New Concepts, Experimental Approaches, and Dereplication Strategies for the Discovery of Novel Phytoestrogens from Natural Sources

Abstract

Phytoestrogens constitute an attractive research topic due to their estrogenic profile and their biological involvement in womanʼs health. Therefore, numerous studies are currently performed in natural products chemistry area aiming at the discovery of novel phytoestrogens. The main classes of phytoestrogens are flavonoids (flavonols, flavanones), isoflavonoids (isoflavones, coumestans), lignans, stilbenoids as well as miscellaneous chemical groups abundant in several edible and/or medicinal plants, belonging mostly to the Leguminosae family. As for other bioactives, the detection of new structures and more potent plant-derived phytoestrogens typically follows the general approaches currently available in the natural product discovery process. Plant-based approaches selected from traditional medicine knowledge and bioguided concepts are routinely employed. However, these approaches are associated with serious disadvantages such as time-consuming, repeated, and labor intensive processes as well as lack of specificity and reproducibility. In recent years, the natural products chemistry became more technology-driven, and several different strategies have been developed. Structure-oriented procedures and miniaturized approaches employing advanced hyphenated analytical platforms have recently emerged. They facilitate significantly not only the discovery of novel phytoestrogens but also the dereplication procedure leading to the anticipation of major drawbacks in natural products discovery. In this review, apart from the traditional concepts followed in phytochemistry for the discovery of novel biologically active compounds, recent applications in the field of extraction, analysis, fractionation, and identification of phytoestrogens will be discussed. Moreover, specific methodologies combining identification of actives and biological evaluation in parallel, such as liquid chromatography-biochemical detection, frontal affinity chromatography-mass spectrometry and pulsed ultrafiltration-MS will also be presented. Finally, miniaturized methods (microchip and biosensor) will be also discussed.

With the current review, we attempt to give a wide and holistic overview of the different approaches which could be employed in the discovery of new phytoestrogens. On the other hand, we anticipate to attract more scientists to the area of phytoestrogens and to indicate the need of multidisciplinary concepts.

Key words

phytoestrogens - plant extract - dereplication - extraction - isolation - identification

• References

• 1 Cos P, De Bruyne T, Apers S, Berghe DV, Pieters L, Vlietinck AJ. Phytoestrogens: recent developments. Planta Med 2003; 69: 589-599
• 2 Ososki AL, Kennelly EJ. Phytoestrogens: a review of the present state of research. Phytother Res 2003; 17: 845-869
• 3 Cornwell T, Cohick W, Raskin I. Dietary phytoestrogens and health. Phytochemistry 2004; 65: 995-1016
• 4 Simons R, Gruppen H, Bovee TFH, Verbruggen MA, Vincken JP. Prenylated isoflavonoids from plants as selective estrogen receptor modulators (phytoSERMs). Food Funct 2012; 3: 810-827
• 5 Pitkin J. Alternative and complementary therapies for the menopause. Menopause Int 2012; 18: 20-27
• 6 Al-Anazi AF, Qureshi VF, Javaid K, Qureshi S. Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapeutic choices: An overview. J Nat Sci Biol Med 2011; 2: 154-163
• 7 Kuiper GGJM, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JÅ. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β . Endocrinology 1998; 139: 4252-4263
• 8 Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids 1999; 64: 310-319
• 9 Katzenellenbogen BS, Korach KS. Editorial: A new actor in the estrogen receptor drama-Enter ER-β . Endocrinology 1997; 138: 861-862
• 10 Brzezinski A, Debi A. Phytoestrogens: the “natural” selective estrogen receptor modulators?. Eur J Obstet Gynecol Reprod Biol 1999; 85: 47-51
• 11 Kellis J, Vickery L. Inhibition of human estrogen synthetase (aromatase) by flavones. Science 1984; 225: 1032-1034
• 12 Pelissero C, Lenczowski MJP, Chinzi D, Davail-Cuisset B, Sumpter JP, Fostier A. Effects of flavonoids on aromatase activity, an in vitro study. J Steroid Biochem Mol Biol 1996; 57: 215-223
• 13 Makela S, Davis VL, Tally WC, Korkman J, Salo L, Vihko R, Santti R, Korach KS. Dietary estrogens act through estrogen receptor-mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environ Health Perspect 1994; 102: 572-578
• 14 Adlercreutz H, Mousavi Y, Clark J, Höckerstedt K, Hämäläinen E, Wähälä K, Mäkelä T, Hase T. Dietary phytoestrogens and cancer: in vitro and in vivo studies. J Steroid Biochem Mol Biol 1992; 41: 331-337
