Recent Advances in Anti-inflammatory Synthetic Flavonoids as Potential Drugs

  • Kim, Hyun-Pyo (College of Pharmacy, Kangwon National University) ;
  • Park, Hae-Il (College of Pharmacy, Kangwon National University)
  • Received : 2010.03.10
  • Accepted : 2010.05.05
  • Published : 2010.06.30

Abstract

Flavonoids are well-known anti-inflammatory agents that exert their effects via a variety of mechanisms including antioxidative action, inhibition of eicosanoid metabolizing enzymes and regulation of theexpression of proinflammatory molecules. In this review, synthetic approaches to obtain more useful flavonoid derivatives are summarized. Human clinical trials of flavonoid therapy are discussed. Through continual investigation to identify more potent and comparable flavonoids, new anti-inflammatory flavonoid therapy will be successfully launched, especially for the treatment of chronic inflammatory disorders.

Keywords

References

  1. Beck, G., Bergmann, K., Kebeler, K., and Wess, G., Synthesis of a new flavonoid-antioxidant. Tetrahedron Lett., 31, 7293-7296 (1990). https://doi.org/10.1016/S0040-4039(00)88547-0
  2. Boots, A.W., Wilms, L.C., Swennen, E.L.R., Kleinjans, J.C.S., Bast, A., and Haenen, G.R.M.M., In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers. Nutr., 24, 703-710 (2008). https://doi.org/10.1016/j.nut.2008.03.023
  3. Chen, X., Cui, L., Duan, X., Ma, B., and Zhong, D., Pharmacokinetics and metabolism of two flavonoid scutellarin in humans after a single oral administration. Drug Metab. Dispos., 34, 1345-1352 (2006). https://doi.org/10.1124/dmd.106.009779
  4. Cho, H., Yun, C.-W., Park, W.-K., Kong, J.-Y., Kim, K.S., Park, Y., Lee, S., and Kim, B.-K., Modulation of the activity of proinflammatory enzymes, COX-2 and iNOS, by chrysin derivatives. Pharm. Res., 49, 37-43 (2004). https://doi.org/10.1016/S1043-6618(03)00248-2
  5. Chung, M.-I., Han, F.-W., Lin, H.-C., Liou, S.-S., Huang, P.-L., Ko, H.-H., Chang, Y.-L., Kang, J.-J., Teng, C.-M., and Lin, C.-N., Synthesis, antiplatelet and vasorelaxing effects of monooxygenated flavones and flavonoxypropanolamines. J. Pharm. Pharmacol., 53, 1601-1609 (2001). https://doi.org/10.1211/0022357011778205
  6. Conquer, J.A., Maiani, G., Azzini, E., Raguzzini, A., and Holub, B.J., Supplementation with quercetin markedly increase plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J. Nutr., 128, 593-597 (1998). https://doi.org/10.1093/jn/128.3.593
  7. Conti, C., Desideri, N., Orsi, N., Sestili, I., and Stein, M.L., Synthesis and antirhinovirus activity of cyano and amidino substituted flavanoids. Eur. J. Chem., 25, 725-730 (1990). https://doi.org/10.1016/0223-5234(90)90191-5
  8. Cunningham, B.D.M., Threadgill, M.D., Grounwater, P.W., Dale, I.L., and Hickman, J.A., Synthesis and biological evaluation of a series of flavones designed as inhibitors of protein tyrosine kinases. Anti- Cancer Drug Design, 7, 365-384 (1992).
