Structure-activity relationships of flavonoids

Current Organic Chemistry

Volumn 15, Issue 15, 2011, Pages 2641-2657

  Jacob, Vaya ^a,b   Hagai, Tavori ^a,b   Soliman, Khatib ^a,b  

^a MIGAL GALILEE TECHNOLOGY CENTER   (Israel)

^b TEL HAI COLLEGE   (Israel)

Author keywords

Antioxidants; Flavonoids; Phytoestrogen; Protein interaction; Whitening agent

Indexed keywords

EID: 79960026678     PISSN: 13852728     EISSN: None     Source Type: Journal    
DOI: 10.2174/138527211796367309     Document Type: Article

References (168)

1. Usui, T. Pharmaceutical prospects of phytoestrogens. Endocr J, 2006, 53, 7-20.
2. Limouzin-Lamothe, M.A.; Mairon, N.; Joyce, C.R.; Le Gal, M. Quality of life after the menopause: influence of hormonal replacement therapy. Am JObstet Gynecol, 1994, 170, 618-624.
3. Manolagas, S.C.; Kousteni, S.; Jilka, R.L. Sex steroids and bone. RecentProg Horm Res, 2002, 57, 385-409.
4. Sourander, L.; Rajala, T.; Raiha, I.; Makinen, J.; Erkkola, R.; Helenius, H.Cardiovascular and cancer morbidity and mortality and sudden cardiac deathin postmenopausal women on oestrogen replacement therapy (ERT). Lancet,1998, 352, 1965-1969.
5. Rossouw, J.E.; Anderson, G.L.; Prentice, R.L.; LaCroix, A.Z.; Kooperberg, C.; Stefanick, M.L.; Jackson, R.D.; Beresford, S.A.; Howard, B.V.; Johnson, K.C.; Kotchen, J.M.; Ockene, J. Risks and benefits of estrogen plus progestinin healthy postmenopausal women: principal results From the Women'sHealth Initiative randomized controlled trial. Jama, 2002, 288, 321-333.
6. Beral, V.; Banks, E.; Reeves, G. Effects of estrogen-only treatment in postmenopausalwomen. Jama, 2004, 292, 684; author reply 685-686.
7. Fournier, A.; Berrino, F.; Clavel-Chapelon, F. Unequal risks for breast cancerassociated with different hormone replacement therapies: results from theE3N cohort study. Breast Cancer Res Treat, 2008, 107, 103-111.
8. Katzenellenbogen, J.A.; Katzenellenbogen, B.S. Nuclear hormone receptors:ligand-activated regulators of transcription and diverse cell responses. ChemBiol, 1996, 3, 529-536.
9. Mangelsdorf, D.J.; Thummel, C.; Beato, M.; Herrlich, P.; Schutz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M.; Chambon, P.; et al. Thenuclear receptor superfamily: the second decade. Cell, 1995, 83, 835-839.
10. Kuiper, G.G.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van derSaag, P.T.; van der Burg, B.; Gustafsson, J.A. Interaction of estrogenicchemicals and phytoestrogens with estrogen receptor beta. Endocrinology,1998, 139, 4252-4263.
11. Barkhem, T.; Carlsson, B.; Nilsson, Y.; Enmark, E.; Gustafsson, J.; Nilsson, S. Differential response of estrogen receptor alpha and estrogen receptor betato partial estrogen agonists/antagonists. Mol Pharmacol, 1998, 54, 105-112.
12. Sotoca, A.M.; Ratman, D.; van der Saag, P.; Strom, A.; Gustafsson, J.A.; Vervoort, J.; Rietjens, I.M.; Murk, A.J. Phytoestrogen-mediated inhibition ofproliferation of the human T47D breast cancer cells depends on the ERalpha/ERbeta ratio. J Steroid Biochem Mol Biol, 2008, 112, 171-178.
13. Nilsson, S.; Makela, S.; Treuter, E.; Tujague, M.; Thomsen, J.; Andersson, G.; Enmark, E.; Pettersson, K.; Warner, M.; Gustafsson, J.A. Mechanisms ofestrogen action. Physiol Rev, 2001, 81, 1535-1565.
14. Sporn, M.B.; Dowsett, S.A.; Mershon, J.; Bryant, H.U. Role of raloxifene inbreast cancer prevention in postmenopausal women: clinical evidence andpotential mechanisms of action. Clin Ther, 2004, 26, 830-840.
15. Muthyala, R.S.; Ju, Y.H.; Sheng, S.; Williams, L.D.; Doerge, D.R.; Katzenellenbogen, B.S.; Helferich, W.G.; Katzenellenbogen, J.A. Equol, a natural estrogenicmetabolite from soy isoflavones: convenient preparation and resolutionof R- and S-equols and their differing binding and biological activitythrough estrogen receptors alpha and beta. Bioorg Med Chem, 2004, 12,1559-1567.
16. Meyers, M.J.; Sun, J.; Carlson, K.E.; Katzenellenbogen, B.S.; Katzenellenbogen, J.A. Estrogen receptor subtype-selective ligands: asymmetric synthesisand biological evaluation of cis- and trans-5,11-dialkyl- 5,6,11, 12-tetrahydrochrysenes. J Med Chem, 1999, 42, 2456-2468.
17. Sun, J.; Meyers, M.J.; Fink, B.E.; Rajendran, R.; Katzenellenbogen, J.A.; Katzenellenbogen, B.S. Novel ligands that function as selective estrogens orantiestrogens for estrogen receptor-alpha or estrogen receptor-beta. Endocrinology,1999, 140, 800-804.
