello, Keiti Alessio, Fábio A. Duarte, Vanessa Bender, Ademir F. Morel

Journal Name: Current Organic Chemistry

Volume 23 , Issue 19 , 2019

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Graphical Abstract:


Triterpenes and phytosterols are classes of natural compounds widespread in plants possessing a great number of pharmacological activities. In our continued search for new compounds from natural sources with pharmacological potential, we prepared a series of novel stigmasterol and ursolic acid (UA) derivatives by coupling with L-proline, L-cysteine and L-glutamic acid. Unlike stigmasterol, the eight derivatives obtained showed good inhibitory capacity against acetylcholinesterase (AChE) or prolyl oligopeptidase (POP). Among these derivatives, we highlight 3 and 5 with IC50 values of 99.0 ± 8.8 and 97.5 ± 5.0 µM against AChE, respectively, and derivative 8 with a POP IC50 value of 75.7 ± 6.3 µM. The ursolic acid derivative 19 was the most promising compound of its class, with IC50 against AChE of 98.3 ± 7.7 µM. These results demonstrate that simple structural modifications on triterpenes and phytosterols can enhance their performance as enzymatic inhibitors.

Keywords: Sterols, triterpenes, stigmasterol derivatives, ursolic acid derivatives, acetylcholinesterase, prolyl oligopeptidase.