  9. Dao, T.T., Chi, Y.S., Kim, J., Kim, H.P., Kim, S.H., and Park, H., Synthesis and PGE2 inhibitory activity of 5,7-dihydroxyflavones and their O-methylated flavone analogs. Arch. Pharm. Res., 26, 345-350 (2003a). https://doi.org/10.1007/BF02976690
  10. Dao, T.T., Chi, Y.S., Kim, J., Kim, H.P., Kim, S., and Park, H., Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives. Bioorg. Med. Chem. Lett., 14, 1165-1167 (2004). https://doi.org/10.1016/j.bmcl.2003.12.087
  11. Dao, T.T., Oh, J.W., Chi, Y.S., Kim, H.P., Sin, K.-S., and Park, H., Synthesis and PGE2 inhibitory activity of vinylated and allylated chrysin analogues. Arch. Pharm. Res., 26, 581-584 (2003b). https://doi.org/10.1007/BF02976703
  12. 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., and Williamson, G., Quercetin metabolites downregulate cyclooxygenase-2 transcription in human lymphocytes ex vivo but not in vivo. J. Nutr., 134, 552-557 (2004). https://doi.org/10.1093/jn/134.3.552
  13. Edwards, R.L., Lyon, T., Litwin, S.E., Rabousky, A., Symons, J.D., and Jalili, T., Quercetin reduces blood pressure in hypertensive subjects. J. Nutr., 137, 2405-2411 (2007). https://doi.org/10.1093/jn/137.11.2405
  14. Egert, S., Bosy-Westphal, A., Seiberi, J., Kurbitz, C., Settler, U., Plachta- Danielzik, S., Wagner, A.E., Frank, J., Schrezenmeir, J., Rimbach, G., Wolffran, S., and Muller, M.J., Quercetin reduces systolic blood pressure and plasma oxidized low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br. J. Nutr., 102, 1065-1074 (2009). https://doi.org/10.1017/S0007114509359127
  15. Ertan, R., Goker, H., Ertan, M., Beretz, A., Cazenave, J.P., Haag, M., and Anton, R., Synthesis of some flavone derivatives: potent inhibitors of human platelet aggregation. Chimie, 26, 735-738 (1991).
  16. Ferry, D.R., Smith, A., Malkhandi, J., Fyfe, D.W., de Takats, P.G., Anderson, D., Baker, J., and Kerr, D.J., Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clinical Cancer Research, 2, 659-668 (1996).
  17. Filipe, P., Silva, A.M.S., Seixas, R.S.G.R., Pinto, D.C.G.A., Santos, A., Patterson, L.K., Silva, J.N., Cavaleir, J.A.S., Freitas, J.P., Maziere, J.- C., Santus, R., and Morliere, P., The alkyl chain length of 3-alkyl- 3',4',5,7-tetrahydroxyflavones modulates effective inhibition of oxidative damage in biological systems: Illustration with LDL, red blood cells and human keratinocytes. Biochem. Pharmacol., 77, 957- 964 (2009). https://doi.org/10.1016/j.bcp.2008.11.023
  18. Gabor, M., Anti-inflammatory and anti-allergic properties of flavonoids, In Cody et al. (eds.), Plant flavonoids in biology and medicine: Biochemical, pharmacological, and structure-activity relationships, Alan R. Liss, New York, 1986, pp. 471-480.
