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Investigations on Aurones As Modulators of Abcg2

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INVESTIGATIONS ON AURONES AS MODULATORS OF ABCG2 SIM HONG MAY (B. Sc. (Pharmacy) (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2010 Acknowledgements First and foremost, I would like to express my heartfelt gratitude to my supervisor Assoc. Prof. Go Mei Lin for her unwavering support and encouragement throughout the whole course of my research. This piece of thesis work would not be possible without her advice and insights into the research topic. I would also like to thank Dr Rachel Ee Pui Lai for her advice in my research and the offer of cell lines (MDA-MB-231/V and R) as well as the opportunity to carry out biological assays (Western Blotting) in her laboratory in the Department of Pharmacy. Special thanks to my senior, Dr Lee Chong Yew for the contribution of his aurones to my research work as well as the constant help in bench work and the encouragement rendered especially in the early years of my graduate studies. Many thanks to the past and present members of the Medicinal Chemistry Laboratory at the Department of Pharmacy for their camaraderie and sharing of knowledge and research experiences: Dr. Liu Xiao Ling, Dr. Suresh Kumar Gorla, Dr Zhang Wei, Dr Leow Jolene, Mr Yeo Wee Kiang, Ms Nguyen Thi Hanh Thuy, Mr Wee Xi Kai, Mr Pondy Murgappan Ramanujulu, Dr Yang Tian Ming, Ms Tan Kheng Lin and Ms Chen Xiao. Appreciation also goes out to the past research assistants and final year students: Ms Tee Hui Wearn, Ms Audrey Chan Xie Wah, and Ms Loh Ker Yun for their help in my project. I would also like to thank Dr Han Yi, Dr Tian Quan, Ms Leow Pay Chin and Ms Ong Zhan Yuin from Dr Rachel Ee’s laboratory for their advice and assistance in biological work. Appreciation goes to Mdm Oh Tang Booy, Ms. Ng Sek Eng and the rest of the technical staff at the Department of Pharmacy. Research is made easier with their help in the purchasing of chemicals/biologicals and trouble-shooting of machines. I would like to acknowledge the financial support for my graduate studies from the National University of Singapore Research Scholarship. ii Last but not least, I would like to thank my parents and family for their constant support, understanding and concern throughout the course of my graduate studies. iii Conferences and Publications 1) Hong-May Sim, Pui-Lai Rachel Ee and Mei-Lin Go, 4, 6-Dimethoxyaurones as Dual Modulators of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), European School of Medicinal Chemistry (ESMEC), 6th to 11th July 2008, Urbino, Italy. 2) Hong-May Sim and Mei-Lin Go, Structurally Modified Aurones as Inhibitors of the ATP Binding Cassette Transport Protein ABCG2 (Breast Cancer Resistance Protein), 10th Asia Pacific Rim Universities Doctoral Students Conference (APRU DSC), 6th to 10th July 2009, Kyoto, Japan. 3) Hong-May Sim and Mei-Lin Go, Structurally Modified Aurones: Inhibitors of the ATP Binding Cassette Transport Proteins Breast Cancer Resistance Protein (ABCG2) and P- glycoprotein (ABCB1), 7th International Symposium for Chinese Medicinal Chemists (ISCMC), 1st to 5th Feb 2010, Kaoshiung, Taiwan. 4) Sim. H.M., Lee, C.Y., Ee, P.L.R., Go, M.L., Dimethoxyaurones: Potent inhibitors of ABCG2 (breast cancer resistance protein) European Journal of Pharmaceutical Sciences, 35, 2008, 293-306. Manuscripts in preparation: 1) Sim. H.M., Lee, C.Y., Yeo, W.K., Loh, K.Y., Ee, P.L.R., Go, M.L., Structurally modified aurones as modulators of ABCG2: Structure-activity relationships and pharmacophore modeling. 