18. Collins, B.M.; McLachlan, J.A.; Arnold, S.F. The estrogenic and antiestrogenicactivities of phytochemicals with the human estrogen receptor expressedin yeast. Steroids, 1997, 62, 365-372.
19. Singh, A.K. Development of QSAR models to predict estrogenic, carcinogenic,and cancer protective effects of phytoestrogens. Cancer Invest, 2001,19, 201-216.
20. Miksicek, R.J. Estrogenic flavonoids: structural requirements for biologicalactivity. Proc Soc Exp Biol Med, 1995, 208, 44-50.
21. Fang, H.; Tong, W.; Perkins, R.; Soto, A.M.; Prechtl, N.V.; Sheehan, D.M. Quantitative comparisons of in vitro assays for estrogenic activities. Environ Health Perspect, 2000, 108, 723-729.
22. Tamir, S.; Eizenberg, M.; Somjen, D.; Stern, N.; Shelach, R.; Kaye, A.; Vaya, J. Estrogenic and antiproliferative properties of glabridin from licoricein human breast cancer cells [In Process Citation]. Cancer Res, 2000, 60,5704-5709.
23. Branham, W.S.; Dial, S.L.; Moland, C.L.; Hass, B.S.; Blair, R.M.; Fang, H.; Shi, L.; Tong, W.; Perkins, R.G.; Sheehan, D.M. Phytoestrogens and mycoestrogensbind to the rat uterine estrogen receptor. J Nutr, 2002, 132, 658-664.
24. Ofir, R.; Tamir, S.; Khatib, S.; Vaya, J. Inhibition of serotonin re-uptake bylicorice constituents. J Mol Neurosci, 2003, 20, 135-140.
25. Somjen, D.; Knoll, E.; Vaya, J.; Stern, N.; Tamir, S. Estrogen-like activity oflicorice root constituents: glabridin and glabrene, in vascular tissues in vitroand in vivo. J Steroid Biochem Mol Biol, 2004, 91, 147-155.
26. Egner, U.; Heinrich, N.; Ruff, M.; Gangloff, M.; Mueller-Fahrnow, A.; Wurtz, J.M. Different ligands-different receptor conformations: modeling ofthe hER alpha LBD in complex with agonists and antagonists. Med Res Rev,2001, 21, 523-539.
27. Vaya, J.; Tamir, S. The relation between the chemical structure of flavonoidsand their estrogen-like activities. Curr Med Chem, 2004, 11, 1333-1343.
28. Belinky, P.A.; Aviram, M.; Fuhrman, B.; Rosenblat, M.; Vaya, J. The antioxidativeeffects of the isoflavan glabridin on endogenous constituents ofLDL during its oxidation. Atherosclerosis, 1998, 137, 49-61.
29. Suetsugi, M.; Su, L.; Karlsberg, K.; Yuan, Y.C.; Chen, S. Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. MolCancer Res, 2003, 1, 981-991.
30. Santell, R.C.; Chang, Y.C.; Nair, M.G.; Helferich, W.G. Dietary genisteinexerts estrogenic effects upon the uterus, mammary gland and the hypothalamic/pituitary axis in rats. J Nutr, 1997, 127, 263-269.
31. Glazier, M.G.; Bowman, M.A. A review of the evidence for the use of phytoestrogensas a replacement for traditional estrogen replacement therapy. Arch Intern Med, 2001, 161, 1161-1172.
32. Miller, C.P.; Collini, M.D.; Harris, H.A. Constrained phytoestrogens andanalogues as ERbeta selective ligands. Bioorg Med Chem Lett, 2003, 13,2399-2403.
33. De Angelis, M.; Stossi, F.; Waibel, M.; Katzenellenbogen, B.S.; Katzenellenbogen, J.A. Isocoumarins as estrogen receptor beta selective ligands: Isomersof isoflavone phytoestrogens and their metabolites. Bioorg Med Chem,2005, 13, 6529-6542.
34. Takeuchi, S.; Takahashi, T.; Sawada, Y.; Iida, M.; Matsuda, T.; Kojima, H. Comparative study on the nuclear hormone receptor activity of various phytochemicalsand their metabolites by reporter gene assays using Chinesehamster ovary cells. Biol Pharm Bull, 2009, 32, 195-202.
35. Kitaoka, M.; Kadokawa, H.; Sugano, M.; Ichikawa, K.; Taki, M.; Takaishi, S.; Iijima, Y.; Tsutsumi, S.; Boriboon, M.; Akiyama, T. Prenylflavonoids: anew class of non-steroidal phytoestrogen (Part 1). Isolation of 8-isopentenylnaringenin and an initial study on its structure-activity relationship.Planta Med, 1998, 64, 511-515.
36. Wang, Z.Q.; Weber, N.; Lou, Y.J.; Proksch, P. Prenylflavonoids as nonsteroidalphytoestrogens and related structure-activity relationships. ChemMed-Chem, 2006, 1, 482-488.
37. Roelens, F.; Heldring, N.; Dhooge, W.; Bengtsson, M.; Comhaire, F.; Gustafsson, J.A.; Treuter, E.; De Keukeleire, D. Subtle side-chain modificationsof the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta. J MedChem, 2006, 49, 7357-7365.
38. Zierau, O.; Kretzschmar, G.; Moller, F.; Weigt, C.; Vollmer, G. Time dependencyof uterine effects of naringenin type phytoestrogens in vivo. MolCell Endocrinol, 2008, 294, 92-99.
39. Le Bail, J.C.; Varnat, F.; Nicolas, J.C.; Habrioux, G. Estrogenic and antiproliferativeactivities on MCF-7 human breast cancer cells by flavonoids. CancerLett, 1998, 130, 209-216.
40. Zand, R.S.; Jenkins, D.J.; Diamandis, E.P. Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res Treat, 2000, 62, 35-49.