• 15 Atkinson C, Newton K, Stanczyk F, Westerlind K, Li L, Lampe J. Daidzein-metabolizing phenotypes in relation to serum hormones and sex hormone binding globulin, and urinary estrogen metabolites in premenopausal women in the United States. Cancer Causes Control 2008; 19: 1085-1093
• 16 Dixon RA. Phytoestrogens. Annu Rev Plant Biol 2004; 55: 225-261
• 17 Tahara S, Ibrahim RK. Prenylated isoflavonoids – an update. Phytochemistry 1995; 38: 1073-1094
• 18 Fokialakis N, Lambrinidis G, Mitsiou DJ, Aligiannis N, Mitakou S, Skaltsounis AL, Pratsinis H, Mikros E, Alexis MN. A new class of phytoestrogens: Evaluation of the estrogenic activity of deoxybenzoins. Chem Biol 2004; 11: 397-406
• 19 Hu JY, Aizawa T. Quantitative structure–activity relationships for estrogen receptor binding affinity of phenolic chemicals. Water Res 2003; 37: 1213-1222
• 20 Veitch NC. Isoflavonoids of the Leguminosae. Nat Prod Rep 2009; 26: 776-802
• 21 Reynaud J, Guilet D, Terreux R, Lussignol M, Walchshofer N. Isoflavonoids in non-leguminous families: an update. Nat Prod Rep 2005; 22: 504-515
• 22 Booth NL, Piersen CE, Banuvar S, Geller SE, Shulman LP, Farnsworth NR. Clinical studies of red clover (Trifolium pratense) dietary supplements in menopause: a literature review. Menopause 2006; 13: 251-264
• 23 Bora KS, Sharma A. Phytochemical and pharmacological potential of Medicago sativa: a review. Pharm Biol 2011; 49: 211-220
• 24 Stevenson PC, Veitch NC. The distribution of isoflavonoids in cicer. Phytochemistry 1998; 48: 995-1001
• 25 Farag MA, Porzel A, Wessjohann LA. Comparative metabolite profiling and fingerprinting of medicinal licorice roots using a multiplex approach of GC–MS, LC–MS and 1D NMR techniques. Phytochemistry 2012; 76: 60-72
• 26 Wong KH, Li GQ, Li KM, Razmovski-Naumovski V, Chan K. Kudzu root: traditional uses and potential medicinal benefits in diabetes and cardiovascular diseases. J Ethnopharmacol 2011; 134: 584-607
• 27 Hong YH, Wang SC, Hsu C, Lin BF, Kuo YH, Huang CJ. Phytoestrogenic compounds in alfalfa sprout (Medicago sativa) beyond coumestrol. J Agric Food Chem 2010; 59: 131-137
• 28 Chadwick LR, Pauli GF, Farnsworth NR. The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties. Phytomedicine 2006; 13: 119-131
• 29 Possemiers S, Bolca S, Grootaert C, Heyerick A, Decroos K, Dhooge W, De Keukeleire D, Rabot S, Verstraete W, Van de Wiele T. The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine. J Nutr 2006; 136: 1862-1867
• 30 Pan JY, Chen SL, Yang MH, Wu J, Sinkkonen J, Zou K. An update on lignans: natural products and synthesis. Nat Prod Rep 2009; 26: 1251-1292
• 31 Sakakibara N, Nakatsubo T, Suzuki S, Shibata D, Shimada M, Umezawa T. Metabolic analysis of the cinnamate/monolignol pathway in Carthamus tinctorius seeds by a stable-isotope-dilution method. Org Biomol Chem 2007; 5: 802-815
• 32 Smeds AI, Eklund PC, Sjöholm RE, Willför SM, Nishibe S, Deyama T, Holmbom BR. Quantification of a broad spectrum of lignans in cereals, oilseeds, and nuts. J Agric Food Chem 2007; 55: 1337-1346
• 33 Dinelli G, Marotti I, Bosi S, Benedettelli S, Ghiselli L, Cortacero-Ramírez S, Carrasco-Pancorbo A, Segura-Carretero A, Fernández-Gutiérrez A. Lignan profile in seeds of modern and old Italian soft wheat (Triticum aestivum L.) cultivars as revealed by CE-MS analyses. Electrophoresis 2007; 28: 4212-4219
• 34 Lee IA, Joh EH, Kim DH. Arctigenin isolated from the seeds of Arctium lappa ameliorates memory deficits in mice. Planta Med 2011; 77: 1525-1527
• 35 Shen T, Wang XN, Lou HX. Natural stilbenes: an overview. Nat Prod Rep 2009; 26: 916-935
• 36 Lopes RM, Agostini-Costa TNDS, Gimenes MA, Silveira DM. Chemical composition and biological activities of Arachis species. J Agric Food Chem 2011; 59: 4321-4330
• 37 Möller F, Zierau O, Jandausch A, Rettenberger R, Kaszkin-Bettag M, Vollmer G. Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731®), its aglycones and structurally related compounds in U2OS human osteosarcoma cells. Phytomedicine 2007; 14: 716-726
• 38 Wober J, Möller F, Richter T, Unger C, Weigt C, Jandausch A, Zierau O, Rettenberger R, Kaszkin-Bettag M, Vollmer G. Activation of estrogen receptor-β by a special extract of Rheum rhaponticum (ERr 731®), its aglycones and structurally related compounds. J Steroid Biochem Mol Biol 2007; 107: 191-201
• 39 Martin PM, Hortwitz KB, Ryan DS, McGuire WL. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 1978; 103: 1860-1867
• 40 Halabalaki M, Aligiannis N, Papoutsi Z, Mitakou S, Moutsatsou P, Sekeris C, Skaltsounis AL. Three new arylobenzofurans from Onobrychis ebenoides and evaluation of their binding affinity for the estrogen receptor. J Nat Prod 2000; 63: 1672-1674
• 41 Suksamrarn A, Ponglikitmongkol M, Wongkrajang K, Chindaduang A, Kittidanairak S, Jankam A, Yingyongnarongkul BE, Kittipanumat N, Chokchaisiri R, Khetkam P, Piyachaturawat P. Diarylheptanoids, new phytoestrogens from the rhizomes of Curcuma comosa: Isolation, chemical modification and estrogenic activity evaluation. Bioorg Med Chem 2008; 16: 6891-6902
