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Design, Synthesis and Biological Evaluation of Retinoid and Non-Retinoid Mimetics of Fenretinide As Chemotherapeutic Agents

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Design, Synthesis and Biological Evaluation of Retinoid and Non-Retinoid Mimetics of Fenretinide As Chemotherapeutic Agents Design, Synthesis and Biological Evaluation of Retinoid and Non-Retinoid Mimetics of Fenretinide as Chemotherapeutic Agents Rachael Elizabeth Tennant Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Chemistry September, 2014 The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. © 2014 The University of Leeds and Rachael Elizabeth Tennant. The right of Rachael Elizabeth Tennant to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. - ii - Acknowledgements Firstly, I would like to thank my supervisors, Dr Richard Foster and Prof. Sue Burchill. It has been an honour to be Richard’s first PhD student and I am very grateful for the opportunity to work on this project. I greatly appreciate his invaluable knowledge, support and guidance throughout my experimental work and write-up. Sue’s enthusiasm and passion for research has inspired me greatly and I appreciate her boundless patience, knowledge and encouragement. I am very proud of what we have achieved together, thank you both. I would also like to thank Prof. Colin Fishwick, Dr Shireen Gopaul and Dr Helen Payne for providing insightful discussions about the research throughout the project. I’d like to thank the EPSRC and the Charles Brotherton Trust for making this research possible by financially supporting the project. Thank you to the Foster research group within the School of Chemistry, particularly Dr Jeff Plante and Dr Jayakanth Kankanala who are two of the nicest, most helpful guys imaginable who are both extremely knowledgeable in just about everything! Also to the past and present group members over the last few years who have made my time in Leeds hugely enjoyable. Jeff also contributed to this project by carrying out the deprotection and coupling of affinity chromatography ligand 354 to Sepharose (Chapter 5). Non-retinoid hybrid molecules ( 350 -352 ) were synthesised by Lewis Turner when he worked with me as part of his undergraduate summer-student placement. Thank you both for these contributions. I’d like to thank the Lab 4 group at LICAP for all of their help; particularly Andrea Berry for teaching me several invaluable biological techniques and never tiring of my ‘daft’ questions! Thank you to Dr Paul O’Regan for contributing to the project by carrying out the affinity chromatography studies (Chapter 5). - iii - Thanks also go to the technical staff within the School of Chemistry (Tanya Marinko-Covell, Simon Barrett, Martin Huscroft) and LICAP (Liz Straszynski) for their support and advice. On a more personal note I would like to thank my friends, especially Sarah and Natalie, for reminding me there is a world outside of my PhD! I am forever grateful to my family- my parents Sharon and Paul, Grandma, Auntie Sue and John. Thank you for your endless support and encouragement. - iv - Abstract Fenretinide is a potent chemotherapeutic and chemopreventive against a range of cancer tumour cell lines, namely Ewing’s Sarcoma Family of Tumours (ESFT) which is an aggressive malignant tumour primarily affecting children and young adults. The mechanism of action of the drug is not known. The major disadvantage to fenretinide as a treatment for cancer is its poor in vivo efficacy due to poor oral bioavailability, requiring the patient to take many tablets per day regularly in order to achieve an adequate plasma concentration. By use of computational drug design and medicinal chemistry-led design, we have identified both novel retinoid and non-retinoid mimetics of fenretinide, which demonstrate comparable in vitro activity to fenretinide against ESFT cell types. This research has investigated the molecular features of fenretinide which contribute to its inhibition of cell growth in order to establish structure-activity relationships (SAR). We have also investigated the mechanism of cell death for a number of compounds and have identified molecules which appear to induce cell death via a similar mechanism to fenretinide as well as those which function via an alternative mechanism. Additional studies aimed at understanding the mechanism of action of fenretinide through affinity chromatography studies, have implicated several proteins as potential binding partners for further investigation. The outcomes of the current project may aid the design of future retinoid or non-retinoid analogues of fenretinide with