Flavonoids as anticancer agents: Recent progress and state of the art?

Current Organic Chemistry

Volumn 15, Issue 15, 2011, Pages 2608-2615

  Genoux, Estelle ^a   Nicolle, Edwige ^a   Boumendjel, Ahcène ^a  

^a Université Joseph Fourier   (France)

Author keywords

Anticancer potential; Clinical trials; Drug candidates; Flavonoids; Structural analog

Indexed keywords

CELL DEATH; DISEASES;

ANTI-CANCER AGENTS; ANTICANCER DRUG; ANTICANCER POTENTIALS; CLINICAL TRIAL; DRUG CANDIDATES; FLAVONOID; MEDICINAL CHEMISTRY; RECENT PROGRESS; RECENT STATE; STRUCTURAL ANALOGUE;

FLAVONOIDS;

EID: 79960013296     PISSN: 13852728     EISSN: None     Source Type: Journal    
DOI: 10.2174/138527211796367363     Document Type: Review

References (95)

1. Cotelle, N.; Bernien, J. L.; Henichart, J. P.; Gaydou, E.; Wallet, J. C. Scavenger and antioxidant properties of ten synthetic flavones. Free. Rad. Biol. Med., 1992, 13, 211-219.
2. Andersen, Ø. M.; Markham, K. R. Flavonoids. Chemistry, Biochemistry and Applications.; CRC press: Boca Raton, 2006.
3. Birt, D. F.; Hendrich, S.; Wang, W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol. Ther., 2001, 90, 157-177.
4. Van Acker, S. A. B. E.; van Balen, G. P.; van den Berg, D.-J.; Bast, A.; van der Vijgh, W. J. F. Influence of iron chelation on the antioxidant activity of flavonoids. Biochem. Pharmacol., 1998, 56, 935-943.
5. Grazul, M.; Budzisz, E. Biological activity of metal ions complexes of chromones, coumarins and flavones. Coord. Chem. Rev., 2009, 253, 2588-2598.
6. Oberheimer, M. T.; White, R. E.; Yang, C. S. Effects of bioflavonoids on hepatic P450 activities. Xenobiotica, 1995, 25, 575-584.
7. Rodgers, E. H.; Grant, M. H. The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF human breast cancer cells. Chem.-Biol. Interact., 1998, 116, 213-228.
8. Ren, Z.; Qiao, Z.; Wang, H.; Zhu, L.; Zhang, L. Flavonoids: promising anticancer agents. Med. Res. Rev., 2003, 23, 519-534.
9. Boumendjel, A.; DiPietro, A.; Dumontet, C.; Barron, D. Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-gp responsible for cancer cell multidrug resistance. Med. Res. Rev., 2002, 22, 512-529.
10. Boumendjel, A.; Boutonnat, J.; Robert, J. ABC Transporters and Multidrug Resistance.; Wiley & Sons: Hoboken, 2009.
11. Patrick, G. L. An Introduction to Medicinal Chemistry, 4th edition.; Oxford University Press, Oxford, 2009.
12. de Azevedo, W. F, Jr.; Mueller-Dieckmann, H. J.; Schulze-Gahmen, U.; Worland, P. J.; Sausville, E.; Kim, S. H. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. U S A., 1996, 93, 2735-2740.
13. Sicheri, F.; Moarefi, I.; Kuriyan, J. Crystal structure of the Src family tyrosine kinase Hck. Nature, 1997, 385, 602-609.
14. Liu, H. L.; Jiang, W.B.; Xie, M. X. Flavonoids: recent advances as anticancer drugs. Recent Patents on Anticancer Drug Discovery, 2010.
15. Kandaswami, C.; Lee, L. T.; Lee, P. P.; Hwang, J. J.; Ke, F. C.; Huang, Y. T.; Lee, M. T. The antitumor activities of flavonoids. In Vivo, 2005, 19, 895-909.
16. Ramanouskaya, T. V.; Smolnykova, V. V.; Grinev, V. V. Anticancer drugs, 2009, 20, 573-583.