41. Fang, H.; Tong, W.; Shi, L.M.; Blair, R.; Perkins, R.; Branham, W.; Hass, B.S.; Xie, Q.; Dial, S.L.; Moland, C.L.; Sheehan, D.M. Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens.Chem Res Toxicol, 2001, 14, 280-294.
42. Tamir, S.; Eizenberg, M.; Somjen, D.; Izrael, S.; Vaya, J. Estrogen-likeactivity of glabrene and other constituents isolated from licorice root. J SteroidBiochem Mol Biol, 2001, 78, 291-298.
43. Casini, M.L.; Marelli, G.; Papaleo, E.; Ferrari, A.; D'Ambrosio, F.; Unfer, V. Psychological assessment of the effects of treatment with phytoestrogens onpostmenopausal women: a randomized, double-blind, crossover, placebocontrolledstudy. Fertil Steril, 2006, 85, 972-978.
44. Sharan, K.; Siddiqui, J.A.; Swarnkar, G.; Maurya, R.; Chattopadhyay, N. Role of phytochemicals in the prevention of menopausal bone loss: evidencefrom in vitro and in vivo, human interventional and pharma-cokinetic studies.Curr Med Chem, 2009, 16, 1138-1157.
45. Nagata, C.; Takatsuka, N.; Kawakami, N.; Shimizu, H. Soy product intakeand hot flashes in Japanese women: results from a community-based prospectivestudy. Am J Epidemiol, 2001, 153, 790-793.
46. Krebs, E.E.; Ensrud, K.E.; MacDonald, R.; Wilt, T.J. Phytoestrogens fortreatment of menopausal symptoms: a systematic review. Obstet Gynecol,2004, 104, 824-836.
47. Teede, H.J.; Dalais, F.S.; McGrath, B.P. Dietary soy containing phytoestrogensdoes not have detectable estrogenic effects on hepatic protein synthesisin postmenopausal women. Am J Clin Nutr, 2004, 79, 396-401.
48. Halliwell, B.; Gutteridge, J.M.C. Free radicals in biology and medicine.Oxford: (2nd Ed) dUK Clarendon Press, 1989.
49. Diplock, A.T.; Charleux, J.L.; Crozier-Willi, G.; Kok, F.J.; Rice-Evans, C.; Roberfroid, M.; Stahl, W.; Vina-Ribes, J. Functional food science and defenceagainst reactive oxidative species. Br J Nutr, 1998, 80, S77-112.
50. Pollack, M.; Leeuwenburgh, C. In: Handbook of oxidants and antioxidants inexercise; Sen, C. K.; Packer, L.; Hanninen, O., Eds. Elsevier Science B. V.:1999; Vol. 30, pp. 881-923.
51. Philpott, M.; Lim, C.C.; Ferguson, L.R. Dietary Protection Against FreeRadicals: A Case for Multiple Testing to Establish Structure-activity Relationshipsfor Antioxidant Potential of Anthocyanic Plant Species. Int J MolSci, 2009, 10, 1081-1103.
52. Melidou, M.; Riganakos, K.; Galaris, D. Protection against nuclear DNAdamage offered by flavonoids in cells exposed to hydrogen peroxide: the roleof iron chelation. Free Radic Biol Med, 2005, 39, 1591-1600.
53. Modak, B.; Contreras, M.L.; Gonzalez-Nilo, F.; Torres, R. Structureantioxidantactivity relationships of flavonoids isolated from the resinousexudate of Heliotropium sinuatum. Bioorg Med Chem Lett, 2005, 15, 309-312.
54. Rajendran, M.; Manisankar, P.; Gandhidasan, R.; Murugesan, R. Free radicalsscavenging efficiency of a few naturally occurring flavonoids: a comparativestudy. J Agric Food Chem, 2004, 52, 7389-7394.
55. Dorta, D.J.; Pigoso, A.A.; Mingatto, F.E.; Rodrigues, T.; Prado, I.M.; Helena, A.F.; Uyemura, S.A.; Santos, A.C.; Curti, C. The interaction of flavonoidswith mitochondria: effects on energetic processes. Chem Biol Interact,2005, 152, 67-78.
56. Boerboom, A.M.; Vermeulen, M.; van der Woude, H.; Bremer, B.I.; Lee-Hilz, Y.Y.; Kampman, E.; van Bladeren, P.J.; Rietjens, I.M.; Aarts, J.M. Newly constructed stable reporter cell lines for mechanistic studies on electrophile-responsive element-mediated gene expression reveal a role for flavonoidplanarity. Biochem Pharmacol, 2006, 72, 217-226.
57. Snijman, P.W.; Joubert, E.; Ferreira, D.; Li, X.C.; Ding, Y.; Green, I.R.; Gelderblom, W.C. Antioxidant activity of the dihydrochalcones Aspalathinand Nothofagin and their corresponding flavones in relation to other Rooibos(Aspalathus linearis) Flavonoids, Epigallocatechin Gallate, and Trolox. J Agric Food Chem, 2009, 57, 6678-6684.
58. Vaya, J.; Mahmood, S.; Goldblum, A.; Aviram, M.; Volkova, N.; Shaalan, A.; Musa, R.; Tamir, S. Inhibition of LDL oxidation by flavonoids in relationto their structure and calculated enthalpy. Phytochemistry, 2003, 62, 89-99.
59. Belinky, P.A.; Aviram, M.; Mahmood, S.; Vaya, J. Structural aspects of theinhibitory effect of glabridin on LDL oxidation. Free Radic Biol Med, 1998,24, 1419-1429.
