槲皮素化学修饰与体内转运过程研究进展

doi:A

摘要/Abstract

摘要： 本文综述了槲皮素的化学修饰和药代动力学等方面的研究进展，为槲皮素的前药分子设计、寻找活性化合物提供科学依据。文献合成的目标产物主要包括槲皮素糖苷等水溶性产物和槲皮素磺酸酯等脂溶性产物，迄今仍未找到药理作用明显，能临床运用的槲皮素修饰物。文献表明槲皮素生物活性低是由于其低的生物利用度，溶解性差与首过效应是影响其生物利用度的主要因素。

关键词: 槲皮素, 化学修饰, 前药, 生物利用度

Abstract: The recent advance of quercetin in the chemical modification and pharmacokinetic are reviewed in order to provide scientific envidences for searching for bioactive compounds and designing prodrug. Target products synthesised include water-soluble products such as quercetin glycosides and other oil-soluble sulfonate products in literature,but the quercetin modifier that can be clinically applied haven’t been found . Documents show that the low biological activity of quercetin is due to its low bioavailability. Poor solubility and first-pass effect are the main factors that affect its bioavailability.

Key words: quercetin, chemical modification, prodrug, bioavailability

中图分类号:

O629.9

彭游,付小兰,陶春元 ,邓泽元. 槲皮素化学修饰与体内转运过程研究进展[J]. 天然产物研究与开发, 2012, 23(3): 398-405.

PENG You, FU Xiao-lan, TAOChun-yuan，DENG Ze-yuan . Research Progress in Chemical Modification and in Vivo Transit Process of Quercetin[J]. NATURAL PRODUCT RESEARCH AND DEVELOPMENT, 2012, 23(3): 398-405.