  19. Gao, H. and Kawabata, J.,$alpha$-Glucosidase inhibition of 6-hydroxyflavones. Part 3: Synthesis and evaluation of 2,3,4-trihydroxybenzoylcontaining flavonoid analogs and 6-aminoflavones as $alpha$-glucosidase inhibitors. Bioorg. Med. Chem., 13, 1661-1671 (2005). https://doi.org/10.1016/j.bmc.2004.12.010
  20. Gugler, R., Leschik, M., and Dengler, H.J., Disposition of quercetin in man after single oral and intraveneous doses. Eur. J. Clin. Pharmacol., 9, 229-234 (1975). https://doi.org/10.1007/BF00614022
  21. Gunnarsson, G.T., Riaz, M., Adams, J., and Desai, U.R., Synthesis of persulfated flavonoids using 2,2,2-trichloroethyl protecting group and their factor Xa inhibition potential. Bioorg. Med. Chem., 13, 1783- 1789 (2005). https://doi.org/10.1016/j.bmc.2004.11.060
  22. Han, C.K., Son, M.J., Chang, H.W., Chi, Y.S., Par, H., and Kim, H.P., Inhibition of prostaglandin production by a structurally-optimized flavonoid derivative, 2',4',7-trimethoxyflavone and cellular action mechanism. Biol. Pharm. Bull., 28, 1366-1370 (2005). https://doi.org/10.1248/bpb.28.1366
  23. Havsteen, B., Flavonoids, a class of natural products of high pharmacological potency. Biochem. Pharmacol., 32, 1141-1148 (1983). https://doi.org/10.1016/0006-2952(83)90262-9
  24. Herencia, F., Ferrandiz, M.L., Ubeda, A., Gwillen, I., Dominguez, J.N., Charris, J.E., Lobo, G.M., and Alcaraz, M.J., Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages. FEBS Lett., 453, 129-134 (1999). https://doi.org/10.1016/S0014-5793(99)00707-3
  25. Hirano, T., Oka, K., Kawashima, E., and Akiba, M., Effects of synthetic and naturally occurring flavonoids on mitogen-induced proliferation of human peripheral-blood lymphocytes. Life Sci., 45, 1407-1441 (1989). https://doi.org/10.1016/0024-3205(89)90028-3
  26. Horie, T., Tsukayama, M., Kourai, H., Yokoyama, C., Furukawa, M., Yoshimoto, T., Yamamoto, S., Waranabe-Kohno, S., and Ohata, K., Synthesis of 5,6,7- and 5,7,8-trioxygenated 3',4'-dihydroxyflavones having alkoxy groups and their inhibitory activities against arachidonate 5-lipoxygenase. J. Med. Chem., 29, 2256-2262 (1986). https://doi.org/10.1021/jm00161a021
  27. Huang, W.-H., Lee, A.-R., Chien, P.-Y., and Chou, T.-Z., Synthesis of baicalein derivatives as potential antiaggregatory and antiinflammatory agents. J. Pharm. Pharmacol., 57, 219-225 (2005). https://doi.org/10.1211/0022357055371
  28. Jang, J., Kim, H.P., and Park, H., Structure and anti-inflammatory activity relationships of wogonin derivatives. Arch. Pharm. Res., 28, 877-884 (2005). https://doi.org/10.1007/BF02973870
  29. Joo, A.H., Kim, J.K., Kang, S.-H., Noh, M.-S., Ha, J.-Y., Choi, J.K., Lim, K.M., Lee, C.H., and Chung, S., 2,3-Diarylbenzopyran derivatives as a novel class of selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett., 13, 413-417 (2003). https://doi.org/10.1016/S0960-894X(02)00952-6
  30. Kim, H.P., Son, K.H., Chang, H.W., and Kang, S.S., Anti-inflammatory flavonoids and cellular action mechanisms. J Pharmacol. Sci., 96, 229-245 (2004a). https://doi.org/10.1254/jphs.CRJ04003X
  31. Kim, S.J., Park, H., and Kim, H.P., Inhibition of nitric oxide production from lipopolysaccharide-treated RAW264.7 cells by synthetic flavones: Structure-activity relationship and action mechanism. Arch. Pharm. Res., 27, 937-943 (2004b). https://doi.org/10.1007/BF02975847