2) Sim. H.M., Wu. C.P., Ee, P.L.R., Ambudkar. S., Go, M.L., In vitro and in vivo evaluations of structurally modified aurones as modulators of ABCG2 iv Table of Contents Acknowledgements………………………………………………………………………………...ii Conferences and Publications………………………………………………………………..........iv Table of contents…...........................................................................................................................v Summary……………………………………………………………………………………..........vi List of Tables…………………………………………………………………………………….viii List of Figures……………………………………………………………………………………...x List of Schemes…………………………………………………………………………………...xv List of Abbreviations…………………………………………………………………………….xvi Chapter 1: Introduction……………………………………………………………………..1 1.1. Multidrug resistance (MDR) and ATP-Binding Cassette (ABC) transporters……………1 1.2. Structural features of ABCB1 and ABCG2………………………………………………2 1.3. Functions of ABCB1 and ABCG2………………………………………………………..4 1.4. Substrates and Inhibitors of ABCB1 and ABCG2………………………………………..6 1.5. Flavonoids as MDR reversal agents……………………………………………………..12 1.6. Aurones as modulators of ABC transporter proteins …………………………………...16 1.7. Statement of Purpose…………………………………………………………………….18 Chapter 2: Design and Synthesis of Target Compounds…………………………………21 2.1. Introduction…………………………………………………………………………21 2.2. Rationale of design………………………………………………………………….22 2.2.1. Series 1-5……………………………………………………………………………23 2.2.2. Series 6-12…………………………………………………………………………..29 2.3. Chemical considerations.............................................................................................37 2.3.1. Aurones (Series 1, 2, 5) and Dehydroaurones (Series 8)…………………………....37 2.3.2. Indanones (Series 6)………………………………………………………………...42 v 2.3.3. Aza-aurones (Series 7)………………………………………………………………43 2.3.4. Chalcones (Series 11)……………………………………………………………….47 2.3.5. Flavones (Series 12)………………………………………………………………...47 2.4. Assignment of configurations……………………………………………………….49 2.4.1. Aurones (Series 1, 2, 5) and dehydroaurones (Series 8)……………………………49 2.4.2. Indanones (Series 6)………………………………………………………………...51 2.4.3. 4, 6-Dimethoxy aza-aurones (Series 7)…………………………………………......52 2.4.4. 2′-Hydroxy, 4’6’-dimethoxy chalcones (Series 11)………………………………...55 2.5. Experimental methods………………………………………………………………57 2.5.1. General details……………………………………………………………………....57 2.5.2. General procedure for the synthesis of series 1, 2, 6 and 8 (4, 6-dimethoxy-aurones, 4, 5, 6-trimethoxy-aurones, unsubstituted (Ring A) aurones and 4, 5, 6-trimethoxy dehydro aurone)……………………………………………………………………………………….58 2.5.2.1. 4, 6-Dimethoxy-aurones…………………………………………………………….58 2.5.2.1.1. 3, 5-Dimethoxyphenoxyacetic acid (A-1)…………………………………………58 2.5.2.1.2. 4, 6-Dimethoxybenzofuran-3(2H)-one (A-3)……………………………………...59 2.5.2.2. 4, 5, 6-Trimethoxy-aurones………………………………………………………….59 2.5.2.2.1. 3, 4, 5-Trimethoxyphenoxyacetic acid (A-2)……………………………………...59 2.5.2.2.2. 4, 5, 6-Dimethoxybenzofuran-3(2H)-one (A-4)…………………………………...59 2.5.2.3 General procedure for the synthesis of 4, 6-dimethoxyaurones and 4, 5, 6- trimethoxyaurones (Compounds 1-1 to 1-28, 2-1 to 2-10)…………………………………..60 2.5.2.4 Procedure for synthesis of (Z)-2-(cyclohexylmethylene)-4, 5, 6- trimethoxybenzofuran-3(2H)-one (2-11)…………………………………………………….61 2.5.2.5 General procedure for the synthesis of unsubstituted aurones (Compounds 5-1 to 5- 8).…………………………………………………………………………………………….61 vi 2.5.2.6 General procedure for the synthesis of 4, 5, 6-trimethoxydehydroaurone (Compound 8-3)……………………………………………………………………………...62 2.5.3 General procedure for the synthesis of 4, 6-dimethoxy-indanones (Compounds 6-1 to 6- 2)……………………………………………………………………………………………..62 2.5.3.1. 3, 5-Dimethoxypropanoic acid (I-1)………………………………………………...62 2.5.3.2. 5, 7-Dimethoxy-2, 3-dihydro-1H-inden-1-one (I-2)………………………………...63 2.5.3.3. Condensation of I-2 with substituted benzaldehydes………………………………..64 2.5.4 General procedure for the synthesis of 4, 6-dimethoxy-aza-aurones (Compounds 7-1 to 7-8)…………………………………………………………………………………………...64 2.5.4.1. 