17. Teillet, F.; Boumendjel, A.; Boutonnat, J.; Ronot, X. Flavonoids as RTK inhibitors and potential anticancer agents. Med. Res. Rev., 2007, 28, 715-745.
18. Boumendjel, A.; Ronot, X.; Boutonnat, J. Chalcones derivatives acting as cell cycle blockers: potential anti cancer drugs? Curr. Drug Targets, 2009, 10, 363-371.
19. Katsori, A. M, Hadjipavlou-Litina, D. Chalcones in cancer: understanding their role in terms of QSAR. Curr. Med. Chem., 2009, 16, 1062-81.
20. Boumendjel, A.; Boccard, J.; Carrupt, P. A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.; Wouessidjewe, D.; Matera, E. L.; Dumontet, C. Antimitotic and antiproliferative activities of chalcones: forward structureactivity relationship. J. Med. Chem., 2008, 51, 2307-2310.
21. Beutler, J. A.; Hamel, E.; Vlietinck, A. J.; Haemers, A.; Rajan, P.; Roitman, J. N.; Cardellina, J. H. 2nd, Boyd, M. R. Structure-activity requirements for flavone cytotoxicity and binding to tubulin. J. Med. Chem., 1998, 41, 2333-2338.
22. Cushman, M.; Nagarathnam, D.; Geahlen, R. L. Synthesis and evaluation of hydroxylated flavones and related compounds as potential inhibitors of the protein-tyrosine kinase p56lck. J. Nat. Prod., 1991, 54, 1345-1352.
23. Cushman, M.; Nagarathnam, D. Cytotoxicities of some flavonoid analogues. J. Nat. Prod., 1991, 54, 1656-1660.
24. Perez-Garcia, F.; Adzet, T.; Canigueral, S. Activity of artichoke leaf extract on reactive oxygen species in human leukocytes. Free. Radical. Res., 2000, 33, 661-665.
25. Casagrande, F.; Darbon, J. Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem. Pharmacol., 2001, 61, 1205-1215.
26. Chowdhury, A. R.; Sharma, S.; Mandal, S.; Goswami, A.; Mukhopadhyay, S.; Majumder, H. K. Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem. J., 2002, 366, 653-661.
27. Hirano, T.; Oka, K.; Akiba, M. Antiproliferative effects of synthetic and naturally occurring flavonoids on tumor cells of human breast carcinoma cell line ZR(75-1). Res. Commun. Chem. Pathol. Pharmacol., 1989, 64, 69-78.
28. Wang, W.; Heideman, L.; Chung, C. S.; Pelling, J. C.; Koehler, K. J.; Birt, D. F. Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol. Carcinog., 2000, 28, 102-110.
29. Ibrahim, A. R.; Abul-Haji, Y. J. Aromatase inhibition by flavonoids. J. Steroid Biochem. Mol. Biol., 1990, 37, 257-260.
30. Akama, T.; Shida, Y.; Sugaya, T.; Ishida, H.; Gomi, K.; Kasai, M. Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer. J. Med. Chem., 1996, 39, 3461-3469.
31. Akama, T.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. Structure-Activity Relationships of the 7-Substituents of 5,4'-Diamino-6,8,3'-Trifluoroflavone, A Potent Antitumor Agent. J. Med. Chem., 1998, 41, 2056-2067.
32. Kosmider, B.; Osiecka, R. Flavonoid compounds: A review of anticancer properties and interactions with cis-diamminedichloroplatinum(II). Drug. Develop. Res.; 2004, 63, 200-211.
33. Meng, L.-H., Kohlhagen, G. Liao, Z.-Y. Antony, S. Sausville, E. Pommier, Y. DNA-Protein cross-links and replication-dependent histone H2AX phosphorylation induced by aminoflavone (NSC 686288), a novel Anticancer agent active against human breast cancer cells. Cancer Res., 2005, 65, 5337-5343.
