Anti-inflammatory Activities and Gastric Ulcer-inducing Properties of Tetraacetylquercetin and Tetrapivaloylquercetin
Quercetin (3,3’4’,5,7-pentahydroxyflavone) has been reported to show anti-inflammatory activity. However, its low oral bioavailability limits the application of quercetin in therapy. Ester derivatives of quercetin have been reported to have higher bioavailability than quercetin. This research aimed to study the anti-inflammatory activities and gastric ulcer-inducing properties of tetraacetylquercetinas well as tetrapivaloylquercetin. Synthesis of tetra-acyl derivatives of quercetin was conducted using acetic anhydride or pivaloyl chloride in the presence of pyridine and the structure was confirmed by 1H-NMR and 13C-NMR spectroscopy as well as elemental analysis. At a dose of 20 mg/kg bw, oral administration of quercetin only showed 20% inhibition activity on carragenan induced rat paw edema, while tetraacetyl and tetrapivaloyl derivatives at equimolar dose showed 11-33% and 5-15% inhibition activity respectively. Contrary to the gastric ulcer healing-promoting action of quercetin, tetraacetylquercetin caused mild gastric ulcers. However, no gastric ulcer was observed after administration of tetrapivaloylquercetin. It was concluded that acylation enhances the anti-inflammatory activity of quercetin but causes mild gastric ulcers in the case of tetraacetylation.
Bellik, Y., Boukraâ, L., Alzahrani, H.A., Bakhotmah, B.A., Abdellah, F., Hammoudi, S.M. & Iguer-Ouada, M., Molecular Mechanism Underlying Anti-Inflammatory and Anti-Allergic Activities of Phytochemicals: An Update, Molecules, 18, pp. 322-353, 2013.
González-Gallego, J., Sánchez-Campos, S. & Tuñón, M.J., Anti-inflammatory Properties of Dietary Flavonoids, Nutr. Hosp., 22(3), pp. 287-293, 2007.
Chen, Y.C., Shen, S.C., Lee, W.R., Hou, W.C., Yang, L.L. & Lee, T.J., Inhibition of Nitric Oxide Synthase Inhibitors and Lipopolysaccharide Induced Inducible NOS and Cyclooxygenase-2 Gene Expressions by Rutin, Quercetin, and Quercetin Pentaacetate in RAW 264.7 Macrophages, J. Cell. Biochem., 82(4), pp. 537-548, 2001.
Guardia, T., Rotelli, A.E., Juarez, A.O. & Pelzer, L.E., Anti-inflammatory Properties of Plant Flavonoids. Effects of Rutin, Quercetin and Hesperidin on Adjuvant Arthritis in Rat, Farmaco, 56(9), pp. 683-687, 2001.
Coşkun, Ő., Kanter, M., Armutçu, F., Çetin, K., Kaybolmaz, B. & Yazgan, Ő., Protective Effects of Quercetin, A Flavonoid Antioxidant, in Absolute Ethanol-Induced Acute Gastric Ulcer, Eur. J. Gen. Med., 1(3), pp. 37-42, 2004.
Peng, Y., Deng, Z. & Whang, C., Preparation and Prodrug Studies of Quercetin Pentabenzensulfonate, Yakugaku Zasshi, 128(2), pp. 1845-1849, 2008.
Beaumont, K., Webster, R., Gardner, I. & Dack, K., Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist, Current Drug Metabolism, 4(6), pp. 461-485, 2003.
Biasutto, L., Marotta, E., De Marchi, U., Zoratti, M. & Paradisi, C., Ester-Based Precursors to Increase the Bioavailability of Quercetin, J. Med. Chem., 50, pp. 241-253, 2007.
Falodun, A. & Agbakwuru, E.O.P., Synthesis of Quercetin tetraacetate, Peoc. Chemical Society of Nigeria, pp. 27-31, 2004.
Mattarei, A., Biasutto, L., Marotta, E., De Marchi, U., Sassi, N., Garbisa, S., Zoratti, M. & Paradisi, C., A Mitochondriotropic Derivative of Quercetin: A Strategy to Increase the Effectiveness of Polyphenols, Chem. Bio. Chem., 9, pp. 2633-2642, 2008.
Morris, C.J. Carrageenan-Induced Paw Edema in the Rat and Mouse, Methods in Molecular Biology, Vol. 225: Inflammation Protocols, Winyard, P.G. & D.A. Willoughby, eds., Humana Press Inc., pp. 115-121, 2003.
Jain, N.K., Patil, C.S., Kartasasmita, R.E., Decker, M., Lehmann, J. & Kulkarni, S.K., Pharmacological Studies on Nitro-Naproxen (Naproxen-2-Nitrooxyethylester), Drug Dev. Res., 61, pp. 66-78, 2004.
Herowati, R., Kartasasmita, R.E., Adnyana, I.K., Harmastuti, N. & Kartawinata, T.G., Anti-inflammatory Activity of Quercetin-3-monoacetate, Selective Acetylation Product of Quercetin, Artocarpus, 8(2), pp. 60-67, 2008.
Posadas, I., Bucci, M., Roviezzo, F., Rossi, A., Parente, L., Sautebin, L. & Cirino, G., Carrageenan-induced Mouse Paw Edema is Biphasic, Age-weight Dependent and Displays Differential Nitric Oxide Cyclooxygenase-2 Expression, British J. of Pharm., 142, pp. 331-338, 2004.
Cermak, R., Landgraf, S. & Wolffram, S., The Bioavailability of Quercetin in Pigs Depends on the Glycoside Moiety and on Dietary Factors, J. Nutr. 133, pp. 2802-2807, 2003.
Williamson, G., Day, A.J., Plumb, G.W. & Couteau, D., Human Metabolic Pathways of Dietary Flavonoids and Cinnamates, Biochem Soc Trans., 28, pp. 16-22, 2000.
Moon, J.H., Tsushida, T., Nakahara, K. & Terao, J., Identification of Quercetin-3-O-β-D-glucuronide as an Antioxidative Metabolite in Rat Plasma After Oral Administration of Quercetin, Free Radic. Biol. Med., 30, pp. 1274-1285, 2001.
De Pascual-Teresa, S., Johnston, K.L., DuPont, M.S., O’Leary, K.A., Needs, P.W., Morgan, L.M., Clifford, M.N., Bao, Y. & Williamson, G., Quercetin Metabolites Down-regulate Cyclooxygenase-2 Transcription in Human Lymphocytes Ex-vivo but not In-vivo, J. Nutr., 134, pp. 552-557, 2004.
Bala, M., Chin, C.N., Logan, A.T., Amin, T., Marnett, L.J., Boutaud, O. & Oates, J.A., Acetylation of Prostaglandin H2 Synthases by Aspirin is Inhibited by Redox Cycling of the Peroxidase, Biochem. Pharmacol., 75(7), pp. 1472-1481, Apr. 2008.
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