60. Furusawa, M.; Tanaka, T.; Ito, T.; Nishikawa, A.; Yamazaki, N.; Nakaya, K.I.; Matsuura, N.; Tsuchiya, H.; Nagayama, M.; Iinuma, M. Antioxidant Activity of Hydroxyflavonoids J.Health Sci., 2005, 51, 376-378.
61. Bjelakovic, G.; Nikolova, D.; Gluud, L.L.; Simonetti, R.G.; Gluud, C. Antioxidantsupplements for prevention of mortality in healthy participants andpatients with various diseases. Cochrane Database Syst Rev, 2008,CD007176.
62. Spritz, R.A.; Hearing, V.J., Jr. Genetic disorders of pigmentation. Adv HumGenet, 1994, 22, 1-45.
63. Hearing, V.J.; Jimenez, M. Analysis of mammalian pigmentation at themolecular level. Pigment Cell Res, 1989, 2, 75-85.
64. Frenk, E. In: Melasma: New Approaches to treatment. London: MartinDunitz Ltd: 1995; Vol. pp. 9-15.
65. Friedman, M. Food Browning and Its Prevention: An Overview. J AgricFood Chem, 1996, 44, 631-653.
66. Nerya, O.; Ben-Arie, R.; Luzzatto, T.; Musa, R.; Khatib, S.; Vaya, J. Prevention of Agaricus bisporus postharvest browning with tyrosinase inhibitors. Postharvest Biology and Technology, 2006, 39, 272-277.
67. Sanchez-Ferrer, A.; Rodriguez-Lopez, J.N.; Garcia-Canovas, F.; Garcia-Carmona, F. Tyrosinase: a comprehensive review of its mechanism. BiochimBiophys Acta, 1995, 1247, 1-11.
68. Seo, S.Y.; Sharma, V.K.; Sharma, N. Mushroom tyrosinase: recent prospects.J Agric Food Chem, 2003, 51, 2837-2853.
69. Asanuma, M.; Miyazaki, I.; Ogawa, N. Dopamine- or L-DOPA-inducedneurotoxicity: the role of dopamine quinone formation and tyrosinase in amodel of Parkinson's disease. Neurotox Res, 2003, 5, 165-176.
70. Xu, Y.; Stokes, A.H.; Roskoski, R., Jr.; Vrana, K.E. Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase. J Neurosci Res, 1998, 54, 691-697.
71. Maeda, K.; Fukuda, M. In vitro of serval whitening cosmetic components inhuman melanocytes. J. Soc. Cosmet. Chem., 1991, 42, 361-368.
72. Chang, T.S. An updated review of tyrosinase inhibitors. Int J Mol Sci, 2009,10, 2440-2475.
73. Brown, J.P. A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat Res, 1980, 75, 243-277.
74. Deschner, E.E.; Ruperto, J.; Wong, G.; Newmark, H.L. Quercetin and rutinas inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis,1991, 12, 1193-1196.
75. Elangovan, V.; Sekar, N.; Govindasamy, S. Chemopreventive potential ofdietary bioflavonoids against 20-methylcholanthrene-induced tumorigenesis[published erratum appears in Cancer Lett 1995 Jan 6; 88(1):119-20]. CancerLett, 1994, 87, 107-113.
76. Ferrandiz, M.L.; Alcaraz, M.J. Anti-inflammatory activity and inhibition ofarachidonic acid metabolism by flavonoids. Agents Actions, 1991, 32, 283-288.
77. Middleton, E., Jr.; Kandaswami, C. Effects of flavonoids on immune andinflammatory cell functions. Biochem Pharmacol, 1992, 43, 1167-1179.
78. Takahama, U. Inhibition of lipoxygenase-dependent lipid per-oxidation byquercetin: Mechanism of antioxidative function. Phytochemistry, 1985, 27,1443-1446.
79. Wilcox, D.E.; Porras, A.G.; Hwang, Y.T.; Lerch, K.; Winkler, M.E.; Solomon, E.I. Substrate analogue binding to the coupled binuclear copper activesite in tyrosinase. J. Am. Chem. Soc., 1985, 107, 4015-4027.
80. Xie, L.P.; Chen, Q.X.; Huang, H.; Wang, H.Z.; Zhang, R.Q. Inhibitoryeffects of some flavonoids on the activity of mushroom tyrosinase. Biochemistry(Mosc), 2003, 68, 487-491.
81. Kubo, I.; Kinst-Hori, I. Flavonols from saffron flower: tyrosinase inhibitoryactivity and inhibition mechanism. J Agric Food Chem, 1999, 47, 4121-4125.
82. Thompson, M.; Williams, C.R.; Elliot, G.E. Stability of flavonoid complexesof copper(II) and flavonoid antioxidant activity. Anal Chim Acta, 1976, 85,375-381.
83. Kubo, I.; Kinst-Hori, I.; Chaudhuri, S.K.; Kubo, Y.; Sanchez, Y.; Ogura, T. Flavonols from Heterotheca inuloides: tyrosinase inhibitory activity andstructural criteria. Bioorg Med Chem, 2000, 8, 1749-1755.
84. Gutteridge, S.; Robb, D. The catecholase activity of Neurospora tyrosinase.Eur J Biochem, 1975, 54, 107-116.
85. Matsuda, H.; Higashino, M.; Chen, W.; Tosa, H.; Iinuma, M.; Kubo, M. Studies of cuticle drugs from natural sources. III. Inhibitory effect of Myricarubra on melanin biosynthesis. Biol Pharm Bull, 1995, 18, 1148-1150.
86. An, S.M.; Kim, H.J.; Kim, J.E.; Boo, Y.C. Flavonoids, taxifolin and luteolinattenuate cellular melanogenesis despite increasing tyrosinase protein levels.Phytother Res, 2008, 22, 1200-1207.
