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Semisynthesis of Derivatives of Oleanolic Acid from Syzygium Aromaticum and Their Antinociceptive and Anti-Inflammatory Properties

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Semisynthesis of Derivatives of Oleanolic Acid from Syzygium Aromaticum and Their Antinociceptive and Anti-Inflammatory Properties Hindawi Publishing Corporation Mediators of Inflammation Volume 2016, Article ID 8401843, 9 pages http://dx.doi.org/10.1155/2016/8401843 Research Article Semisynthesis of Derivatives of Oleanolic Acid from Syzygium aromaticum and Their Antinociceptive and Anti-Inflammatory Properties Sibusiso Rali,1 Opeoluwa O. Oyedeji,1 Olukayode O. Aremu,2 Adebola O. Oyedeji,3 and Benedicta N. Nkeh-Chungag4 1 Department of Chemistry, Faculty of Science and Agriculture, University of Fort Hare, Private Bag X1314, Alice 5700, South Africa 2Department of Human Biology, Faculty of Health Sciences, Walter Sisulu University, Private Bag X1, Mthatha 5117, South Africa 3Department of Chemical and Physical Sciences, Faculty of Natural Sciences, Walter Sisulu University, Private Bag X1, Mthatha 5117, South Africa 4Department of Biological and Environmental Science, Faculty of Natural Sciences, Walter Sisulu University, Private Bag X1, Mthatha 5117, South Africa Correspondence should be addressed to Opeoluwa O. Oyedeji; [email protected] Received 17 March 2016; Revised 13 May 2016; Accepted 15 May 2016 Academic Editor: Kyung H. Kim Copyright © 2016 Sibusiso Rali et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Oleanolic acid is a pentacyclic triterpenoid compound widely found in plants and well known for its medicinal properties. Oleanolic acid (OA) was isolated from the ethyl acetate extract of Syzygium aromaticum flower buds. Semisynthesis afforded both acetate and ester derivatives. The derived compounds were monitored with thin layer chromatography and confirmed with nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), Fourier infrared (FT-IR) spectroscopy, and melting point (Mp). All these compounds were evaluated for their analgesic and anti-inflammatory properties at a dose of 40 mg/kg. Significant analgesic and anti-inflammatory effects were noted for all OA-derived compounds. In the formalin-induced pain test, the derivatives showed better analgesic effects compared to their precursor, whereas, in the tale flick test, oleanolic acid proved to be superior in analgesic effects compared to all its derivatives with the exception of the acetyl derivative. Acute inflammatory tests showed that acetyl derivatives possessed better anti-inflammatory activity compared to the other compounds. In conclusion, semisynthesis of oleanolic acid yielded several derivatives with improved solubility and enhanced analgesic and anti-inflammatory properties. 1. Introduction chronic liver injury [10], breast cancer [11], inflammation [9], and HIV [12]. Plant secondary metabolites have several properties which Despite the many potential uses of OA, it has not been are useful for the treatment of diseases. Consequently, natural developed into pharmaceuticals due to its instability and low productsplayanessentialroleinenhancingmoderndrug water solubility. Hence, several studies have been designed discovery [1–4]. to modify the structure of OA with the hope of improving Oleanolic acid (3-hydroxy-olea-12-en-28-oic acid, its physical properties for better bioavailability to enhance (OA)) is a well-known pentacyclic triterpenoid isolated from its bioactivity. Moreover, it is clearly demonstrated that the various plants [5, 6]. This compound has shown potent effects chemical structure of oleanolic acid has three “active” sites, against a wide range of pathogens and health conditions [7– the C3 hydroxy, the C12 to C13 double bond, and the C28 9] and has thus held the interest of researchers in the last carboxylic acid [7, 13, 14], which may be chemically modified few decades. OA has shown protection against acute and and thus change its physical and pharmacological effects. 2 Mediators of Inflammation The work described herein focuses on semisynthesis of in pyridine (5 mL) and acetic anhydride (10 mL) was added oleanane-derived compounds and compares their analgesic in a 150 mL round bottom flask. The mixture was stirred ∘ and anti-inflammatory effects with those of oleanolic acid, an for 12 h at room temperature for compound 2 and 0 Cfor isolate of S. aromaticum. compound 5. The product was poured into 100 mL of water and stirred for 2 h to hydrolyze excess acetic anhydride. 