  32. Kim, Y.H., Kim, J., Park, H., and Kim, H.P., Anti-inflammatory activity of the synthetic chalcone derivatives: Inhibition of inducible nitric oxide synthase-catalyzed nitric oxide production from lipopolysaccharidetreated RAW 264.7 cells. Biol. Pharm. Bull., 30, 1450-1455 (2007). https://doi.org/10.1248/bpb.30.1450
  33. Knekt, P., Kumpulainen, J., Jarvinen, R., Rissanen, H., Heliovaara, M., Reunanen, A., Hakulinen, T., and Aromaa, A., Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr., 76, 560-568 (2002). https://doi.org/10.1093/ajcn/76.3.560
  34. Kometani, T., Fukuda, T., Kakuma, T., Kawaguchi, K., Tamura, W., Kumazawa, Y., and Nagata, K., Effects of $\alpha$-glucosylhesperidin, a bioactive food material, on collagen-induced arthritis in mice and rheumatoid arthritis in humans. Immunopharmacol. Immunotoxicol., 30, 117-134 (2008). https://doi.org/10.1080/08923970701812688
  35. Lebeau, J., Furman, C., Bernier, J.-U., Duriez, P., Teissier, E., and Cotelle, N., Antioxidant properties of di-tert-butylhydroxylated flavonoids. Free Rad. Biol. Med., 29, 900-912 (2000). https://doi.org/10.1016/S0891-5849(00)00390-7
  36. Lee, S.J., Baek, H.J., Lee, C.H., and Kim, H.P., Anti-inflammatory activity of isoflavonoids from Pueraria radix and biochanin A derivatives. Arch. Pharm. Res., 17, 31-35 (1994). https://doi.org/10.1007/BF02978244
  37. Levy, R.M., Saikovsky, R., Shmidt, E., Khokhlov, A., and Burnett, B.P., Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study. Nutr. Res., 29, 298-304 (2009). https://doi.org/10.1016/j.nutres.2009.04.003
  38. Liao, H.-L. and Hu, M.-K., Synthesis and anticancer activities of 5,6,7- trimethylbaicalein derivatives. Chem. Pharm. Bull., 52, 462-465 (2004).
  39. Lin, C.-N., Lee, T.-H., Hsu, M.-F., Wang, J.-P., Ko, F.-N., and Teng, C.- M., 2'.5'-Dihydroxychalcone as a potent chemical mediator and cyclooxygenase inhibitor. J. Pharm. Pharmacol., 49, 530-536 (1997). https://doi.org/10.1111/j.2042-7158.1997.tb06837.x
  40. Liu, T., Xu, Z., He, Q., Chen, Y., Yang, B., and Hu, Y., Nitrogencontaining flavonoids as CDK1/cyclin B inhibitors: Design, synthesis, and biological evaluation. Bioorg. Med. Chem. Lett., 17, 278-281 (2007). https://doi.org/10.1016/j.bmcl.2006.07.088
  41. Loke, W.M., Hodgson, J.M., Proudfoot, J.M., McKinly, A.J., Puddey, I.B., and Croft, K.D., Pure dietary flavonoids quercetin and (-)- epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am. J. Clin. Nutr., 88, 1018-1025 (2008). https://doi.org/10.1093/ajcn/88.4.1018
  42. Losiewicz, M.D., Carlson, B.A., Kaur, G., Sausville, E.A., and Worland, P.J., Potent inhibition of CDC2 kinase activity by the flavonoid L86- 8275. Biochem. Biophys. Res. Comm., 201, 589-595 (1994). https://doi.org/10.1006/bbrc.1994.1742
  43. McAnulty, S.R., McAnulty, L.S., Nieman, D.C., Quindry, J.C., Hosick, P.A., Hudson, M.H., Still, L., Henson, D.A., Milne, G.L., Morrow, J.D., Dumke, C.L., Utter, A.C., Triplett, N.T., and Dibarnardi, A., Chronic quercetin ingestion and exercise-induced oxidative damage and inflammation. Appl. Physiol. Nutr. Metab., 33, 254-262 (2008). https://doi.org/10.1139/H07-177
  44. Middleton, E., Kandaswami, C., and Theoharides, T.C., The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol. Rev., 52, 673-751 (2000).
