Methylation of Quercetin by Diazomethane and Hypoglycemic Activity of its Tetra- O -Methyl Ether
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METHYLATION OF QUERCETIN BY DIAZOMETHANE AND HYPOGLYCEMIC ACTIVITY OF ITS TETRA-O-METHYL ETHER
E. R. Karimova,1 L. A. Baltina,2* L. V. Spirikhin,2 T. A. Sapozhnikova,2 S. F. Gabdrakhmanova,2 and N. S. Makara2
The tetra-O-methyl ether of quercetin (QU) 3 (54%), 3,7,4′-tri-O-methyl ether 4 (30%), and a previously unreported 3,7,3-tri-O-methyl ether of QU 5 (7%) were obtained via methylation of QU by an excess of diazomethane in dioxane. Their structures were established using 2D NMR (1H–1H COSY, 1H–1H NOESY, 1H– 13C HSQC, 1H–13C HMBC). Tetra-O-methyl ether of QU 3 exhibited pronounced hypoglycemic activity, reduced alloxan-induced hyperglycemia in rats by 44.5% compared to a control, and was 2.7 times more active than QU. Keywords: quercetin, diazomethane, methyl ethers, hypoglycemic activity. Quercetin (QU, 1) is a well-known bioflavonoid with P-vitamin activity [1] combined with antioxidant [2], hepatoprotective [3], antibacterial [4], and antiviral properties [5, 6] and anticancer activity [7, 8]. QU can detoxify carcinogens, cause DNA to deform, and protect cellular membranes from lipid peroxidation [9]. It is used in medicine as a therapeutic and prophylactic agent for diseases associated with disturbed capillary-wall permeability and damage, for liver hypertonia, ischemic cardiac disease and atherosclerosis, myocardial infarct, diabetes mellitus, and other diseases [10–12]. However, the use of QU in medicine and pharmacy is limited by its poor solubility, low bioavailability and permeability through biomembranes, and rapid metabolism in the gastrointestinal tract [13]. Chemical modification of QU is a modern approach to producing new biologically active compounds with improved bioavailability and pharmacological activity. Ether synthesis is a widely used chemical transformation of QU and other bioflavonoids that allows the production of polyphenolic prodrugs capable of penetrating membranes and regenerating the native compounds during in vivo circulation [14]. Addition of lipophilic or mitochondria-seeking groups to the QU phenolic hydroxyls was shown to enhance the cell permeability and membrane affinity, resulting in the improvement of the biochemical and pharmacological parameters [15, 16]. Therefore, methoxylated QU derivatives that were metabolically more stable than the native flavonoid and possessed various types of pharmacological activity seemed especially interesting. Thus, QU penta-O-methyl ether could regulate production of adiponectin, a hormone playing a key role in regulating lipid and glucose metabolism and the destruction of which leads to type 2 diabetes, obesity, atherosclerosis, etc. [15]. Multi-step syntheses of several QU monomethyl ethers, e.g., natural polyphenolic antioxidants 7-O-methyl-QU (rhamnetin), 3′-O-methylQU (isorhamnetin), 4′-O-methyl-QU (tamarixetin), 5-O-methyl-QU (azaleatin) [16, 17], and QU 3,7,4′-tri-O-methyl ether (ayanin) [18], using various protecting groups have been proposed. Previously, one-step methods for preparing penta-O-methyl (2), 3,7,3′,4′-tetra-O-methyl (3
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