2. Material and Method The final product was separated by suction filtration and recrystallized in methanol and, then, purified by column 2.1. Plant Identification. The dried flower buds of S. aro- chromatography to give 92% yield of compound 2 (C32H50O4, maticum were purchased from the spice market in Durban, AOA) and 87% yield of compound 5 (C32H47O4F3,TOA). South Africa, and authenticated in the School of Biological Compound 2 (C32H50O4,AOA)wasawhiteamorphous ∘ −1 and Conservation Sciences, University of KwaZulu-Natal, powder, Mz+ 498, Mp 265-266 C, FT-IR (ATR, ]max cm ): Westville Campus. A voucher specimen number 004 was 3205 (-OH, COOH), 2969–2853 (aliphatic -CH), 1723 (-C=O, deposited at the University Herbarium. COOH), 1680 (-C=O, CH3COOR), 1457 (-C=C), 1008 (-C- 1 O). H-NMR(400MHz,CDCl3): (3H, eight methyl singlets) 2.2. Plant Preparation and Extraction. Dried flower buds of 1.00 s, 1.00 s, 0.91 s, 1.05 s, 1.30 s, 0.92 s, 0.93 s, 2.08 s, (1H, five S. aromaticum (L.) were pulverized into fine powder with methine proton, C3,C5,C9,C12,C18) 4.45, 1.36, 1.60, 5.25, 2.34 an electrical food processor. A powdered sample (1.95 kg) respectively, (2H, twenty methylene proton, C1,C2,C6,C7, was sequentially extracted (twice per solvent) with n-hexane, C11,C15,C16,C19,C21,C22)1.45 ,1.46 ,1.81 ,1.67 ,1.39 , 1.55 ,1.28,1.43,0.91,1.88,1.10,1.66,1.60,1.95, dichloromethane, ethyl acetate, and methanol, respectively. 13 Each solvent extraction used 1500 mL of the solvent with the 1.15 ,1.64,1.23,1.33,1.58,1.67. C-NMR (400 MHz, clovesamplemixtureplacedonashakerforfivedaysafter CDCl3,C1-C2 ): 38.07, 27.66, 80.93, 37.69, 55.29, 18.18, 32.44, which the filtrate was obtained and solvent recovered. Later, 39.28, 47.55, 36.98, 23.39, 122.57, 143.59, 41.59, 27.66, 23.57, 1200mLofthesamesolventwasaddedtothesameclove 46.51, 41.00, 45.84, 30.67,33.79, 32.43, 28.04, 16.66, 15.38, 17.13, sample as before and extracted on a shaker for two days. A 25.88, 182.76, 33.05, 23.57, 171.05, 21.31. well refined solution was filtered and concentrated with a Compound 5 (C32H47O3F3, TOA) was a white crystalline ∘ −1 rotary evaporator and then air-dried at room temperature. compound, Mz+ 552, Mp 271-272 C, FT-IR (ATR, ]max cm ): 3204 (-OH of COOH), 2970 and 2945 (aliphatic -CH), 1771 (-C=O, COOH), 1723 (-C=O, CH3COOR), 1455 (-C=C), 1010 2.3. Isolation Method. The ethyl acetate extract (15.535 g) was 1 loaded into a column for column chromatograph using silica (-C-O). H-NMR(400MHz,CDCl3): (3H, seven methyl gel60(0.063–0.200mm).Thecolumnwaselutedwithaseries protons, C23–C27 and C29-C30) 0.95 s, 0.98 s, 0.93 s, 1.15 s, of solvent mixtures, n-hexane: ethyl acetate (9 : 1, 8 : 2, 7 : 3, 1.29 s, 1.02 s, 1.32 s, (1H, five methine protons,3 C ,C5,C9, 6 : 4, 4 : 6), respectively, and the fractions were visualized on C12,C18),4.73,1.35,1.42,5.30,2.87respectively,(2H,twenty a thin layer chromatography (TLC) plate with anisaldehyde methylene proton, C1,C2,C6,C7,C11,C15,C16,C19,C21,C22) spray reagent. The single spot isolates were characterized for 1.45 ,1.58,1.80,1.61,1.51,1.62,1.36,1.79,2.01 ,2.06,1.94,1.80,1.90,1.91,1.64,1.34,1.52, structural elucidation using MS, Mp, FT-IR, and NMR. 13 The single spot isolate, compound 1 (C30H48O3,OA), 1.45 ,1.91 ,175 . C-NMR (400 MHz, CDCl3,C1-C2 ): was 2.68 g (17.3%) with the following data obtained as a 39.19, 23.85, 86.89, 37.96, 55.54, 18.11, 33.05, 40.97,48.05, 36.95, ∘ white amorphous powder, Mz+ 456, Mp 294-295 C. FT-IR 23.56, 123.69, 143.66, 41.91, 27.87, 23.09, 46.34, 34.76, 45.83, −1 (ATR, ]max cm ): 3404 (-OH), 2941 and 2859 (aliphatic 29.65, 32.48, 32.41, 22.89, 22.38, 15.35, 17.10, 25.90, 187.41, 27.65, -CH), 1717–1690 (-C=O, COOH), 1465 (-C=C), 1032 (-C-O) 27.26, 157.60, 48.04. 1 respectively. H-NMR (400 MHz, CDCl3): (3H, seven methyl protons, C23–C27 and C29-C30) 0.90 s, 0.90 s, 0.89 s, 1.02 s, 3.2. 28-Methyl-3-acetyloleanane (Compound 3) and 28-Meth- 1.31 s, 0.91 s, 0.94 s, (1H, five methine proton, C3,C5,C9, yl-3-trifluoroacetyloleanane (Compound 6). Compounds 3 C12,C18) 3.43, 1.35, 1.63, 5.59, 2.47 respectively, (2H, twenty and 6 were synthesized using the modified procedure doc- methylene proton, C1,C2,C6,C7,C11,C15,C16,C19,C21,C22) umented by Cheng et al. [15]. Acetyl derivatives of OA 1.38 ,1.53 ,1.89 ,1.64 ,1.58 ,1.59 ,1.38 ,1.79 ,2.19 (0.2 g, 0.4 mmol) were methylated by iodomethane (2.0 g), ,2.18 ,1.84 ,1.74 ,1.95 ,1.92 ,1.45 ,1.55 ,1.44 , then sodium carbonate anhydrous (2.0 g) was added to 13 1.55 ,1.78 ,2.08 . C-NMR (400 MHz, CDCl3,C1–C30): stabilizethepH,andthewholesolutionwasdissolvedin 38.41, 27.66, 78.09, 39.28, 55.29, 18.17, 32.52, 47.55, 37.69, 23.39, 40 mL dimethylformamide in 150 mL round bottom flask.
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