• 42 Lim SH, Ha TY, Ahn J, Kim S. Estrogenic activities of Psoralea corylifolia L. seed extracts and main constituents. Phytomedicine 2011; 18: 425-430
• 43 Choo WS, Birch J, Dufour JP. Physicochemical and quality characteristics of cold-pressed flaxseed oils. J Food Comp Anal 2007; 20: 202-211
• 44 Takeda S, Yamamoto I, Watanabe K. Modulation of Δ9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase. Toxicology 2009; 259: 25-32
• 45 Su SL, Duan JA, Tang YP, Zhang X, Yu L, Jiang FR, Zhou W, Luo D, Ding AW. Isolation and biological activities of neomyrrhaol and other terpenes from the resin of Commiphora myrrha . Planta Med 2009; 75: 351-355
• 46 Michel JL, Chen Y, Zhang H, Huang Y, Krunic A, Orjala J, Veliz M, Soni KK, Soejarto DD, Caceres A, Perez A, Mahady GB. Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae). J Ethnopharmacol 2010; 129: 220-226
• 47 Maiti A, Reddy PVN, Sturdy M, Marler L, Pegan SD, Mesecar AD, Pezzuto JM, Cushman M. Synthesis of casimiroin and optimization of its quinone reductase 2 and aromatase inhibitory activities. J Med Chem 2009; 52: 1873-1884
• 48 Flemming J, Madarnas Y, Franek J. Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review. Breast Cancer Res Treat 2009; 115: 255-268
• 49 Fang N, Casida JE. New bioactive flavonoids and stilbenes in cubé resin insecticide. J Nat Prod 1999; 62: 205-210
• 50 Harvey AL. Natural products in drug discovery. Drug Discov Today 2008; 13: 894-901
• 51 Nahrstedt A, Butterweck V. Lessons learned from herbal medicinal products: the example of St. Johnʼs wort. J Nat Prod 2010; 73: 1015-1021
• 52 Tu Y, Jeffries C, Ruan H, Nelson C, Smithson D, Shelat AA, Brown KM, Li XC, Hester JP, Smillie T, Khan IA, Walker L, Guy K, Yan B. Automated high-throughput system to fractionate plant natural products for drug discovery. J Nat Prod 2010; 73: 751-754
• 53 van Beek T, Tetala K, Koleva I, Dapkevicius A, Exarchou V, Jeurissen S, Claassen F, van der Klift E. Recent developments in the rapid analysis of plants and tracking their bioactive constituents. Phytochem Rev 2009; 8: 387-399
• 54 Zaugg J, Eickmeier E, Rueda DC, Hering S, Hamburger M. HPLC-based activity profiling of Angelica pubescens roots for new positive GABAA receptor modulators in Xenopus oocytes. Fitoterapia 2011; 82: 434-440
• 55 Potterat O, Hamburger M. Drug discovery and development with plant-derived compounds. Prog Drug Res 2008; 65: 45-118
• 56 Giera M, Heus F, Janssen L, Kool J, Lingeman H, Irth H. Microfractionation revisited: a 1536 well high resolution screening assay. Anal Chem 2009; 81: 5460-5466
• 57 Grata E, Guillarme D, Glauser G, Boccard J, Carrupt PA, Veuthey JL, Rudaz S, Wolfender JL. Metabolite profiling of plant extracts by ultra-high-pressure liquid chromatography at elevated temperature coupled to time-of-flight mass spectrometry. J Chromatogr A 2009; 1216: 5660-5668
• 58 Wolfender JL, Ndjoko K, Hostettmann K. Liquid chromatography with ultraviolet absorbance–mass spectrometric detection and with nuclear magnetic resonance spectrometry: a powerful combination for the on-line structural investigation of plant metabolites. J Chromatogr A 2003; 1000: 437-455
• 59 Koehn FE. High impact technologies for natural products screening. In: Petersen F, Amstutz R, editors Natural compounds as drugs, Volume I. Progress in drug research, Vol. 65. Basel: Birkhäuser; 2008: 175-210
• 60 Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 2005; 4: 206-220
• 61 Armenta S, Garrigues S, de la Guardia M. Green analytical chemistry. Trends Anal Chem 2008; 27: 497-511
• 62 Mendiola JA, Herrero M, Cifuentes A, Ibañez E. Use of compressed fluids for sample preparation: food applications. J Chromatogr A 2007; 1152: 234-246
• 63 Vinatoru M, Toma M, Radu O, Filip PI, Lazurca D, Mason TJ. The use of ultrasound for the extraction of bioactive principles from plant materials. Ultrason Sonochem 1997; 4: 135-139
• 64 Sparr Eskilsson C, Björklund E. Analytical-scale microwave-assisted extraction. J Chromatogr A 2000; 902: 227-250
• 65 Rostagno MA, Villares A, Guillamón E, García-Lafuente A, Martínez JA. Sample preparation for the analysis of isoflavones from soybeans and soy foods. J Chromatogr A 2009; 1216: 2-29
• 66 Zgórka G. Pressurized liquid extraction versus other extraction techniques in micropreparative isolation of pharmacologically active isoflavones from Trifolium L. species. Talanta 2009; 79: 46-53
• 67 Zgórka G. Studies on phytoestrogenic and nonphytoestrogenic compounds in Trifolium incarnatum L. and other clover species using pressurized liquid extraction and high performance column liquid chromatography with photodiode-array and fluorescence detection. J AOAC Int 2011; 94: 22-31