34. Meng, L. H.; Shankavaram, U.; Chen, C.; Agama, K.; Fu, H. Q.; Gonzalez, F. J.; Weinstein, J.; Pommier, Y. Activation of aminoflavone (NSC 686288) by a sulfotransferase is required for the antiproliferative effect of the drug and for induction of histone gamma-H2AX. Cancer Res. 2006, 66, 9656-9664.
35. Reinicke, K. E.; Kuffel, M. J.; Goetz, M. P.; Ames, M. M. Synergistic interactions between aminoflavone, paclitaxel and camptothecin in human breast cancer cells. Cancer Chemother. Pharmacol., 2009 [Epub ahead of print]
36. Cummings, J.; Smyth, J. F. Flavone 8-acetic acid: our current understanding of its mechanism of action in solid tumours. Cancer Chemother. Pharmacol., 1989, 24, 269-272.
37. Weiss, R. B.; Greene, R. F.; Knight, R. D.; Collins, J. M.; Pelosi, J. J.; Sulkes, A.; Curt, G. A. Phase I and clinical pharmacology study of intravenous flavone acetic acid (NSC 347512). Cancer Res., 1988, 48, 5878-5882.
38. Finlay, G. J.; Smith, G. P.; Fray, L. M.; Baguley, B. C. Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect. J. Natl. Cancer Inst., 1988, 80, 241-245.
39. Zwi, L. J.; Baguley, B. C.; Gavin, J. B.; Wilson, W. R. Blood flow failure as a major determinant in the antitumor action of flavone acetic acid. J. Natl. Cancer Inst., 1989, 81, 1005-1013.
40. Mace, K. F.; Hornung, R.L.; Wiltrout, R. H.; Young, H. A. Correlation between in vivo induction of cytokine gene expression by flavone acetic acid and strict dose dependency and therapeutic efficacy against murine renal cancer. Cancer Res., 1990, 50, 1742-1747.
41. Futami, H; Eader, L. A.; Komschlies, K. L.; Bull, R.; Gruys, M. E.; Ortaldo, J. R.; Young, H. A.; Wiltrout, R. H. Flavone acetic acid directly induces expression of cytokine genes in mouse splenic leukocytes but not in human peripheral blood leukocytes. Cancer Res., 1991, 51, 6596-6602.
42. Malolanarasimhan, K.; Lai, C. C.; Kelley, J. A.; Iaccarino, L.; Reynolds, D.; Young H. A.; Marquez, V. E. Synthesis and biological study of a flavone acetic acid analogue containing an azido reporting group designed as a multifunctional binding site probe. Bioorg. Med. Chem., 2005, 13, 2717-2722.
43. Double, J. A.; Bibby, M. C.; Loadman, P. M. Pharmacokinetics and antitumour activity of LM985 in mice bearing transplantable adenocarcinomas of the colon. Br. J. Cancer, 1986, 54, 595-600.
44. Kerr, D. J.; Kaye, S. B.; Graham, J.; Cassidy, J.; Harding, M.; Setanoians, A. McGrath, J. C.; Vezin, W. R.; Cunningham, D.; Forrest, G. et al. Phase I and pharmacokinetic study of LM985 (flavone acetic). Cancer Res., 1986, 46, 3142-3146.
45. Aitken, R. A.; Bibby, M. C.; Cooper, P. A.; Double, J. A.; Laws, A. L.; Ritchie, R. B.; Wilson, D. W. Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 4: Variation of the basic structure. Arch. Pharm., 2000, 333, 181-188.
46. Xia, Y.; Yang, Z. Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J. H.; Lee, K. H. Antitumor agents. 211. fluorinated 2-phenyl-4-quinolone derivatives as antimitotic antitumor agents. J. Med. Chem., 2001, 44, 3932-3936.
47. Lai, Y. Y.; Huang, L. J.; Lee, K. H.; Xiao, Z.; Bastow, K. F.; Yamori, T.; Kuo, S. C. Synthesis and biological relationships of 3',6-substituted 2-phenyl-4-quinolone-3-carboxylic acid derivatives as antimitotic agents. Bioorg. Med. Chem., 2005, 13, 265-275.