87. Miyazawa, M.; Tamura, N. Inhibitory compound of tyrosinase activity fromthe sprout of Polygonum hydropiper L. (Benitade). Biol Pharm Bull, 2007,30, 595-597.
88. Zheng, Z.P.; Cheng, K.W.; To, J.T.; Li, H.; Wang, M. Isolation of tyrosinaseinhibitors from Artocarpus heterophyllus and use of its extract as antibrowningagent. Mol Nutr Food Res, 2008, 52, 1530-1538.
89. Jeong, S.H.; Ryu, Y.B.; Curtis-Long, M.J.; Ryu, H.W.; Baek, Y.S.; Kang, J.E.; Lee, W.S.; Park, K.H. Tyrosinase inhibitory polyphenols from roots of Morus lhou. J Agric Food Chem, 2009, 57, 1195-1203.
90. Yokota, T.; Nishio, H.; Kubota, Y.; Mizoguchi, M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res, 1998, 11, 355-361.
91. Kim, D.; Park, J.; Kim, J.; Han, C.; Yoon, J.; Kim, N.; Seo, J.; Lee, C. Flavonoidsas mushroom tyrosinase inhibitors: a fluorescence quenching study.J Agric Food Chem, 2006, 54, 935-941.
92. Chang, T.S. Two potent suicide substrates of mushroom tyrosinase: 7,8,4'-trihydroxyisoflavone and 5,7,8,4'-tetrahydroxyisoflavone. J Agric Food Chem, 2007, 55, 2010-2015.
93. Chang, T.S.; Ding, H.Y.; Lin, H.C. Identifying 6,7,4'-trihydroxyisoflavone asa potent tyrosinase inhibitor. Biosci Biotechnol Biochem, 2005, 69, 1999-2001.
94. Chang, T.S.; Ding, H.Y.; Tai, S.S.K.Y.W.C. Mushroom tyrosinase inhibitory effects of isoflavones isolated from soygerm koji fermented with Aspergillusoryzae BCRC 32288. Food Chemistry, 2007, 105, 1430-1438.
95. Nerya, O.; Vaya, J.; Musa, R.; Izrael, S.; Ben-Arie, R.; Tamir, S. Glabreneand isoliquiritigenin as tyrosinase inhibitors from licorice roots. J Agric FoodChem, 2003, 51, 1201-1207.
96. Khatib, S.; Nerya, O.; Musa, R.; Shmuel, M.; Tamir, S.; Vaya, J. Chalconesas potent tyrosinase inhibitors: the importance of a 2,4-substituted resorcinolmoiety. Bioorg Med Chem, 2005, 13, 433-441.
97. Nerya, O.; Musa, R.; Khatib, S.; Tamir, S.; Vaya, J. Chalcones as potenttyrosinase inhibitors: the effect of hydroxyl positions and numbers. Phytochemistry,2004, 65, 1389-1395.
98. Star, A.E.; Mabry, T.J. Flavonoid frond exudates from two Jamaican frens,Pityrogramma tartarea and P. calomelanos. Phytochemistry, 1971, 10,2812-2817.
99. Stevens, J.F.; Taylor, A.W.; Nickerson, G.B.; Ivancic, M.; Henning, J.; Haunold, A.; Deinzer, M.L. Prenylflavonoid variation in Humulus lupulus:distribution and taxonomic significance of xanthogalenol and 4'-Omethylxanthohumol.Phytochemistry, 2000, 53, 759-775.
100. Khatib, S.; Nerya, O.; Musa, R.; Tamir, S.; Peter, T.; Vaya, J. Enhancedsubstituted resorcinol hydrophobicity augments tyrosinase inhibition potency. J Med Chem, 2007, 50, 2676-2681.
101. 1 virus neuraminidase inhibitors. Eur J Med Chem, 45, 1724-1730.
102. Nicolle, E.; Boumendjel, A.; Macalou, S.; Genoux, E.; Ahmed-Belkacem, A.; Carrupt, P.A.; Di Pietro, A. QSAR analysis and molecular modeling ofABCG2-specific inhibitors. Adv Drug Deliv Rev, 2009, 61, 34-46.
103. Wright, B.; Moraes, L.A.; Kemp, C.F.; Mullen, W.; Crozier, A.; Lovegrove, J.A.; Gibbins, J.M. A structural basis for the inhibition of collagenstimulatedplatelet function by quercetin and structurally related flavonoids. Br J Pharmacol, 159, 1312-1325.
104. Androutsopoulos, V.P.; Papakyriakou, A.; Vourloumis, D.; Tsatsakis, A.M.; Spandidos, D.A. Dietary flavonoids in cancer therapy and prevention: substratesand inhibitors of cytochrome P450 CYP1 enzymes. Pharmacol Ther,126, 9-20.
105. Wong, Y.C.; Zhang, L.; Lin, G.; Zuo, Z. Structure-activity relationships ofthe glucuronidation of flavonoids by human glucuronosyltransferases. ExpertOpin Drug Metab Toxicol, 2009, 5, 1399-1419.
106. Gomes, A.; Fernandes, E.; Lima, J.L.; Mira, L.; Corvo, M.L. Molecular mechanisms of anti-inflammatory activity mediated by flavonoids. Curr Med Chem, 2008, 15, 1586-1605.
107. Kumazawa, Y.; Kawaguchi, K.; Takimoto, H. Immunomodulating effects of flavonoids on acute and chronic inflammatory responses caused by tumornecrosis factor alpha. Curr Pharm Des, 2006, 12, 4271-4279.
108. Yamada, K.; Tachibana, H.; Matsuo, N.; Nishiyama, K.; Sugano, M. Structure-activity relationship of immuno regulatory factors in foodstuffs. Food Sci. Technol. Res., 1999, 5, 1-8.
