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Isolation and Identification of Compounds Conferring ISOLATION AND IDENTIFICATION OF COMPOUNDS CONFERRING PHYTOESTROGENIC ACTIVITY TO CYCLOPIA EXTRACTS by Morné Francois Mortimer Thesis presented in partial fulfilment of the requirements for the degree of Master of Science in the Faculty of Science at Stellenbosch University Supervisor: Prof. Ann Louw Co-supervisor: Prof. Elizabeth Joubert December 2014 i Stellenbosch University http://scholar.sun.ac.za Declaration By submitting this thesis electronically, I declare that the entirety of the work contained therein is my own, original work, that I am the sole author thereof (save to the extent explicitly otherwise stated), that reproduction and publication thereof by Stellenbosch University will not infringe any third party rights and that I have not previously in its entirety or in part submitted it for obtaining any qualification. April 2014 Copyright © 2014 Stellenbosch University All rights reserved ii Stellenbosch University http://scholar.sun.ac.za Summary Phytoestrogens are perceived as a safer alternative to conventional hormone replacement therapy (HRT) for the alleviation of menopausal symptoms as they present a decreased side-effect profile. The Cyclopia subternata (honeybush) methanol extract, SM6Met, displays estrogenic attributes desirable for the development of an phytoestrogenic nutraceutical, namely, estrogen receptor (ER) α antagonism, ERβ agonism, and antagonism of 17β-estradiol (E2)-induced breast cancer cell proliferation. Activity-guided fractionation was employed in an attempt to isolate and identify the compounds inducing the specific estrogenic profile of SM6Met. Fractions were evaluated for estrogenic attributes and major polyphenols present. Initial liquid-liquid fractionation of SM6Met yielded a polar fraction (PF) and a non-polar fraction (NPF), with the estrogenic attributes of interest retained and concentrated in NPF. Subsequent high performance counter-current chromatography (HPCCC) fractionation of NPF yielded three fractions (F1-F3). Interestingly, the fractions revealed separation of the previously demonstrated positive estrogenic attributes of NPF into separate fractions, with F1 and F2 acting as ERα antagonists, only F2 inducing antagonism of E2-induced breast cancer cell proliferation and only F3 retaining ERβ agonist activity. Although ERβ agonism displayed by F3 -11 was robust and significantly higher than that of 10 M E2, it also displayed weak ERα agonism. Fractionation also for the first time in the study revealed ERβ antagonism, as induced by F1. In terms of major polyphenols HPCCC fractionation resulted in a divergence with F1 emerging as the dihydrochalcone-rich fraction and F2 as the flavanone and benzophenone-rich fraction, while the xanthones, flavones and phenolic acids were retained in F3. In addition, a preliminary absorption study was conducted using the ex vivo flow-through diffusion assay whereby the permeability of porcine small and large intestine for polyphenols in SM6Met was evaluated. The major compounds present in SM6Met were not able to penetrate the large intestinal mucosa, but small intestinal permeation of all major compounds in SM6Met ensued, with apparent iii Stellenbosch University http://scholar.sun.ac.za -6 -1 permeability coefficient (Papp) values ranging from 1.91-3.74 x 10 cm.s , indicative of good intestinal absorption. Open source programs used for theoretical prediction of absorption gave conflicting results, emphasising the need to confirm predictions experimentally. ACD/Labs predicted poor intestinal absorption of SM6Met compounds based on physicochemical profiling, while OSIRIS and ChemAxon anticipated good absorption. In conclusion, activity-guided fractionation results suggest that retention of all the positive estrogenic attributes of the original SM6Met in one fraction is not an attainable goal. This suggests that several of the polyphenols present in SM6Met or NPF, through antagonistic, synergistic, or additive effects, may together be conferring these desired estrogenic traits. Thus production or isolation of a mixture of compounds, i.e. an ―intelligent‖ mixture, should serve as a superior strategy in designing a nutraceutical product tailored to user demand of estrogenic activity. iv Stellenbosch University http://scholar.sun.ac.za Opsomming Fitoestrogene word beskou as ‗n veiliger alternatief vir konvensionele hormoon-vervangingsterapie (HVT) vir die verligting van simptome geassosiaeer met menopause aangesien dit ‗n verminderde newe-effek profiel vertoon. Die metanol ekstrak van Cyclopia subternata (heuningbos), SM6Met, vertoon estrogeniese eienskappe wat wenslik is vir die ontwikkeling van ‗n fitoestrogeen nutraseutiese middel, naamlik, estrogeen reseptor (ER) α antagonisme en ERβ agonisme, asook