  45. Moon, Y.J., Wang, L., DiCenzo, R., and Morris, M.E., Quercetin pharmacokinetics in humans. Biopharm. Drug. Dispos., 29, 205-217 (2008). https://doi.org/10.1002/bdd.605
  46. Nagai, T., Miyaichi, Y., Tomimori, T., and Yamada, H., Inhibition of mouse liver sialidase by plant flavonoids. Biochem. Biophys. Res. Comm., 163, 25-31 (1989). https://doi.org/10.1016/0006-291X(89)92093-7
  47. Park, H., Dao, T.T., and Kim, H.P., Synthesis and inhibition of PGE2 production of 6,8-disubstituted chrysin derivatives. Eur. J. Med. Chem., 40, 943-948 (2005). https://doi.org/10.1016/j.ejmech.2005.04.013
  48. Quintin, J., Buisson, D., Thoret, S., Cresteil, T., and Lewin, G., Semisynthesis and antiproliferative evaluation of a series of 3'- aminoflavones. Bioorg. Med. Chem. Lett., 19, 3502-3506 (2009). https://doi.org/10.1016/j.bmcl.2009.05.008
  49. Ullmann, U., Metzner, J., Frank, T., Cohn, W., and Riegger, C., Safety, tolerability, and pharmacokinetics of single ascending doses of synthetic genistein (Bonistein) in healthy volunteers. Adv. Ther., 22, 65-78 (2005). https://doi.org/10.1007/BF02850186
  50. Vasquez-Martinez, Y., Ohri, R.V., Kenyon, V., Holman, T.R., and Sepulveda-Boza, S., Structure-activity relationship studies of flavonoids as potent inhibitors of human platelet 12-hLO, reticulocyte 15hLO-1, and prostate epithelial 15hLO-2. Bioorg. Med. Chem., 15, 7408-7425 (2007). https://doi.org/10.1016/j.bmc.2007.07.036
  51. Viola, H., Marder, M., Wasowski, C., Giorgi, O., Paladini, A.C., and Medina, J.H., 6,3'-Dibromoflavone and 6-nitro-3'-bromoflavone: New additions to the 6,3'-disubstituted flavone family of high-affinity ligands of the brain benzodiazepine binding site with agonistic properties. Biochem. Biophys. Res. Comm., 273, 694-698 (2000). https://doi.org/10.1006/bbrc.2000.2979
  52. Wu, E.S.C., Cole, T.E., Davidson, T.A., Blosser, J.C., Borrelli, A.R., Kingsolving, C.R., and Parker, R.B., Flavones. I. Synthesis and antihypertensive activity of 3-phenylflavone-oxopropanolamines without $\beta$-adrenergic receptor antagonism. J. Med. Chem., 30, 788-792 (1987). https://doi.org/10.1021/jm00388a007
  53. Wu, E.S.C., Loch, J.T., Toder, B.H., Borrelli, A.R., Gawlak, D., Radov, L.A., and Gensmantel, N.P., Flavones. 3. Synthesis, biological activities, and conformational analysis of isoflavone derivatives and related compounds. J. Med. Chem., 35, 3519-3525 (1992). https://doi.org/10.1021/jm00097a009
  54. Yahiaoui, S., Fagnere, C., Pouget, C., Buxeraud, J., and Chulia, A.-J., New 7,8-benzoflavanones as potent aromatase inhibitors: Synthesis and biological evaluation. Bioorg. Med. Chem., 16, 1474-1480 (2008). https://doi.org/10.1016/j.bmc.2007.10.057
  55. Yamada, H., Tateishi, M., Harada, K., Ohashi, T., Shimizu, T., Atsumi, T., Komagata, Y., Iijima, H., Komiyama, K., Watanabe, H., Hara, Y., and Ohashi, K., A randomized clinical study of tea catechin inhalation effects on methicillin-resistant Staphylococcus aureus in disabled elderly patients. J. Am. Med. Dir. Assoc., 7, 79-83 (2006). https://doi.org/10.1016/j.jamda.2005.06.002
  56. Yarishkin, O.V., Ryu, H.W., Park, J.-Y., Yang, M.S., Hong, S.-G., and Park, K.H., Sulfonate chalcone as new class voltage-dependent $K^{+}$ channel blocker. Bioorg. Med. Chem. Lett., 18, 137-140 (2008). https://doi.org/10.1016/j.bmcl.2007.10.114