• 68 Luthria DL, Biswas R, Natarajan S. Comparison of extraction solvents and techniques used for the assay of isoflavones from soybean. Food Chem 2007; 105: 325-333
• 69 Ho CHL, Cacace JE, Mazza G. Extraction of lignans, proteins and carbohydrates from flaxseed meal with pressurized low polarity water. Food Sci Technol 2007; 40: 1637-1647
• 70 Gil-Ramírez A, Mendiola JA, Arranz E, Ruíz-Rodríguez A, Reglero G, Ibáñez E, Marín FR. Highly isoxanthohumol enriched hop extract obtained by pressurized hot water extraction (PHWE). Chemical and functional characterization. Innov Food Sci Emerg Technol 2012;
• 71 Teo CC, Tan SN, Yong JWH, Hew CS, Ong ES. Pressurized hot water extraction (PHWE). J Chromatogr A 2010; 1217: 2484-2494
• 72 Herrero M, Mendiola JA, Cifuentes A, Ibáñez E. Supercritical fluid extraction: Recent advances and applications. J Chromatogr A 2010; 1217: 2495-2511
• 73 Pyo D, Yoo J, Surh J. Comparison of supercritical fluid extraction and solvent extraction of isoflavones from soybeans. J Liq Chromatogr Relat Technol 2009; 32: 923-932
• 74 Bajer T, Adam M, Galla L, Ventura K. Comparison of various extraction techniques for isolation and determination of isoflavonoids in plants. J Sep Sci 2007; 30: 122-127
• 75 Pascual-Martí MC, Salvador A, Chafer A, Berna A. Supercritical fluid extraction of resveratrol from grape skin of Vitis vinifera and determination by HPLC. Talanta 2001; 54: 735-740
• 76 Casas L, Mantell C, Rodríguez M, Martinez de la Ossa EJ, Roldán A, Ory ID, Caro I, Blandino A. Extraction of resveratrol from the pomace of Palomino fino grapes by supercritical carbon dioxide. J Food Eng 2010; 96: 304-308
• 77 Chafer A, Pascual-Martí MC, Salvador A, Berna A. Supercritical fluid extraction and HPLC determination of relevant polyphenolic compounds in grape skin. J Sep Sci 2005; 28: 2050-2056
• 78 Choi Y, Kim J, Yoo KP. High performance liquid chromatography-electrospray lonization MS-MS analysis Forsythia koreana fruits, leaves, and stems. Enhancement of the efficiency of extraction of arctigenin by use of supercritical-fluid extraction. Chromatographia 2003; 57: 73-79
• 79 Michel T, Destandau E, Elfakir C. Evaluation of a simple and promising method for extraction of antioxidants from sea buckthorn (Hippophaë rhamnoides L.) berries: Pressurised solvent-free microwave assisted extraction. Food Chem 2011; 126: 1380-1386
• 80 Du G, Zhao HY, Zhang QW, Li GH, Yang FQ, Wang Y, Li YC, Wang YT. A rapid method for simultaneous determination of 14 phenolic compounds in Radix Puerariae using microwave-assisted extraction and ultra high performance liquid chromatography coupled with diode array detection and time-of-flight mass spectrometry. J Chromatogr A 2010; 1217: 705-714
• 81 Terigar BG, Balasubramanian S, Boldor D, Xu Z, Lima M, Sabliov CM. Continuous microwave-assisted isoflavone extraction system: design and performance evaluation. Bioresour Technol 2010; 101: 2466-2471
• 82 Nemes S, Orsat V. Microwave-assisted extraction of secoisolariciresinol diglucoside-method development. Food Bioprocess Technol 2011; 4: 1219-1227
• 83 Yu R, Yu R, Zhang X, Luo Z, Zhang H, Shao Y, Mei L, Tao Y. Dynamic microwave-assisted extraction of arctigenin from Saussurea medusa Maxim. Chromatographia 2010; 71: 335-339
• 84 Zgórka G. Ultrasound-assisted solid-phase extraction coupled with photodiode-array and fluorescence detection for chemotaxonomy of isoflavone phytoestrogens in Trifolium L. (Clover) species. J Sep Sci 2009; 32: 965-972
• 85 Wu Y, Wang X, Fan E. Optimisation of ultrasound-assisted extraction of puerarin and total isoflavones from Puerariae Lobatae Radix (Pueraria lobata (Wild.) Ohwi) with response surface methodology. Phytochem Anal 2012; 23: 513-519
• 86 Jiang RW, Lau KM, Lam HM, Yam WS, Leung LK, Choi KL, Waye MMY, Mak TCW, Woo KS, Fung KP. A comparative study on aqueous root extracts of Pueraria thomsonii and Pueraria lobata by antioxidant assay and HPLC fingerprint analysis. J Ethnopharmacol 2005; 96: 133-138
• 87 Lee MH, Lin CC. Comparison of techniques for extraction of isoflavones from the root of Radix puerariae: Ultrasonic and pressurized solvent extractions. Food Chem 2007; 105: 223-228
• 88 Lou Z, Wang H, Zhu S, Zhang M, Gao Y, Ma C, Wang Z. Improved extraction and identification by ultra performance liquid chromatography tandem mass spectrometry of phenolic compounds in burdock leaves. J Chromatogr A 2010; 1217: 2441-2446
• 89 Cheng XL, Wan JY, Li P, Qi LW. Ultrasonic/microwave assisted extraction and diagnostic ion filtering strategy by liquid chromatography–quadrupole time-of-flight mass spectrometry for rapid characterization of flavonoids in Spatholobus suberectus . J Chromatogr A 2011; 1218: 5774-5786
• 90 Chukwumah YC, Walker LT, Verghese M, Bokanga M, Ogutu S, Alphonse K. Comparison of extraction methods for the quantification of selected phytochemicals in peanuts (Arachis hypogaea). J Agric Food Chem 2006; 55: 285-290