109. Yamada, K.; Matsuo, N.; Shoji, K.; Mori, M.; Ueyama, T.; Yunoki, S.; Kaku, S.; Oka, S.; Nishiyama, K.; Nonaka, M.; Tachibana, H.; Sugano, M. In: Functional foods: overview and disease Prevention Shibamoto, T., Ed.:ACS Symposium Series: 1998; Vol. pp.
110. Yamada, K.; Shoji, K.; Mori, M.; Ueyama, T.; Matsuo, N.; Sugano, M. Suppression by flavonoids of histamine and LTB4 release from peritonealexudate cells of Wistar rats. Proceedings of IUFoST '96 Regional Symposium', 1996c, 363-369.
111. Comalada, M.; Ballester, I.; Bailon, E.; Sierra, S.; Xaus, J.; Galvez, J.; deMedina, F.S.; Zarzuelo, A. Inhibition of pro-inflammatory markers in primarybone marrow-derived mouse macrophages by naturally occurring flavonoids:analysis of the structure-activity relationship. Biochem Pharmacol,2006, 72, 1010-1021.
112. Richard, N.; Porath, D.; Radspieler, A.; Schwager, J. Effects of resveratrol, piceatannol, tri-acetoxystilbene, and genistein on the inflammatory responseof human peripheral blood leukocytes. Mol Nutr Food Res, 2005, 49, 431-442.
113. Lindahl, M.; Tagesson, C. Flavonoids as phospholipase A2 inhibitors: importanceof their structure for selective inhibition of group II phospholipase A2.Inflammation, 1997, 21, 347-356.
114. Bas, E.; Recio, M.C.; Giner, R.M.; Manez, S.; Cerda-Nicolas, M.; Rios, J.L. Anti-inflammatory activity of 5-O-demethylnobiletin, a polymethoxyflavoneisolated from Sideritis tragoriganum. Planta Med, 2006, 72, 136-142.
115. Chi, Y.S.; Jong, H.G.; Son, K.H.; Chang, H.W.; Kang, S.S.; Kim, H.P.Effects of naturally occurring prenylated flavonoids on enzymes metabolizingarachidonic acid: cyclooxygenases and lipoxygenases. Biochem Pharmacol,2001, 62, 1185-1191.
116. Kim, H.P.; Son, K.H.; Chang, H.W.; Kang, S.S. Anti-inflammatory plantflavonoids and cellular action mechanisms. J Pharmacol Sci, 2004, 96, 229-245.
117. Takano-Ishikawa, Y.; Goto, M.; Yamaki, K. Structure-activity relations ofinhibitory effects of various flavonoids on lipopolysaccharide-induced prostaglandinE2 production in rat peritoneal macrophages: comparison betweensubclasses of flavonoids. Phytomedicine, 2006, 13, 310-317.
118. Cho, H.; Yun, C.W.; Park, W.K.; Kong, J.Y.; Kim, K.S.; Park, Y.; Lee, S.; Kim, B.K. Modulation of the activity of pro-inflammatory enzymes, COX-2and iNOS, by chrysin derivatives. Pharmacol Res, 2004, 49, 37-43.
119. Aviram, M.; Kaplan, M.; Rosenblat, M.; Fuhrman, B. Dietary antioxidantsand paraoxonases against LDL oxidation and atherosclerosis development.Handb Exp Pharmacol, 2005, 263-300.
120. Grassi, D.; Desideri, G.; Croce, G.; Tiberti, S.; Aggio, A.; Ferri, C. Flavonoids,vascular function and cardiovascular protection. Curr Pharm Des,2009, 15, 1072-1084.
121. Dembinska-Kiec, A.; Mykkanen, O.; Kiec-Wilk, B.; Mykkanen, H. Antioxidant phytochemicals against type 2 diabetes. Br J Nutr, 2008, 99 E Suppl 1,ES109-117.
122. Perez-Vizcaino, F.; Ibarra, M.; Cogolludo, A.L.; Duarte, J.; Zaragoza-Arnaez, F.; Moreno, L.; Lopez-Lopez, G.; Tamargo, J. Endotheliumindependentvasodilator effects of the flavonoid quercetin and its methylatedmetabolites in rat conductance and resistance arteries. J Pharmacol ExpTher, 2002, 302, 66-72.
123. Kim, H.K.; Cheon, B.S.; Kim, Y.H.; Kim, S.Y.; Kim, H.P. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cellline RAW 264.7 and their structure-activity relationships. Biochem Pharmacol,1999, 58, 759-765.
124. Benavente-Garcia, O.; Castillo, J. Update on uses and properties of citrusflavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem, 2008, 56, 6185-6205.
125. Curtiss, L.K. Reversing atherosclerosis? N Engl J Med, 2009, 360, 1144-1146.
126. Steffen, Y.; Gruber, C.; Schewe, T.; Sies, H. Mono-O-methylated flavanolsand other flavonoids as inhibitors of endothelial NADPH oxidase. Arch BiochemBiophys, 2008, 469, 209-219.
127. Nishikawa, H.; Wakano, K.; Kitani, S. Inhibition of NADPH oxidasesubunits translocation by tea catechin EGCG in mast cell. Biochem Biophys Res Commun, 2007, 362, 504-509.
128. Xu, J.W.; Ikeda, K.; Yamori, Y. Genistein inhibits expressions of NADPHoxidase p22phox and angiotensin II type 1 receptor in aortic endothelial cellsfrom stroke-prone spontaneously hypertensive rats. Hypertens Res, 2004, 27,675-683.