improved efficacy, whilst retaining the minimal toxicity profile of fenretinide as well as to better understand the mechanism of the chemotherapeutic induction of the cell death process in ESFT cells. - v - Abbreviations % percent °C degrees celsius 1D one-dimensional 3D three-dimensional 4’-MPR 4’-methoxyphenylretinamide 4-HBR 4-hydroxybenzylretinone 4-HPROG N-(4-hydroxyphenyl) retinamide-O-glucuronide ACR acyclic retinoic acid ADME adsorption, distribution, metabolism and excretion ANP32 acidic (leucine-rich) nuclear phosphoprotein 32 family app. apparent Ar aromatic ASK1 apoptosis signal-regulating kinase 1 BAK BCL2-antagonist/killer BAX BCL2-associated X protein BCL-2 B-cell lymphoma 2 Bn benzyl Boc tert -butoxycarbonyl br broad BSA bovine serum albumin Bu butyl ca . circa ; approximately CDR coding region determinant - vi - ClogP calculated logarithm (base 10) of partition coefficient c-Myc v-myc avian myelocytomatosis viral oncogene homolog CNS central nervous system CRABP cellular retinoic acid binding protein CYP cytochrome P450 δ chemical shift d doublet DCC dicyclohexylcarbodiimide DCFDA 2',7' –dichlorofluorescein diacetate DCM dichloromethane dd doublet of doublets DIPEA N,N-Diisopropylethylamine DMAP 4-dimethylamino pyridine DMBA 7,12-dimethylbenz[ α]anthracene DMF dimethylformamide DMSO dimethyl sulphoxide DNA deoxyribose nucleic acid DNA-PK deoxyribose nucleic acid-dependent protein kinase DR death receptor E entgegen e.g. exempl ī gr āti ā; for example EC 50 half maximal effective concentration EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide EDTA ethylenediaminetetraacetic acid EF1a1 elongation factor 1-alpha 1 eHiTS electronic high-throughput screening - vii - EI electron impact equiv. equivalent ER endoplasmic reticulum ESFT Ewing’s sarcoma family of tumours ESI electrospray ionisation Et ethyl EtOAc ethyl acetate EtOH ethanol EWS Ewing’s Sarcoma FACS fluorescence-activated cell sorting FCS fetal calf serum flex-hets flexible heteroarotinoids g G-force GTP guanosine-5'-triphosphate h hour HBTU O-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry hTERT telomerase reverse transcriptase HTS high-throughput screening Hz Hertz IC 50 half maximal inhibitory concentration i.e. id est ; that is IGF insulin-like growth factor - viii - IGF1R insulin-like growth factor 1 receptor IGF2BP1 insulin-like growth factor 2 mRNA binding protein 1 in silico performed by computer simulation in vitro process taking place outside a living organism in vivo process taking place within a living organism iPr iso -propyl IR infrared J coupling constant JNK c-Jun N-terminal kinases KO knock-out LCMS liquid chromatography mass spectrometry LDA lithium diisopropylamide logS logarithm (base 10) of solubility LXS Lym-X-Sorb m multiplet MAPK mitogen-activated protein kinases Me methyl Ms mesyl MeI methyl iodide MeOH methanol mg milligram MHz megahertz ml millilitre µl microlitre mM millimolar mmol millimole - ix - mol mole MP melting point mRNA messenger ribonucleic acid MsCl methanesulfonyl chloride MSCs mesenchymal stem cells MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium) MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MW molecular weight n number N/A not applicable NADPH nicotinamide adenine dinucleotide phosphate-oxidase NaHMDS sodium hexamethyldisilazide NaOH sodium hydroxide NCI National Cancer Institute ND not determined NEt 3 triethylamine NMR nuclear magnetic resonance nOe nuclear Overhauser effect PAGE polyacrylamide gel electrophoresis PBS phosphate buffered saline PDB Protein Data Bank Ph phenyl pH power of hydrogen pKa acid dissociation constant PMSF phenylmethylsulfonyl fluoride - x - PP2A phosphatase 2A inhibitor Pr propyl q quadruplet r.t. room temperature RA retinoic acid Rac1 Ras-related C3 botulinum toxin substrate 1 RAMBAs retinoic acid metabolism blocking agents RAR retinoic acid receptor RBP4 retinol binding protein 4 RIPA radioimmunoprecipitation RNA ribonucleic acid ROCS rapid overlay of chemical structures ROS reactive oxygen species RPMI Roswell Park Memorial Institute medium RPSA ribosomal protein SA RT retention time RXR retinoid X receptor s singlet SAR structure-activity relationship SDS sodium dodecyl sulfate SEM standard error of the mean STRA6 stimulated by retinoic acid 6 t triplet T3P ® propylphosphonic anhydride solution TBAF tetra-n-butylammonium fluoride TBDMSCl tert-butyldimethylsilyl chloride - xi - tert tertiary TFA trifluoroacetic acid TFAA trifluroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TMS tetramethylsilane TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TOF time of flight TRAIL tumour
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