Kaur, N.; Chaudhary, J.; Jain, A.; Kishore, L. Stigmasterol: A comprehensive review. Int. J. Pharm. Sci. Res., 2011, 2, 2259-2265.
López-Hortas, L.; Pérez-Larrán, P.; González-Muñoz, M.J.; Falqué, E.; Domínguez, H. Recent developments on the extraction and application of ursolic acid. A review. Food Res. Int., 2018, 103, 130-149.
[http://dx.doi.org/10.1016/j.foodres.2017.10.028] [PMID: 29389599]
Hac-Wydro, K.; Wydro, P.; Jagoda, A.; Kapusta, J. The study on the interaction between phytosterols and phospholipids in model membranes. Chem. Phys. Lipids, 2007, 150(1), 22-34.
[http://dx.doi.org/10.1016/j.chemphyslip.2007.06.211] [PMID: 17632093]
Hartmann, M.A. Plant sterols and the membrane environment. Trends Plant Sci. Rev., 1998, 3, 170-175.
Valitova, J.N.; Minibayeva, F.V.; Kotlova, E.R.; Novikov, A.V.; Shavarda, A.L.; Murtazina, L.I.; Ryzhkina, I.S. Effects of sterol-binding agent nystatin on wheat roots: The changes in membrane permeability, sterols and glycoceramides. Phytochemistry, 2011, 72(14-15), 1751-1759.
[http://dx.doi.org/10.1016/j.phytochem.2011.06.004] [PMID: 21726881]
Gnoatto, S.C.B.; Dassonville-Klimpt, A.; Da Nascimento, S.; Galéra, P.; Boumediene, K.; Gosmann, G.; Sonnet, P.; Moslemi, S. Evaluation of ursolic acid isolated from Ilex paraguariensis and derivatives on aromatase inhibition. Eur. J. Med. Chem., 2008, 43(9), 1865-1877.
[http://dx.doi.org/10.1016/j.ejmech.2007.11.021] [PMID: 18192087]
Venugopal, R.; Liu, R.H. Phytochemicals in diets for breast cancer prevention: The importance of resveratrol and ursolic acid. Food Sci. Hum. Wellness, 2012, 1, 1-13.
Gabay, O.; Sanchez, C.; Salvat, C.; Chevy, F.; Breton, M.; Nourissat, G.; Wolf, C.; Jacques, C.; Berenbaum, F. Stigmasterol: A phytosterol with potential anti-osteoarthritic properties. Osteoarthritis Cartilage, 2010, 18(1), 106-116.
[http://dx.doi.org/10.1016/j.joca.2009.08.019] [PMID: 19786147]
Kurek, A.; Nadkowska, P.; Pliszka, S.; Wolska, K.I. Modulation of antibiotic resistance in bacterial pathogens by Oleanolic acid and ursolic acid. Phytomedicine, 2012, 19(6), 515-519.
[http://dx.doi.org/10.1016/j.phymed.2011.12.009] [PMID: 22341643]
Lee, S.Y.; Kim, Y.J.; Chung, S.O.; Park, S.U. Recent studies on ursolic acid and its biological and pharmacological activity. EXCLI J., 2016, 15, 221-228.
[PMID: 27231476]
Liu, J. Oleanolic acid and ursolic acid: Research perspectives. J. Ethnopharmacol., 2005, 100(1-2), 92-94.
[http://dx.doi.org/10.1016/j.jep.2005.05.024] [PMID: 15994040]
Gade, S.; Rajamanikyam, M.; Vadlapudi, V.; Nukala, K.M.; Aluvala, R.; Giddigari, C.; Karanam, N.J.; Barua, N.C.; Pandey, R.; Upadhyayula, V.S.V.; Sripadi, P.; Amanchy, R.; Upadhyayula, S.M. Acetylcholinesterase inhibitory activity of stigmasterol & hexacosanol is responsible for larvicidal and repellent properties of Chromolaena odorata. Biochim. Biophys. Acta, Gen. Subj., 2017, 1861(3), 541-550.
[http://dx.doi.org/10.1016/j.bbagen.2016.11.044] [PMID: 27916676]
Öztürk, M.; Kolak, U.; Topçu, G.; Öksüz, S.; Choudhary, M.I. Antioxidant and anticholinesterase active constituents from Micromeria cilicica by radical-scavenging activity-guided fractionation. Food Chem., 2011, 126, 31-38.
Rahman, A.; Zareen, S.; Choudhary, M.I.; Ngounou, F.N.; Yasin, A.; Parvez, M.; Terminalin, A. A novel triterpenoid from Terminalia glaucescens. Tetrahedron Lett., 2002, 43, 6233-6236.
Richmond, V.; Garrido Santos, G.A.; Murray, A.P.; Maier, M.S. Synthesis and acetylcholinesterase inhibitory activity of 2β,3α-disulfoxy-5α-cholestan-6-one. Steroids, 2011, 76(10-11), 1160-1165.
[http://dx.doi.org/10.1016/j.steroids.2011.05.005] [PMID: 21640741]
Yoon, Y.N.; Chung, H.Y.; Kim, H.R.; Choi, J.S. Acetyl- and butyrylcholinesterase inhibitory activities of sterols and phlorotannins from Ecklonia stolonifera. Fish. Sci., 2008, 74, 200-207.
Hyde, C.; Peters, J.; Bond, M.; Rogers, G.; Hoyle, M.; Anderson, R.; Jeffreys, M.; Davis, S.; Thokala, P.; Moxham, T. Evolution of the evidence on the effectiveness and cost-effectiveness of acetylcholinesterase inhibitors and memantine for Alzheimer’s disease: Systematic review and economic model. Age Ageing, 2013, 42(1), 14-20.
[http://dx.doi.org/10.1093/ageing/afs165] [PMID: 23179169]