48. Zhao, L.; Ching, L. M.; Kestell, P.; Kelland, L. R. Baguley, B. C. Mechanisms of tumor vascular shutdown induced by 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Increased tumor vascular permeability. Int. J. Cancer, 2005, 116, 322-326.
49. Ching, L. M.; Zwain, S.; Baguley, B. C. Relationship between tumour endothelial cell apoptosis and tumour blood flow shutdown following treatment with the antivascular agent DMXAA in mice. Br. J. Cancer, 2004, 90, 906-910.
50. McKeage, M. J.; Baguley, B.C. Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer. Cancer, 2010 [Epub ahead of print]
51. Rizzolio, F.; Tuccinardi, T.; Caligiuri, I.; Lucchetti, C.; Giordano, A. CDK inhibitors: from the bench to clinical trials. Curr. Drug Targets, 2009, 11, 271-290.
52. Kryštof, V. Uldrijan, S. Cyclin-dependent kinase inhibitors as anticancer drugs. Curr. Drug Targets, 2010, 11, 291-302.
53. Delgado, J.; Briones, J.; Sierra, J. Emerging therapies for patients with advanced chronic lymphocytic leukaemia. Blood Rev., 2009, 23, 217-224.
54. Christian, B. A.; Grever, M. R.; Byrd, J. C.; Lin, T. S. Flavopiridol in the treatment of chronic lymphocytic leukemia. Curr. Opin. Oncol., 2007, 19, 573-578.
55. Senderowicz, A. M. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest. New Drugs, 1999, 17, 313-320.
56. Malumbres, M.; Barbacid, M. Cell Cycle, Cdks And Cancer: A Changing Paradigm. Nat. Rev. Cancer., 2009, 9, 153-166.
57. Kim, K. S.; Sack, J. S.; Tokarski, J. S.; Qian, L.; Chao, S. T.; Leith, L.; Kelly, Y. F.; Misra, R. N.; Hunt, J. T.; Kimball, S. D.; Humphreys, W. G.; Wautlet, B. S.; Mulheron, J. G.; Webster, K. R. Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects. J. Med. Chem., 2000, 43, 4126-4134.
58. Schoepfer, J.; Fretz, H.; Chaudhuri, B.; Muller, L.; Seeber, E.; Meijer, L.; Lozach O.; Vangrevelinghe, E.; Furet, P. Structure-based design and synthesis of 2-benzylidene-benzofuran-3-ones as flavopiridol mimics. J. Med. Chem., 2002, 45, 1741-1747.
59. Glossmann, H.; Presek, P.; Eigenbrodt, E. Quercetin inhibits tyrosine phosphorylation by the cyclic nucleotide-independent, transforming protein kinase, pp60src. Naunyn-Schmiedebergs Arch. Pharmacol., 1981, 317, 100-102.
60. Yoshida, M.; Yamamoto, M.; Nikaido, T. Quercetin arrests human leukemic T-cells in late G1 phase of the cell cycle. Cancer Res., 1992, 52, 6676-6681.
61. Avila, M. A.; Velasco, J. A.; Cansado, J.; Notario, V. Quercetin mediates the down-regulation of mutant p53 in the human breast cancer cell line mdamb468. Cancer Res., 1994, 54, 2424-2428.
62. Wei, Y. Q.; Zhao, X.; Kariya, Y.; Fukata, H.; Teshigawara, K.; Uchida, A. Induction of apoptosis by quercetin: involvement of heat shock protein. Cancer Res., 1994, 54, 4952-4957.
63. Dimas, K.; Demetzos, C.; Mitaku, S.; Marselos, M.; Tzavaras, T.; Kokkinopoulos, D. Cytotoxic activity of kaempferol glycosides against human leukaemic cell lines in vitro. Pharmacol. Res., 2000, 41, 85-88.