• 91 Pauli GF, Pro SM, Friesen JB. Countercurrent separation of natural products. J Nat Prod 2008; 71: 1489-1508
• 92 Costa FD, Leitão GG. Strategies of solvent system selection for the isolation of flavonoids by countercurrent chromatography. J Sep Sci 2010; 33: 336-347
• 93 Yoon KD, Chin YW, Kim J. Centrifugal partition chromatography: Application to natural products in 1994–2009. J Liq Chromatogr Relat Technol 2010; 33: 1208-1254
• 94 Du Q, Li B. Identification of antioxidant compounds of Mucuna sempervirens by high-speed counter-current chromatographic separation–DPPH radical scavenging detection and their oestrogenic activity. Food Chem 2012; 131: 1181-1186
• 95 Simons R, Vincken JP, Mol LAM, The SAM, Bovee TFH, Luijendijk TJC, Verbruggen MA, Gruppen H. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra). Anal Bioanal Chem 2011; 401: 301-313
• 96 Guillarme D, Ruta J, Rudaz S, Veuthey JL. New trends in fast and high-resolution liquid chromatography: a critical comparison of existing approaches. Anal Bioanal Chem 2010; 397: 1069-1082
• 97 Chen G, Pramanik BN, Liu YH, Mirza UA. Applications of LC/MS in structure identifications of small molecules and proteins in drug discovery. J Mass Spectrom 2007; 42: 279-287
• 98 Glish GL, Vachet RW. The basics of mass spectrometry in the twenty-first century. Nat Rev Drug Discov 2003; 2: 140-150
• 99 Rostagno MA, Palma M, Barroso CG. Fast analysis of soy isoflavones by high-performance liquid chromatography with monolithic columns. Anal Chim Acta 2007; 582: 243-249
• 100 Apers S, Naessens T, Van den Steen K, Cuyckens F, Claeys M, Pieters L, Vlietinck A. Fast high-performance liquid chromatography method for quality control of soy extracts. J Chromatogr A 2004; 1038: 107-112
• 101 Rostagno MA, Palma M, Barroso CG. Solid-phase extraction of soy isoflavones. J Chromatogr A 2005; 1076: 110-117
• 102 Rostagno MA, Palma M, Barroso CG. Microwave assisted extraction of soy isoflavones. Anal Chim Acta 2007; 588: 274-282
• 103 Du G, Zhao H, Song Y, Zhang Q, Wang Y. Rapid simultaneous determination of isoflavones in Radix puerariae using high-performance liquid chromatography–triple quadrupole mass spectrometry with novel shell-type column. J Sep Sci 2011; 34: 2576-2585
• 104 Manchón N, DʼArrigo M, García-Lafuente A, Guillamón E, Villares A, Ramos A, Martínez JA, Rostagno MA. Fast analysis of isoflavones by high-performance liquid chromatography using a column packed with fused-core particles. Talanta 2010; 82: 1986-1994
• 105 Klejdus B, Mikelová R, Petrlová J, Potěšil D, Adam V, Stiborová M, Hodek P, Vacek J, Kizek R, Kubáň V. Determination of isoflavones in soy bits by fast column high-performance liquid chromatography coupled with UV–visible diode-array detection. J Chromatogr A 2005; 1084: 71-79
• 106 Klejdus B, Mikelova R, Petrlova J, Potesil D, Adam V, Stiborova M, Hodek P, Vacek J, Kizek R, Kuban V. Evaluation of isoflavone aglycon and glycoside distribution in soy plants and soybeans by fast column high-performance liquid chromatography coupled with a diode-array detector. J Agric Food Chem 2005; 53: 5848-5852
• 107 Klejdus B, Lojková L, Lapčík O, Koblovská R, Moravcová J, Kubáň V. Supercritical fluid extraction of isoflavones from biological samples with ultra-fast high-performance liquid chromatography/mass spectrometry. J Sep Sci 2005; 28: 1334-1346
• 108 Klejdus B, Lojková L, Plaza M, Šnóblová M, Štěrbová D. Hyphenated technique for the extraction and determination of isoflavones in algae: ultrasound-assisted supercritical fluid extraction followed by fast chromatography with tandem mass spectrometry. J Chromatogr A 2010; 1217: 7956-7965
• 109 Klejdus B, Vacek J, Benešová L, Kopecký J, Lapčík O, Kubáň V. Rapid-resolution HPLC with spectrometric detection for the determination and identification of isoflavones in soy preparations and plant extracts. Anal Bioanal Chem 2007; 389: 2277-2285
• 110 Churchwell MI, Twaddle NC, Meeker LR, Doerge DR. Improving LC–MS sensitivity through increases in chromatographic performance: comparisons of UPLC–ES/MS/MS to HPLC–ES/MS/MS. J Chromatogr B 2005; 825: 134-143
• 111 Klejdus B, Vacek J, Lojková L, Benešová L, Kubáň V. Ultrahigh-pressure liquid chromatography of isoflavones and phenolic acids on different stationary phases. J Chromatogr A 2008; 1195: 52-59
• 112 Oleszek W, Stochmal A, Janda B. Concentration of isoflavones and other phenolics in the aerial parts of Trifolium species. J Agric Food Chem 2007; 55: 8095-8100
• 113 Prokudina EA, Havlíček L, Al-Maharik N, Lapčík O, Strnad M, Gruz J. Rapid UPLC–ESI–MS/MS method for the analysis of isoflavonoids and other phenylpropanoids. J Food Comp Anal 2012; 26: 36-42
• 114 Simons R, Vincken JP, Roidos N, Bovee TFH, van Iersel M, Verbruggen MA, Gruppen H. Increasing soy isoflavonoid content and diversity by simultaneous malting and challenging by a fungus to modulate estrogenicity. J Agric Food Chem 2011; 59: 6748-6758