参考文献

1 Middleton JE,et al.The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev, 2000, 52: 673-751.
2 Zhu ML(朱茉莉),et al.Relation between autophagy and apoptosis of quercetin-Induced death of human breast cancer cell line MCF-7.Chin Pharm J(中国药学杂志), 2010, 45:434-439.
3 Rao MK,Ghosh B.Quercetin inhibits LPS-induced nitric oxide and tumor necrosis factor-a production in murine macrophages.Int J Immunopharmacol,1999,21:435-443.
4 Shen SC,et al.Differential apop tosis-inducing effect of quercetin and its glyco-sides in human promyelo leukemic HL-60 cells by alternative activation of the caspase 3 cascade.J Cell Biochem,2003, 89:1044-1055
5 Boots AW, Haenen GRMM, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol,2008,585:325-337.
6 Moskaug JΦ,et al.Molecular imaging of the biological effects of quercetin and quercetin-rich foods.Mech Ageing Dev,2004,125:315-324.
7 Sestili P,et al.Quercetin prevents DNA single strand breakage and cytotoxicity caused by tert-butylhydroperoxide free radical scavenging versus iron chelating mechanism. Free Radical Biol Med 1998,25:196-200.
8 Yamamoto N,et al.Inhibitory effects of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation in human low-density lipoprotein. Arch Biochem Biophys,999, 372:347-354.
9 Petrick T,et al.A DFT study of reactivity of OH group in quercetin and taxifolin antioxidants: The specificity of 3-OH site.Food Chemistry, 2006, 97: 679- 688.
10 Glasser G,et al.Comparison of antioxidative capacities and inhibitory effects on cholesterol biosynthesis of quercetin and potential metabolites.Phytornedicine, 2002, 9(1): 33-40.
11 Zhao CZ(赵雏中), et al. Quercetin in vivo pharmacokinetics in rabbits.Chin J Pharm (中国药理学报),1993, 4：263-265.
12 Wu XX(伍贤学).Studies on prodrug design and synthesis of bioactive flavonoid quercetin. Chendu: Sichuan University(四川大学), ScM. 2005.
13 Ader P,et al.Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic Biol Med, 2000,28:1056-1067.
14 Chen X,et al.Low bioavailability of quercetin in rats: Contribu- tions by the gut and liver. AAPS Pharm Sci, 2001, 3(3): 1194-1197.
15 Hu LB(胡良彬),Tan ZC(谭主川). Synthesis of tetaacetoxy quercetin. Chin Tradit Herb Drugs(中草药). 1982, 13: 16-19.
16 Barron D, Ibrahim RK.Synthesis of flavonoid sulfates. I. Stepwise sulfation of positions 3, 7 and 4' using N,N'-dicyclohexylcarbodiimide and tetrabutylammonium hydrogen sulfate.Tetrahedron,1987, 43:5197-5202.
17 Demetzos C,et al. Phasetransfer-catalyzed synthesis flavonoid glycosides. Carbahydr Res,1990,207:131-137.
18 Callas P,et al. Synthesis of inositol 2-phosphate-quercetin conjugates.Carbahydr Res, 1996, 292: 83-90.
19 Alluis B,et al. Water-soluble flavol derivates. Helv Chim Acta,2000,83: 428-443.
20 Caldwell ST,et al.Isotopic labelling of quercetin 4-O-beta-D-glucoside. Tetrahedron, 2000, 56: 4101-4106.
21 Yu J(余戟),et al.Preparation and activities of water-soluble derivatives of quercetin. Chin Pharm J(中国药物化学杂志), 1998, 8:287-289.
22 Li HJ(李化军). Studies on the synthesis of the 3-substituted quercetin. Beijing: Academy of Military Medical Sciences of China, PhM. 2004.
23 Sha JQ(沙靖全),et al.Study on the synthesis, characterization and properties of quercetin schiff bases and their metal-complexes.J Jiamusi Univ,Nat Sci (佳木斯大学学报,自科版), 2006, 24: 105-107.
24 Li F(李芳),et al.Synthesis and character iza tion of the chrom ium(Ⅲ) complexes with rutin and quercetin. Chem Res Appl，2009，21:899-902
25 Yu YY(余燕影),et al.Study on Synthesis and Scavenging Radical Activity of Complex Chromium(III) – Quercetin.Food Sci,2006,27(10):29-32.
26 Wu C(吴春),Huang MG(黄梅桂).Study on inhibition effects of quercetin-zinc complex on nitrosamine synthesis in vivo and in vitro.Food Sci, 2007, 28(9), 35-38.
27 Ga XY(贾小燕),et al.Clean ing effects of complex of quercetin andM olybdenum on superox ide an ion and hydroxyl rad ica l.West China J Pharm Sci, 2008, 23 (1) : 42-44.
28 Zhou J(周晶), et al. Synthesis of cpmplexes of quercetin and metal Cd (II) or Sc (III) and their antioxidant research. J Lanzhou Univ ,Nat Sci, 2001,37(1):123-125.
29 Biasutto L,et al. A mitochondriotropic derivative of quercetin: a strategy to increase the effectiveness of polyphenols. J Med Chem, 2007, 50: 241-253.
30 Yu SY(于姝燕),et al. Study on the synthesis of 3-amino carboxylate hydrochloride of quercetin. Chem Res Appl(化学研究与应用), 2008, 20:235-239.
31 Chen XP(陈小平). Quercetin combined ammoniaplatinum anti-cancer drug and its preparation method. CN200810183126.1, 2008-12-12.
32 Zhai GY(翟广玉), et al. Synthesis of quercetinplatinum. CN200810141369.9, 2008-9-16.
33 Yong DQ(雍德卿), Xi YW(席延伟), Zai GX(翟光喜). Study on the physico2chemical properties of quercetin2phospholipid complex. Chin J Biocheml Pharm, 2005, 26(5), 285-287.
34 Guan M(关明),et al.Preparation and physico-chemical properties of quercetin-phosphatidylcholine Compound. Food Sci, 2010,31(2),51-53.
35 Jurd L, Plant polyphenols V. selective alkylation of the 7-Hydroxyl group in polyhydroxyflavones. J Am Chem Soc,1958, 80: 5531-5536.
36 Picq M,et al.O-alkylation dela quercetineet synthese dela tetra O-ethyl-3,7,3',4' O-ethyl [3H]-5 quercetine.Tetrahedron Lett,1984,25:2227-2230.
37 Torre DL,et al.Synthesis of [60]fullerene-quercetin dyads.Tetrahedron Lett,2002,43: 4617-4620.
38 Sun TM(孙铁民),et al.Syntheses of derivatives of 4-alkylam inoalkylquercetin.Chin J Med Chem (中国药物化学杂志),2003,13:345-348.
39 Liu YF(刘玉法),et al.Preparation method of quercetin derivatives and their application. CN200610045292.6, 2006-7-7.
40 Peng Y,et al.Preparation and prodrug studies of quercetin pentabenzensulfonate，YAKUGAKU ZASSHI, 2008,12:1485-1489.
41 Crespy V,et al.Comparison of the intestinal absorption of quercetin, phloretin and their glucosides in rats. J Nutr,2001,131:2109-2114.
42 Ueno I,et al.Metabolic fate of [14C] quercetin in the ACI rat.Jpn J Exp Med,1983,53: 41-50.
43 Mariusz K, Priskula TJ.Quercetin's solubility affects its accumulation in rat plasma after oral administration.J Agric Food Chem,1998, 46:4313-4317.
44 Walle T,et al.Carbon dioxide is the major metabolite of quercetin in humans.J Nutr,2001,131:2648-2652.
45 Gugler R,et al.Disposition of quercetin in man after single oral and intravenous doses.J Eur J Clin Pharmacol,1975, 9:229-234.
46 Zsila F,et al.Probing the binding of the flavonoid, quercetin to human serum albumin by circular dichroism, electronic absorption spectroscopy and molecular modelling methods.Biochem Phannacol,2003,65: 447-456.
47 Day AJ,et al.Conjugation position of quercetin glucuronides and effect on biological activity.Free Radic Biol Med,2000, 29:1234-1243.
48 Manach C,et al.Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties.FEBS Lett, 1998, 426:331-336.
49 Piskula MK,Terao J.Accumulation of (-)-epicatechin metabolites in rat plasma after oral administration and distribution of conjugation enzymes in rat. Tissues.J Nutr,1998,128: 1172-1178.
50 Hollman PC,Katan MB.Bioavailability and health effects of dietary flavonols in man.Arch Toxicol Suppl,1998,20:237-248.

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