2-Amino-4,6-dimethoxy-α-chloroacetophenone (AZ-1)……………………………64 2.5.4.2. 1-Acetyl-4,6-dimethoxy-2,3-dihydro-1H-indole-3-one (AZ-2)……………………..65 2.5.4.3. Condensation of AZ-2 with substituted benzaldehydes……………………………..66 2.5.5. General procedure for the synthesis of 2′-hydroxy-4′, 6′-dimethoxychalcones (Compounds 11-1 to 11-5)…………………………………………………………………...66 2.5.6. General procedure for the synthesis of 5, 7-dimethoxy flavones (Compounds 12-1 to 12-5)………………………………………………………………………………………….67 2.5.7. Protection and deprotection of phenolic hydroxyl groups on 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 3, 4-dihydroxybenzaldehyde, 3, 5-dihydroxybenzaldehyde, 3- hydroxy-4-methoxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde………………..67 2.5.8. X-ray crystallography of compounds 1-2 and 6-20…………………………………..68 2.5.9 High pressure liquid chromatography (HPLC) analyses………………………………68 2.6 Summary…………………………………………………………………………………69 Chapter 3: Effects of aurones and related compounds on the efflux of pheophorbide a (PhA) by ABCG2 over-expressing human breast cancer (MDA-MB-231/R) cells and calcein-AM (CAM) by ABCB1 over-expressing Mardin-Darby canine kidney (MDCK) cells………………………………………………………………………………………….70 3.1. Introduction……………………………………………………………………………..70 3.2. Experimental…………………………………………………………………………….70 3.2.1. Cell lines and materials for biological assay…………………………………………..70 vii 3.2.2. Procedure for western blot analysis…………………………………………………...71 3.2.3. Procedure for PhA accumulation assay………………………………………………..71 3.2.4. Procedure for calcein-AM (CAM) accumulation assay……………………………….73 3.2.5. Statistical Analysis…………………………………………………………………….75 3. 3. Results…………………………………………………………………………………..76 3.3.1. Determination of EC50 from PhA assay……………………………………………….76 3.3.2. Determination of EC50 from CAM assay……………………………………………...78 3.3.3. Effect of structural modifications on efflux of PhA by ABCG2 over-expressing human breast cancer (MDA-MB-231/R) cells……………………………………………………….81 3.3.3.1. Series 1-5 compounds with mono-substituted
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    ResearchOnline@JCU This is the Accepted Version of a paper published in the Journal: Critical Reviews in Food Science and Nutrition Hughes, Samuel D., Ketheesan, Natkunam, and Haleagrahara, Nagaraja (2017) The therapeutic potential of plant flavonoids on rheumatoid arthritis. Critical Reviews in Food Science and Nutrition, 57 (17). pp. 3601-3613. http://dx.doi.org/10.1080/10408398.2016.1246413 © 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Critical Reviews in Food Science and Nutrition ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: http://www.tandfonline.com/loi/bfsn20 The Therapeutic Potential of Plant Flavonoids on Rheumatoid Arthritis Samuel D. Hughes, Natkunam Ketheesan & Nagaraja Haleagrahara To cite this article: Samuel D. Hughes, Natkunam Ketheesan & Nagaraja Haleagrahara (2016): The Therapeutic Potential of Plant Flavonoids on Rheumatoid Arthritis, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2016.1246413 To link to this article: http://dx.doi.org/10.1080/10408398.2016.1246413 Accepted author version posted online: 22 Nov 2016. Submit your article to this journal Article views: 122 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=bfsn20 Download by: [JAMES COOK UNIVERSITY] Date: 23 March 2017, At: 16:37 ACCEPTED MANUSCRIPT The Therapeutic Potential of Plant Flavonoids on Rheumatoid Arthritis Samuel D. Hughes1, Natkunam Ketheesan2 & Nagaraja Haleagrahara3,* 1,2,3Biomedicine, College of Public Health, Medical & Veterinary Sciences, and 2, 3Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Townsville, Australia *Address correspondence to: Nagaraja Haleagrahara, Biomedicine, College of Public Health, Medical & Veterinary Sciences, James Cook University, Townsville, Australia.