• 115 Eugster PJ, Guillarme D, Rudaz S, Veuthey JL, Carrupt PA, Wolfender JL. Ultra high pressure liquid chromatography for crude plant extract profiling. J AOAC Int 2011; 94: 51-70
• 116 Farag MA, Porzel A, Schmidt J, Wessjohann LA. Metabolite profiling and fingerprinting of commercial cultivars of Humulus lupulus L. (hop): a comparison of MS and NMR methods in metabolomics. Metabolomics 2012; 8: 492-507
• 117 Farag MA, Huhman DV, Lei Z, Sumner LW. Metabolic profiling and systematic identification of flavonoids and isoflavonoids in roots and cell suspension cultures of Medicago truncatula using HPLC–UV–ESI–MS and GC–MS. Phytochemistry 2007; 68: 342-354
• 118 Montoro P, Maldini M, Russo M, Postorino S, Piacente S, Pizza C. Metabolic profiling of roots of liquorice (Glycyrrhiza glabra) from different geographical areas by ESI/MS/MS and determination of major metabolites by LC-ESI/MS and LC-ESI/MS/MS. J Pharm Biomed Anal 2011; 54: 535-544
• 119 Simons R, Vincken JP, Bakx EJ, Verbruggen MA, Gruppen H. A rapid screening method for prenylated flavonoids with ultra-high-performance liquid chromatography/electrospray ionisation mass spectrometry in licorice root extracts. Rapid Commun Mass Spectrom 2009; 23: 3083-3093
• 120 Hanhineva K, Rogachev I, Aura AM, Aharoni A, Poutanen K, Mykkänen H. Identification of novel lignans in the whole grain rye bran by non-targeted LC–MS metabolite profiling. Metabolomics 2012; 8: 399-409
• 121 Jaroszewski JW. Hyphenated NMR methods in natural products research, Part 2: HPLC-SPE-NMR and other new trends in NMR hyphenation. Planta Med 2005; 71: 795-802
• 122 Lambert M, Hansen SH, Sairafianpour M, Jaroszewski JW. Rapid extract dereplication using HPLC-SPE-NMR: analysis of isoflavonoids from Smirnowia iranica . J Nat Prod 2005; 68: 1500-1509
• 123 Wang CY, Lam SH, Tseng LH, Lee SS. Rapid screening of lignans from Phyllanthus myrtifolius and stilbenoids from Syagrus romanzoffiana by HPLC-SPE-NMR. Phytochem Anal 2011; 22: 352-360
• 124 Wang CY, Lee SS. Analysis and identification of lignans in Phyllanthus urinaria by HPLC-SPE-NMR. Phytochem Anal 2005; 16: 120-126
• 125 Schütz C, Quitschau M, Hamburger M, Potterat O. Profiling of isoflavonoids in Iris germanica rhizome extracts by microprobe NMR and HPLC–PDA–MS analysis. Fitoterapia 2011; 82: 1021-1026
• 126 Djiogue S, Halabalaki M, Alexi X, Njamen D, Fomum ZT, Alexis MN, Skaltsounis AL. Isoflavonoids from Erythrina poeppigiana: evaluation of their binding affinity for the estrogen receptor. J Nat Prod 2009; 72: 1603-1607
• 127 Djiogue S, Njamen D, Halabalaki M, Kretzschmar G, Beyer A, Mbanya JC, Skaltsounis AL, Vollmer G. Estrogenic properties of naturally occurring prenylated isoflavones in U2OS human osteosarcoma cells: Structure–activity relationships. J Steroid Biochem Mol Biol 2010; 120: 184-191
• 128 Boué SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE. Evaluation of the estrogenic effects of legume extracts containing phytoestrogens. J Agric Food Chem 2003; 51: 2193-2199
• 129 Lai WC, Wang HC, Chen GY, Yang JC, Korinek M, Hsieh CJ, Nozaki H, Hayashi KI, Wu CC, Wu YC, Chang FR. Using the pER8:GUS reporter system to screen for phytoestrogens from Caesalpinia sappan . J Nat Prod 2011; 74: 1698-1706
• 130 Tsai YC, Lai WC, Du YC, Wu SF, El-Shazly M, Lee CL, Yen MH, Hou MF, Wu YC, Chang FR. Lignan and flavonoid phytoestrogens from the seeds of Cuscuta chinensis . J Nat Prod 2012;
• 131 Umehara K, Nemoto K, Matsushita A, Terada E, Monthakantirat O, De-Eknamkul W, Miyase T, Warashina T, Degawa M, Noguchi H. Flavonoids from the heartwood of the thai medicinal plant Dalbergia parviflora and their effects on estrogenic-responsive human breast cancer cells. J Nat Prod 2009; 72: 2163-2168
• 132 De Naeyer A, Vanden Berghe W, Pocock V, Milligan S, Haegeman G, De Keukeleire D. Estrogenic and anticarcinogenic properties of kurarinone, a lavandulyl flavanone from the roots of Sophora flavescens . J Nat Prod 2004; 67: 1829-1832
• 133 Shi SY, Zhang YP, Jiang XY, Chen XQ, Huang KL, Zhou HH. Coupling HPLC to on-line, post-column (bio)chemical assays for high-resolution screening of bioactive compounds from complex mixtures. Trends Anal Chem 2009; 28: 865-877
• 134 Oosterkamp AJ, Villaverde Herraiz MT, Irth H, Tjaden UR, van der Greef J. Reversed-phase liquid chromatography coupled on-line to receptor affinity detection based on the human estrogen receptor. Anal Chem 1996; 68: 1201-1206
• 135 van Elswijk DA, Irth H. Analytical tools for the detection and characterization of biologically active compounds from nature. Phytochem Rev 2002; 1: 427-439
• 136 Schobel U, Frenay M, Van Elswijk DA, McAndrews JM, Long KR, Olson LM, Bobzin SC, Irth H. High resolution screening of plant natural product extracts for estrogen receptor α and β binding activity using an online HPLC-MS biochemical detection system. J Biomol Screen 2001; 6: 291-303