129. Jeon, Y.H.; Heo, Y.S.; Kim, C.M.; Hyun, Y.L.; Lee, T.G.; Ro, S.; Cho, J.M. Phosphodiesterase: overview of protein structures, potential therapeutic applicationsand recent progress in drug development. Cell Mol Life Sci, 2005,62, 1198-1220.
130. Dell'Agli, M.; Galli, G.V.; Bosisio, E. Inhibition of cGMP phosphodiesterase-5 by biflavones of Ginkgo biloba. Planta Med, 2006, 72,468-470.
131. Ferrell, J.E., Jr.; Chang Sing, P.D.; Loew, G.; King, R.; Mansour, J.M.; Mansour, T.E. Structure/activity studies of flavonoids as inhibitors of cyclicAMP phosphodiesterase and relationship to quantum chemical indices. MolPharmacol, 1979, 16, 556-568.
132. Chan, A.L.; Huang, H.L.; Chien, H.C.; Chen, C.M.; Lin, C.N.; Ko, W.C. Inhibitory effects of quercetin derivatives on phosphodiesterase isozymesand high-affinity [(3) H]-rolipram binding in guinea pig tissues. Invest New Drugs, 2008, 26, 417-424.
133. Peluso, M.R. Flavonoids attenuate cardiovascular disease, inhibit phosphodiesterase, and modulate lipid homeostasis in adipose tissue and liver. Exp Biol Med (Maywood), 2006, 231, 1287-1299.
134. Navab, M.; Berliner, J.A.; Watson, A.D.; Hama, S.Y.; Territo, M.C.; Lusis, A.J.; Shih, D.M.; Van Lenten, B.J.; Frank, J.S.; Demer, L.L.; Edwards, P.A.; Fogelman, A.M. The Yin and Yang of oxidation in the development of thefatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture.Arterioscler Thromb Vasc Biol, 1996, 16, 831-842.
135. Aviram, M.; Rosenblat, M.; Bisgaier, C.L.; Newton, R.S.; Primo-Parmo, S.L.; La Du, B.N. Paraoxonase inhibits high-density lipoprotein oxidationand preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest, 1998, 101, 1581-1590.
136. Mackness, M.I.; Mackness, B.; Durrington, P.N.; Connelly, P.W.; Hegele, R.A. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins.Curr Opin Lipidol, 1996, 7, 69-76.
137. Rozenberg, O.; Shih, D.M.; Aviram, M. Human serum paraoxonase 1 decreasesmacrophage cholesterol biosynthesis: possible role for its phospholipase-A2-like activity and lysophosphatidylcholine formation. ArteriosclerThromb Vasc Biol, 2003, 23, 461-467.
138. Tavori, H.; Aviram, M.; Khatib, S.; Musa, R.; Nitecki, S.; Hoffman, A.; Vaya, J. Human carotid atherosclerotic plaque increases oxidative state ofmacrophages and low-density lipoproteins, whereas paraoxonase 1 (PON1)decreases such atherogenic effects. Free Radic Biol Med, 2009, 46, 607-615.
139. Marsillach, J.; Mackness, B.; Mackness, M.; Riu, F.; Beltran, R.; Joven, J.; Camps, J. Immunohistochemical analysis of paraoxonases-1, 2, and 3 expressionin normal mouse tissues. Free Radic Biol Med, 2008, 45, 146-157.
140. Jarvik, G.P.; Rozek, L.S.; Brophy, V.H.; Hatsukami, T.S.; Richter, R.J.; Schellenberg, G.D.; Furlong, C.E. Paraoxonase (PON1) phenotype is a betterpredictor of vascular disease than is PON1(192) or PON1(55) genotype. ArteriosclerThromb Vasc Biol, 2000, 20, 2441-2447.
141. Martinelli, N.; Girelli, D.; Olivieri, O.; Guarini, P.; Bassi, A.; Trabetti, E.; Friso, S.; Pizzolo, F.; Bozzini, C.; Tenuti, I.; Annarumma, L.; Schiavon, R.; Franco Pignatti, P.; Corrocher, R. Novel serum paraoxonase activity assaysare associated with coronary artery disease. Clin Chem Lab Med, 2009, 47,432-440.
142. Karabina, S.A.; Lehner, A.N.; Frank, E.; Parthasarathy, S.; Santanam, N. Oxidative inactivation of paraoxonase--implications in diabetes mellitus andatherosclerosis. Biochim Biophys Acta, 2005, 1725, 213-221.
143. Mackness, M.I.; Mackness, B.; Durrington, P.N. Paraoxonase and coronaryheart disease. Atheroscler Suppl, 2002, 3, 49-55.
144. Inoue, M.; Suehiro, T.; Nakamura, T.; Ikeda, Y.; Kumon, Y.; Hashimoto, K. Serum arylesterase/diazoxonase activity and genetic polymorphisms in patientswith type 2 diabetes. Metabolism, 2000, 49, 1400-1405.
145. Dantoine, T.F.; Debord, J.; Charmes, J.P.; Merle, L.; Marquet, P.; Lachatre, G.; Leroux-Robert, C. Decrease of serum paraoxonase activity in chronic renalfailure. J Am Soc Nephrol, 1998, 9, 2082-2088.
146. Tanimoto, N.; Kumon, Y.; Suehiro, T.; Ohkubo, S.; Ikeda, Y.; Nishiya, K.; Hashimoto, K. Serum paraoxonase activity decreases in rheumatoid arthritis.Life Sci, 2003, 72, 2877-2885.
147. Khateeb, J.; Gantman, A.; Kreitenberg, A.J.; Aviram, M.; Fuhrman, B. Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranatepolyphenols: a role for PPAR-gamma pathway. Atherosclerosis,2010, 208, 119-125.