  • EP1776161B1.Pdf

    EP1776161B1.Pdf

    (19) TZZ____T (11) EP 1 776 161 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61Q 5/02 (2006.01) A61Q 7/00 (2006.01) 26.10.2016 Bulletin 2016/43 A61Q 19/00 (2006.01) A61K 8/36 (2006.01) A61K 8/362 (2006.01) A61K 8/37 (2006.01) (2006.01) (2006.01) (21) Application number: 05718804.7 A61K 8/39 A61Q 1/02 A61Q 5/06 (2006.01) A61K 8/64 (2006.01) A61Q 5/12 (2006.01) A61Q 11/00 (2006.01) (22) Date of filing: 25.04.2005 A61K 8/81 (2006.01) A61Q 19/06 (2006.01) A61Q 19/08 (2006.01) A61K 8/97 (2006.01) A61K 8/42 (2006.01) A61K 8/49 (2006.01) A61Q 5/00 (2006.01) A61K 8/73 (2006.01) (86) International application number: PCT/IB2005/051344 (87) International publication number: WO 2005/102266 (03.11.2005 Gazette 2005/44) (54) COSMETIC OR DERMOPHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ONE UDP GLUCURONOSYL TRANSFERASE (UGT) ENZYMES INDUCER KOSMETISCHE ODER DERMOPHARMAZEUTISCHE ZUSAMMENSETZUNG MIT MINDESTENS EINEM UDP-GLUCURONOSYL-TRANSFERASE (UGT) ENZYM-INDUKTOR COMPOSITION COSMETIQUE OU DERMOPHARMACEUTIQUE COMPRENANT AU MOINS UN INDUCTEUR D’ENZYMES UDP-GLUCURONOSYLTRANSFERASES (UGT) (84) Designated Contracting States: • PATENT ABSTRACTS OF JAPAN vol. 2000, no. DE ES FR GB IT 14, 5 March 2001 (2001-03-05) & JP 2000 319154 A(NIPPON MENAADEKESHOHIN KK; ICHIMARU (30) Priority: 26.04.2004 FR 0404408 PHARCOS CO LTD), 21 November 2000 (2000-11-21) (43) Date of publication of application: • DATABASE WPI Derwent Publications Ltd., 25.04.2007 Bulletin 2007/17 London, GB; AN 2001-481491 XP002309671 CHEOUNG J H ET AL.: "Chrysin 7-o-crotonate, its (73) Proprietor: Sederma S.A.S.
  • Identification of Compounds That Rescue Otic And

    Identification of Compounds That Rescue Otic And

    bioRxiv preprint doi: https://doi.org/10.1101/520056; this version posted January 16, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Identification of compounds that rescue otic and myelination defects in the 2 zebrafish adgrg6 (gpr126) mutant 3 4 Elvira Diamantopoulou1,*, Sarah Baxendale1,*, Antonio de la Vega de León2, Anzar Asad1, 5 Celia J. Holdsworth1, Leila Abbas1, Valerie J. Gillet2, Giselle R. Wiggin3 and Tanya T. 6 Whitfield1# 7 8 1Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, 9 S10 2TN, UK 10 2Information School, University of Sheffield, Sheffield, S1 4DP, UK 11 3Sosei Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK 12 13 *These authors contributed equally 14 15 #Corresponding author: 16 Tanya T. Whitfield: [email protected] 17 ORCID iD: 0000-0003-1575-1504 18 19 Key words: zebrafish, aGPCR, Adgrg6, Gpr126, phenotypic screening, chemoinformatics, 20 versican, myelination, inner ear, lateral line, Schwann cells 21 22 1 bioRxiv preprint doi: https://doi.org/10.1101/520056; this version posted January 16, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 23 ABSTRACT 24 Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in 25 myelination of the peripheral nervous system.