• 137 van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J. Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry 2004; 65: 233-241
• 138 Reinen J, Kool J, Vermeulen N. Reversed-phase liquid chromatography coupled on-line to estrogen receptor bioaffinity detection based on fluorescence polarization. Anal Bioanal Chem 2008; 390: 1987-1998
• 139 Jonker N, Kool J, Irth H, Niessen W. Recent developments in protein–ligand affinity mass spectrometry. Anal Bioanal Chem 2011; 399: 2669-2681
• 140 Schriemer DC, Bundle DR, Li L, Hindsgaul O. Micro-scale frontal affinity chromatography with mass spectrometric detection: A new method for the screening of compound libraries. Angew Chem Int Ed 1998; 37: 3383-3387
• 141 Slon-Usakiewicz JJ, Ng W, Dai JR, Pasternak A, Redden PR. Frontal affinity chromatography with MS detection (FAC-MS) in drug discovery. Drug Discov Today 2005; 10: 409-416
• 142 Calleri E, Temporini C, Caccialanza G, Massolini G. Target-based drug discovery: the emerging success of frontal affinity chromatography coupled to mass spectrometry. ChemMedChem 2009; 4: 905-916
• 143 Chan NWC, Lewis DF, Rosner PJ, Kelly MA, Schriemer DC. Frontal affinity chromatography–mass spectrometry assay technology for multiple stages of drug discovery: applications of a chromatographic biosensor. Anal Biochem 2003; 319: 1-12
• 144 Moaddel R, Lu L, Baynham M, Wainer IW. Immobilized receptor- and transporter-based liquid chromatographic phases for on-line pharmacological and biochemical studies: a mini-review. J Chromatogr B 2002; 768: 41-53
• 145 Ng W, Dai JR, Slon-Usakiewicz JJ, Redden PR, Pasternak A, Reid N. Automated multiple ligand screening by Frontal Affinity Chromatography–Mass Spectrometry (FAC-MS). J Biomol Scr 2007; 12: 167-174
• 146 van Breemen RB, Huang CR, Nikolic D, Woodbury CP, Zhao YZ, Venton DL. Pulsed ultrafiltration mass spectrometry: a new method for screening combinatorial libraries. Anal Chem 1997; 69: 2159-2164
• 147 Johnson BM, Nikolic D, van Breemen RB. Applications of pulsed ultrafiltration-mass spectrometry. Mass Spectrom Rev 2002; 21: 76-86
• 148 Liu J, Burdette JE, Xu H, Gu C, van Breemen RB, Bhat KPL, Booth N, Constantinou AI, Pezzuto JM, Fong HHS, Farnsworth NR, Bolton JL. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001; 49: 2472-2479
• 149 Liu J, Burdette JE, Sun Y, Deng S, Schlecht SM, Zheng W, Nikolic D, Mahady G, van Breemen RB, Fong HHS, Pezzuto JM, Bolton JL, Farnsworth NR. Isolation of linoleic acid as an estrogenic compound from the fruits of Vitex agnus-castus L. (chaste-berry). Phytomedicine 2004; 11: 18-23
• 150 Overk CR, Yao P, Chadwick LR, Nikolic D, Sun Y, Cuendet MA, Deng Y, Hedayat AS, Pauli GF, Farnsworth NR, van Breemen RB, Bolton JL. Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). J Agric Food Chem 2005; 53: 6246-6253
• 151 Choi Y, van Breemen RB. Development of a screening assay for ligands to the estrogen receptor based on magnetic microparticles and LC-MS. Comb Chem High Throughput Screen 2008; 11: 1-6
• 152 Onorato J, Henion JD. Evaluation of triterpene glycoside estrogenic activity using LC/MS and immunoaffinity extraction. Anal Chem 2001; 73: 4704-4710
• 153 Jonker N, Kretschmer A, Kool J, Fernandez A, Kloos D, Krabbe JG, Lingeman H, Irth H. Online magnetic bead dynamic protein-affinity selection coupled to LC−MS for the screening of pharmacologically active compounds. Anal Chem 2009; 81: 4263-4270
• 154 Voldman J, Gray ML, Schmidt MA. Microfabrication in biology and medicine. Annu Rev Biomed Eng 1999; 1: 401-425
• 155 Kostelac D, Rechkemmer G, Briviba K. Phytoestrogens modulate binding response of estrogen receptors α and β to the estrogen response element. J Agric Food Chem 2003; 51: 7632-7635
• 156 Chuang YJ, Huang JW, Makamba H, Tsai ML, Li CW, Chen SH. Electrophoretic mobility shift assay on poly(ethylene glycol)-modified glass microchips for the study of estrogen responsive element binding. Electrophoresis 2006; 27: 4158-4165
• 157 Imura Y, Sato K, Yoshimura E. Micro total bioassay system for ingested substances: Assessment of intestinal absorption, hepatic metabolism, and bioactivity. Anal Chem 2010; 82: 9983-9988
• 158 Lavecchia T, Tibuzzi A, Giardi M. Biosensors for functional food safety and analysis. In: Giardi M, Rea G, Berra B, editors Bio-farms for nutraceuticals, Vol 698. Advances in experimental medicine and biology. Berlin, Heidelberg: Springer; 2010: 267-281
• 159 Andreescu S, Sadik OA. Correlation of analyte structures with biosensor responses using the detection of phenolic estrogens as a model. Anal Chem 2003; 76: 552-560
• 160 Dumbrepatil AB, Lee SG, Chung SJ, Lee MG, Park BC, Kim TJ, Woo EJ. Development of a nanoparticle-based FRET sensor for ultrasensitive detection of phytoestrogen compounds. Analyst 2010; 135: 2879-2886