antagonisme van 17β-estradiol (E2) geïnduseerde proliferasie van borskankerselle. Aktiwiteit-begeleide fraksionering (ABF) is gebruik om die verbindings wat die spesifieke estrogeniese profiel aan SM6Met verleen te probeer isoleer en identifiseer. Fraksies is ge-evalueer vir estrogeniese eienskappe, asook vir die hoof polifenole teenwoordig. Aanvankilike vloeistof- vloeistof fraksionering van SM6Met het ‗n polêre fraksie (PF) en ‗n nie-polêre fraksie (NPF) opgelewer met behoud en konsentrering van die wenslike estrogeniese eienskappe in NPF. Daaropeenvolgende hoë werkverrigting teen-vloei chromatografie (HPCCC) van NPF het drie fraksies (F1-F3) opgelewer. Interessant genoeg het hierdie fraksies ‗n verdeling van die wenslike estrogeniese eienskappe van NPF in die individuele fraksies teweeggebring, deurdat F1 en F2 ERα antagonisme getoon het, F2 E2-geïnduseerde proliferasie van borskankerselle antagoniseer het, en net F3 ERβ agonis-aktiwiteit behou het. Alhoewel die ERβ agonis-aktiwiteit van F3 betekenisvol -11 hoër was in vergelyking met die aktiwiteit van 10 M E2, het dit ook swak ERα agonisme getoon. Verder het fraksionering, vir die eerste keer in hierdie studie, ERβ antagonisme meegebring soos getoon deur F1. HPCCC het ook ‗n skeiding van die hoof polifenole veroorsaak, waarvolgens F1 as die dihidrogalkoon-ryke fraksie, F2 as die bensofenoon-ryke en flavanoon-ryke fraksie, en F3 as die xantoon-, flavoon- en fenoliese suur-ryke fraksie tevoorskyn gekom het. ‗n Voorlopige absorpsie studie, wat gebruik gemaak het van die ex vivo deurvloei diffusie toetssisteem, is uitgevoer om die deurlaatbaarheid van vark dik- en dunderm vir SM6Met polifenole te evalueer. Die hoof verbindings van SM6Met kon nie die dikderm mukosa penetreer nie, maar die v Stellenbosch University http://scholar.sun.ac.za deurlaatbaarheid van die dunderm vir alle SM6Met hoof polifenole is aangetoon, met skynbare -6 -1 deurlaatbaarheidskoëffisiënt (Papp) waardes wat strek vanaf 1.91 tot 3.74 x 10 cm.s , ooreenstemmend met goeie intestinale absorpsie. Oopbron programme, wat gebruik is vir die teoretiese voorspelling van absorpsie deur gebruik te maak van fisiese-chemiese profilering van verbindings, het teenstellende resultate opgelewer wat daarop dui dat hierdie voorspellings eksperimenteel bevestig moet word. ACD/Labs, wat van die fisiese-chemiese eienskappe van die verbinding gebruik maak, het swak intestinale absorpsie van die polifenole voorspel, terwyl OSIRIS en ChemAxon goeie absorpsie voorspel het. Ten slotte, resultate van aktiwiteit-begeleide fraksionering het getoon dat behoud van al die gewensde estrogeniese eienskappe van SM6Met in een fraksie nie ‗n haalbare doelwit is nie. Hierdie bevinding dui daarop dat verskeie van die polifenole teenwoordig in SM6Met of NPF saam, deur middel van antagonistiese, sinergistiese of additiewe effekte, die wenslike estrogeniese eieskappe verleen. Die ontwikkeling of isolering van ‗n mengsel van verbindings, met ander woorde‗n ―intelligente‖ mengsel is dus ‗n beter strategie vir die ontwerp van ‗n estrogeniese nutraseutiese produk om die verbruikers-aanvraag van estrogeniese aktiwiteit te voorsien. vi Stellenbosch University http://scholar.sun.ac.za Acknowledgements My supervisor, Prof. Ann Louw, and co-supervisor, Prof. Elizabeth Joubert, thank you so much for giving me the opportunity to pursue this study. Your guidance and patience is greatly appreciated as it allowed me to understand the makings of a well-rounded scientist. To the members of the Louw and Africander laboratory, thank you for all your kind words, support, and for making these two laboratories a friendly environment, which allowed sharing of not only knowledge but also personal issues. Carmen Langeveldt, thank you for managing the Louw and Africander laboratories so efficiently, but more importantly, thank you for the vast amount of hours spent in tissue culture in order to maintain and seed our cells. Dr. Dalene de Beer, I greatly appreciate the time you expended helping me to correctly execute the HPCCC, qHPLC and LC-MS/MS techniques, furthermore, I thank you for your help with the analysis the of results obtained by means of these techniques. Dr. Elize Willenburg, thank you very much for your help with the use of the HPCCC machine, and also your help with the analysis of the HPCCC-obtained results. I would also like to thank Dr. Willenburg for supplying us with the necessary amounts of the scolymoside-enriched fraction and the iriflophenone-3-C-glucoside-enriched fraction. The Harry Crossley Foundation, thank you for financial support. Employees of the Central Analytical Facility (CAF), Stellenbosch University, thank you for your time and guidance with the LC-MS/MS analyses. Thank you to my friends and family for emotional support, and standing by me through thick
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