64. Yoshida, T.; Konishi, M.; MHorinaka, M.; Yasuda, T.; Goda, A. E.; Taniguchi, H.; Yano, K.; Wakada, M.; Sakai, T. Kaempferol sensitizes colon cancer cells to TRAIL-induced apoptosis. Biochem. Biophys. Res. Commun., 2008, 375, 129-133.
65. Siegelin, M. D.; Reuss, D. E.; Habel, A.; Herold-Mende, C.; Von Deimling, A. The flavonoid kaempferol sensitizes human glioma cells to TRAILmediated apoptosis by proteasomal degradation of surviving. Mol. Cancer Ther., 2008, 7, 3566-3574.
66. Sharma, V.; Joseph, C.; Ghosh, S.; Agarwal, A.; Mishra, M. K.; Sen, E. Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. Mol. Cancer Ther., 2007, 6, 2544-2553.
67. Rubio, S.; Quintana, J.; Eiroa, J. L.; Triana, J.; Estévez, F. Acetyl derivative of quercetin 3-methyl ether-induced cell death in human leukemia cells is amplified by the inhibition of ERK. Carcinogenesis, 2007, 28, 2105-2113.
68. Mulholland, P. J.; Ferry, D. R.; Anderson, D.; Hussain, S. A.; Young, A. M.; Cook, J. E.; Hodgkin, E.; Seymour, L. W.; Kerr, D. J. Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin. Ann. Oncol., 2001, 12, 245-248.
69. Hirpara, K. V.; Aggarwal, P.; Mukherjee, A. J.; Joshi, N.; Burman, A. C. Quercetin and its derivatives: synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bioavailability. Anti-Canc. Agents Med. Chem., 2009, 9, 138-161.
70. Kim, M. K.; Park, K. S.; Yeo, W. S.; Choo, H.; Chong, Y. In vitro solubility, stability and permeability of novel quercetin-amino acid conjugates. Bioorg. Med. Chem., 2009, 17, 1164-1171.
71. Huang, H.; Jia, Q.; Ma, J.; Qin, G.; Chen, Y.; Xi, Y.; Lin, L.; Zhu, W.; Ding, J.; Jiang, H.; Liu, H. Discovering novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors. Eur. J. Med. Chem., 2009, 44, 1982-1988.
72. Hsiao, Y.-C.; Kuo, W.-H.; Chen, P.-N.; Change, H.-R.; Lin, T.-S.; Yang, W.-E.; Hsieh, Y.-S.; Chud, S.-C. Flavanone and 2'-OH flavanone inhibit metastasis of lung cancer cells via down-regulation of proteinases activities and MAPK pathway. Chemico-Biol. Interact., 2007, 167, 193-206.
73. So, F.; Guthrie, N.; Chambers, A. F.; Moussa, M.; Carroll, K. K. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr. Cancer, 1996, 26, 167-181.
74. Gao, K.; Henning, S. M.; Niu, Y.; Youssefian, A. A.; Seeram, N. P.; Xu, A.; Heber, D. The citrus flavonoid naringenin stimulates DNA repair in prostate cancer cells. J. Nutr. Biochem., 2006, 17, 89-95.
75. Ying, M.; Tu, C.; Ying, H.; Hu, Y.; He, Q.; Yang, B. MSFTZ, a Flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway. Pharmacology, 2008, 325, 758-765.
76. Choi, E. J. Hesperetin induced G1-phase cell cycle arrest in human breast cancer MCF-7 cells: involvement of CDK4 and p21. Nutr. Cancer, 2007, 59, 115-119.
77. Kaufman, P. B.; Duke, J. A.; Brielmann, H.; Boik, J.; Hoyt, J. E. A comparative survey of leguminous plants as sources of the isoflavones, genistein and daidzein: implications for human nutrition and health. J. Altern. Complement Med., 1997, 3, 7-12.
78. Schmidt, F.; Knobbe, C. B.; Franck, B.; Wolburg, H.; Weller, M. The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. Oncol. Rep., 2008, 19, 1061-1066.
79. Bandele, O. J.; Osheroff, N. Bioflavonoids as poisons of human topoisomerase II alpha and II beta. Biochemistry, 2007, 46, 6097-6108.