Siatka, T.; Adamcová, M.; Opletal, L.; Cahlíková, L.; Jun, D.; Hrabinová, M.; Kuneš, J.; Chlebek, J. Cholinesterase and prolyl oligopeptidase inhibitory activities of alkaloids from Argemone platyceras (Papaveraceae). Molecules, 2017, 22(7), 1-14.
[http://dx.doi.org/10.3390/molecules22071181] [PMID: 28708094]
Jalkanen, A.J.; Leikas, J.V.; Forsberg, M.M. Prolyl oligopeptidase inhibition decreases extracellular acetylcholine levels in rat hippocampus and prefrontal cortex. Neurosci. Lett., 2014, 579, 110-113.
[http://dx.doi.org/10.1016/j.neulet.2014.07.026] [PMID: 25064702]
Orhan, I.E. Current concepts on selected plant secondary metabolites with promising inhibitory effects against enzymes linked to Alzheimer’s disease. Curr. Med. Chem., 2012, 19(14), 2252-2261.
[http://dx.doi.org/10.2174/092986712800229032] [PMID: 22414107]
Akhtar, M.N.; Lam, K.W.; Abas, F. Maulidiani.; Ahmad, S.; Shah, S.A.; Atta-Ur-Rahman.; Choudhary, M.I.; Lajis, N.H. New class of acetylcholinesterase inhibitors from the stem bark of Knema laurina and their structural insights. Bioorg. Med. Chem. Lett., 2011, 21(13), 4097-4103.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.065] [PMID: 21641207]
Filho, A.G.; Morel, A.F.; Adolpho, L.; Ilha, V.; Giralt, E.; Tarragó, T.; Dalcol, I.I. Inhibitory effect of verbascoside isolated from Buddleja brasiliensis Jacq. ex Spreng on prolyl oligopeptidase activity. Phytother. Res., 2012, 26(10), 1472-1475.
[http://dx.doi.org/10.1002/ptr.4597] [PMID: 22275311]
Sowndhararajan, K.; Deepa, P.; Kim, M.; Park, S.J.; Kim, S. Neuroprotective and cognitive enhancement potentials of baicalin: A review. Brain Sci., 2018, 8(6), 104.
[http://dx.doi.org/10.3390/brainsci8060104] [PMID: 29891783]
Dufourc, E.J. Sterols and membrane dynamics. J. Chem. Biol., 2008, 1(1-4), 63-77.
[http://dx.doi.org/10.1007/s12154-008-0010-6] [PMID: 19568799]
Pripp, A.H. Quantitative structure-activity relationship of prolyl oligopeptidase inhibitory peptides derived from β-casein using simple amino acid descriptors. J. Agric. Food Chem., 2006, 54(1), 224-228.
[http://dx.doi.org/10.1021/jf0521303] [PMID: 16390203]
Tarragó, T.; Frutos, S.; Rodriguez-Mias, R.A.; Giralt, E. Identification by 19F NMR of traditional chinese medicinal plants possessing prolyl oligopeptidase inhibitory activity. ChemBioChem, 2006, 7(5), 827-833.
[http://dx.doi.org/10.1002/cbic.200500424] [PMID: 16628753]
Lawandi, J.; Toumieux, S.; Seyer, V.; Campbell, P.; Thielges, S.; Juillerat-Jeanneret, L.; Moitessier, N. Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors. J. Med. Chem., 2009, 52(21), 6672-6684.
[http://dx.doi.org/10.1021/jm901013a] [PMID: 19888757]
Marques, M.R.; Stüker, C.; Kichik, N.; Tarragó, T.; Giralt, E.; Morel, A.F.; Dalcol, I.I. Flavonoids with prolyl oligopeptidase inhibitory activity isolated from Scutellaria racemosa Pers. Fitoterapia, 2010, 81(6), 552-556.
[http://dx.doi.org/10.1016/j.fitote.2010.01.018] [PMID: 20117183]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7, 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
Toide, K.; Iwamoto, Y.; Fujiwara, T.; Abe, H. JTP-4819: A novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer. J. Pharmacol. Exp. Ther., 1995, 274(3), 1370-1378.
[PMID: 7562510]
Park, Y.; Jang, H.; Paik, Y. Prolyl endopeptidase inhibitory activity of ursolic and oleanolic acids from Corni fructus. Agric. Chem. Biotechnol., 2005, 48, 207-212.
Haffner, C.D.; Diaz, C.J.; Miller, A.B.; Reid, R.A.; Madauss, K.P.; Hassell, A.; Hanlon, M.H.; Porter, D.J.T.; Becherer, J.D.; Carter, L.H. Pyrrolidinyl pyridone and pyrazinone analogues as potent inhibitors of prolyl oligopeptidase (POP). Bioorg. Med. Chem. Lett., 2008, 18(15), 4360-4363.
[http://dx.doi.org/10.1016/j.bmcl.2008.06.067] [PMID: 18606544]
Ma, C.M.; Cai, S.Q.; Cui, J.R.; Wang, R.Q.; Tu, P.F.; Hattori, M.; Daneshtalab, M. The cytotoxic activity of ursolic acid derivatives. Eur. J. Med. Chem., 2005, 40(6), 582-589.
[http://dx.doi.org/10.1016/j.ejmech.2005.01.001] [PMID: 15922841]

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Year: 2019
Page: [2131 - 2140]
Pages: 10
DOI: 10.2174/1385272823666191014154939
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