• 161 Liang K, Yang L, Xiao Z, Huang J. A bipartite recombinant yeast system for the identification of subtype-selective estrogen receptor ligands. Mol Biotechnol 2009; 41: 53-62
• 162 Carmon KS, Baltus RE, Luck LA. A biosensor for estrogenic substances using the quartz crystal microbalance. Anal Biochem 2005; 345: 277-283
• 163 Shinomiya K, Kabasawa Y, Nakazawa H, Ito Y. Countercurrent chromatographic separation of soybean isoflavones by two different types of coil planet centrifuges with various two-phase solvent systems. J Liq Chromatogr Relat Technol 2003; 26: 3497-3509
• 164 Yanga F, Mab Y, Ito Y. Separation and purification of isoflavones from a crude soybean extract by high-speed counter-current chromatography. J Chromatogr A 2001; 928: 163-170
• 165 Feng ZF, Chen XF, Zhang J, Di DL. Activity-screening-guided isolation and purification for vasodilative effects compounds from Radix Astragali by high-speed counter-current chromatography using gradient elution. Nat Prod Res [in press]
• 166 Ma CJ, Li GS, Zhang DL, Liu K, Fan X. One step isolation and purification of liquiritigenin and isoliquiritigenin from Glycyrrhiza uralensis Risch. using high-speed counter-current chromatography. J Chromatogr A 2005; 1078: 188-192
• 167 Zhang T, Cao X, Han X. Preparation of national certified reference materials of active compounds from natural products by CCC. J Liq Chromatogr Relat Technol 2003; 26: 1565-1577
• 168 Sil Lee Y, Ha Kim S, Kyu Kim J, Shin HK, Kang YH, Yoon Park JH, Lim SS. Rapid identification and preparative isolation of antioxidant components in licorice. J Sep Sci 2010; 33: 664-671
• 169 Chen QH, Fu ML, Chen MM, Liu J, Liu XJ, He GQ, Pu SC. Preparative isolation and purification of xanthohumol from hops (Humulus lupulus L.) by high-speed counter-current chromatography. Food Chem 2012; 132: 619-623
• 170 Renault JH, Voutquenne L, Caron C, Zeches-Hanrot M, Berwanger S, Becker H. Purification of xanthohumol from Humulus lupulus by centrifugal partition chromatography using an original acetone based solvent scale. J Liq Chromatogr Relat Technol 2006; 29: 761-771
• 171 Chu X, Sun A, Liu R. Preparative isolation and purification of five compounds from the Chinese medicinal herb Polygonum cuspidatum Sieb. et Zucc by high-speed counter-current chromatography. J Chromatogr A 2005; 1097: 33-39
• 172 Bisson J, Poupard P, Pawlus AD, Pons A, Darriet P, Mérillon JM, Waffo-Téguo P. Development of hybrid elution systems for efficient purification of stilbenoids using centrifugal partition chromatography coupled to mass spectrometry. J Chromatogr A 2011; 1218: 6079-6084
• 173 Zga N, Papastamoulis Y, Toribio A, Richard T, Delaunay JC, Jeandet P, Renault JH, Monti JP, Mérillon JM, Waffo-Téguo P. Preparative purification of antiamyloidogenic stilbenoids from Vitis vinifera (Chardonnay) stems by centrifugal partition chromatography. J Chromatogr B 2009; 877: 1000-1004
• 174 Delaunay JC, Castagnino C, Chèze C, Vercauteren J. Preparative isolation of polyphenolic compounds from Vitis vinifera by centrifugal partition chromatography. J Chromatogr A 2002; 964: 123-128
• 175 Yang F, Zhang T, Ito Y. Large-scale separation of resveratrol, anthraglycoside A and anthraglycoside B from Polygonum cuspidatum Sieb. et Zucc by high-speed counter-current chromatography. J Chromatogr A 2001; 919: 443-448
• 176 Abbott JA, Medina-Bolivar F, Martin EM, Engelberth AS, Villagarcia H, Clausen EC, Carrier DJ. Purification of resveratrol, arachidin-1, and arachidin-3 from hairy root cultures of peanut (Arachis hypogaea) and determination of their antioxidant activity and cytotoxicity. Biotechnol Prog 2010; 26: 1344-1351
• 177 Degenhardt A, Habben S, Winterhalter P. Isolation of the lignan secoisolariciresinol diglucoside from flaxseed (Linum usitatissimum L.) by high-speed counter-current chromatography. J Chromatogr A 2002; 943: 299-302
• 178 Ma CJ, Li GS, Zhang DL, Liu K, Fan X. One step isolation and purification of liquiritigenin and isoliquiritigenin from Glycyrrhiza uralensis Risch. using high-speed counter-current chromatography. J Chromatogr A 2005; 1078: 188-192
• 179 Liu H, Yuan Q, Li CF, Huang TX. Isolation and purification of silychristin, silydianin and taxifolin in the co-products of the silybin refined process from the silymarin by high-speed counter-current chromatography. Proce Biochem 2010; 45: 799-804
• 180 Engelberth AS, Carrier DJ, Clausen EC. Separation of silymarins from milk thistle (Silybum marianum L.) extracted with pressurized hot water using fast centrifugal partition chromatography. J Liq Chromatogr Relat Technol 2008; 31: 3001-3011
• 181 Qizhen D, Weijian C, Ito Y. Preparative separation of fruit extract of Silybum marianum using a high-speed countercurrent chromatograph with scale-up columns. J Liq Chromatogr Relat Technol 2002; 25: 2515-2520