148. Fuhrman, B.; Volkova, N.; Aviram, M. Pomegranate juice polyphenolsincrease recombinant paraoxonase-1 binding to high-density lipoprotein:studies in vitro and in diabetic patients. Nutrition, 26, 359-366.
149. Pinent, M.; Castell, A.; Baiges, I.; Montagut, G.; Arola, L.; Ardevol, A. Bioactivity of flavonoids on insulin-secreting cells. Comprehensive ReviewsIn Food Science And Food Safety, 2008, 7, 299-308.
150. Jayaprakasam, B.; Vareed, S.K.; Olson, L.K.; Nair, M.G. Insulin secretion bybioactive anthocyanins and anthocyanidins present in fruits. J Agric FoodChem, 2005, 53, 28-31.
151. Soto, C.; Mena, R.; Luna, J.; Cerbon, M.; Larrieta, E.; Vital, P.; Uria, E.; Sanchez, M.; Recoba, R.; Barron, H.; Favari, L.; Lara, A. Silymarin inducesrecovery of pancreatic function after alloxan damage in rats. Life Sci, 2004,75, 2167-2180.
152. Coskun, O.; Kanter, M.; Korkmaz, A.; Oter, S. Quercetin, a flavonoid antioxidant,prevents and protects streptozotocin-induced oxidative stress andbeta-cell damage in rat pancreas. Pharmacol Res, 2005, 51, 117-123.
153. Kim, S.J.; Son, K.H.; Chang, H.W.; Kang, S.S.; Kim, H.P. Tyrosinase inhibitoryprenylated flavonoids from Sophora flavescens. Biol Pharm Bull, 2003,26, 1348-1350.
154. Kwon, O.; Eck, P.; Chen, S.; Corpe, C.P.; Lee, J.H.; Kruhlak, M.; Levine, M. Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FasebJ, 2007, 21, 366-377.
155. Noriega-Lopez, L.; Tovar, A.R.; Gonzalez-Granillo, M.; Hernandez-Pando, R.; Escalante, B.; Santillan-Doherty, P.; Torres, N. Pancreatic insulin secretionin rats fed a soy protein high fat diet depends on the interaction betweenthe amino acid pattern and isoflavones. J Biol Chem, 2007, 282, 20657-20666.
156. Lopez-Lazaro, M. Flavonoids as anticancer agents: structure-activity relationshipstudy. Curr Med Chem Anticancer Agents, 2002, 2, 691-714.
157. Martinez, C.; Yanez, J.; Vicente, V.; Alcaraz, M.; Benavente-Garcia, O.; Castillo, J.; Lorente, J.; Lozano, J.A. Effects of several polyhydroxylated flavonoidson the growth of B16F10 melanoma and Melan-a melanocyte celllines: influence of the sequential oxidation state of the flavonoid skeleton.Melanoma Res, 2003, 13, 3-9.
158. Rodriguez, J.; Yanez, J.; Vicente, V.; Alcaraz, M.; Benavente-Garcia, O.; Castillo, J.; Lorente, J.; Lozano, J.A. Effects of several flavonoids on thegrowth of B16F10 and SK-MEL-1 melanoma cell lines: relationship betweenstructure and activity. Melanoma Res, 2002, 12, 99-107.
159. Manthey, J.A.; Guthrie, N. Antiproliferative activities of citrus flavonoidsagainst six human cancer cell lines. J Agric Food Chem, 2002, 50, 5837-5843.
160. Hirano, T.; Gotoh, M.; Oka, K. Natural flavonoids and lignans are potentcytostatic agents against human leukemic HL-60 cells. Life Sci, 1994, 55,1061-1069.
161. Kawaii, S.; Tomono, Y.; Katase, E.; Ogawa, K.; Yano, M. Antiproliferative activity of flavonoids on several cancer cell lines. Biosci Biotechnol Biochem, 1999, 63, 896-899.
162. Sanchez, I.; Calderon, J.; Ruiz, B.; Tellez, J.; Calzada, L.; Taboada, J. Invitro cytotoxicity of flavonoids against MK2 and C6 tumour cells. PhytotherRes, 2001, 15, 290-293.
163. Agullo, G.; Gamet-Payrastre, L.; Manenti, S.; Viala, C.; Remesy, C.; Chap, H.; Payrastre, B. Relationship between flavonoid structure and inhibition ofphosphatidylinositol 3-kinase: a comparison with tyrosine kinase and proteinkinase C inhibition. Biochem Pharmacol, 1997, 53, 1649-1657.
164. Casagrande, F.; Darbon, J.M. Effects of structurally related flavonoids oncell cycle progression of human melanoma cells: regulation of cyclindependentkinases CDK2 and CDK1. Biochem Pharmacol, 2001, 61, 1205-1215.
165. Agullo, G.; Gamet-Payrastre, L.; Fernandez, Y.; Anciaux, N.; Demigne, C.; Remesy, C. Comparative effects of flavonoids on the growth, viability andmetabolism of a colonic adenocarcinoma cell line (HT29 cells). Cancer Lett,1996, 105, 61-70.
166. Albini, A.; Tosetti, F.; Benelli, R.; Noonan, D.M. Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res, 2005, 65, 10637-10641.
167. Kim, J.D.; Liu, L.; Guo, W.; Meydani, M. Chemical structure of flavonols inrelation to modulation of angiogenesis and immune-endothelial cell adhesion.J Nutr Biochem, 2006, 17, 165-176.
168. Amic, D.; Davidovic-Amic, D.; Beslo, D.; Rastija, V.; Lucic, B.; Trinajstic, N. SAR and QSAR of the antioxidant activity of flavonoids. Curr MedChem, 2007, 14, 827-845.