80. Sanderson, J. T.; Hordijk, J.; Denison, M. S.; Springsteel, M. F.; Nantz, M. H.; van den Berg, M. Induction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cells. Toxicol. Sci., 2004, 82, 70-79.
81. Iwasaki, T.; Mukai, M.; Tsujimura, T.; Tatsuta, M.; Nakamura, H.; Terada, N.; Akedo, H. Ipriflavone inhibits osteolytic bone metastasis of human breast cancer cells in a nude mouse model. Int. J. Cancer, 2002, 100, 381-387.
82. Choueiri, T. K.; Wesolowski, R.; Mekhail, T. M. Phenoxodiol: isoflavone analog with antineoplastic activity. Curr. Oncol. Rep., 2006, 8,104-107.
83. Sanderson, J. T.; Hordijk, J.; Denison, M. S.; Springsteel, M. F.; Nantz, M. H.; van den Berg, M. Induction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cells. Toxicol Sci., 2004, 82, 70-79.
84. Gottesman, M. M.; Pastan, I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem., 1993, 62, 385-427.
85. Juliano, R. L.; Ling, V. A surface glycoprotein modulating drug permeability in chinese hamster ovary cell mutants. Biochim. Biophys. Acta., 1976, 455, 152-162.
86. Borst, P.; Evers, R.; Kool, M.; Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl. Cancer Inst., 2000, 92, 1295-1302.
87. Doyle, L. A.; Yang, W.; Abruzzo, L. V.; Krogmann, T.; Gao, Y.; Rishi, A. K.; Ross, D. D. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 15665-15670.
88. Phang, J. M.; Poore, C. M.; Lopaczynska, J.; Yeh, G. C. Flavonol-stimulated efflux of 7,12-dimethylbenz(a)-anthracene in multidrug-resistant breast cancer cells. Cancer Res., 1993, 53, 5977-5981.
89. Critchfield, J. W.; Welsh, C. J.; Phang, J. M.; Yeh, G. C. Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells: activation of P-glycoprotein as a putative mechanism. Biochem. Pharmacol., 1994, 48, 1437-1445.
90. Bracke, M. E.; Depypere, H. T.; Boterberg, T.; Van Marck, V. L.; Vennekens, K. M.; Vanluchene, E.; Nuytinck, M.; Serreyn, R.; Mareel, M. M. Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer. J. Natl. Cancer Inst., 1999, 91:354-359.
91. Scambia, G.; Ranellett, F. O.; Benedetti, P.; De Vincenzo, R.; Bonanno, G.; Ferrandina, G.; Piantelli, M.; Bussa, S.; Rumi, C.; Clanfriglia, M.; Manucuso, S. Quercetin potentiates the effect of adriamycin in a multidrug resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother. Pharmacol., 1994, 34, 459-464.
92. Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A. M.; Boumendjel, A.; Boutonnat, J. Modulation of P-glycoprotein-mediated multidrug resistance by flavonoid derivatives and analogues. J. Med. Chem., 2003, 46, 2125-2131.
93. Ferté, J.; Kühnel, J. M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M. A. Flavonoid-related modulators of multidrug resistance: synthesis, pharmacological activity, and structure-activity relationships. J. Med. Chem., 1999, 42, 478-489.
94. Florin, A.; Boutonnat, J.; Boumendjel, A. Overcoming BCRP-mediated multidrug resistance. Drugs Future, 2008, 33, 533-540.
95. Boccard, J.; Bajot, F.; Di Pietro, A.; Rudaz, S.; Boumendjel, A.; Nicolle, E.; Carrupt, P. A. A 3D linear solvation energy model to quantify the affinity of flavonoid derivatives toward P-glycoprotein. Eur. J. Pharm. Sci., 2009, 36, 254-264.