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Novel Retinoid Enhancers for Anti- Cancer Therapies

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Novel Retinoid Enhancers for Anti- Cancer Therapies NOVEL RETINOID ENHANCERS FOR ANTI- CANCER THERAPIES A thesis submitted in fulfilment of the degree of Doctor of Philosophy By Christopher R Gardner Supervisors: Prof. Naresh Kumar Dr. Belamy Cheung Prof. David StC. Black School of Chemistry The University of New South Wales Kensington, Australia July, 2015 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Gardner First name: Christopher Other namefs: Robert Abbreviation for degree as given in the University calendar: PhD School: Chemistry Faculty: Science Title: Novel retinoid enhancers for anti-cancer therapies Abstract 350 words maximum: (PLEASE TYPE) Retinoids play a crucial role in the treatment of multiple human cancers, particularly neuroblastoma and leukaemia. However, their utility is often hampered by the inherent toxicities associated with the concentrations necessary for therapeutic benefit, as well as innate or acquired resistance to treatment. This thesis focuses on the discovery and development of novel scaffolds that possess cytotoxic activity mediated through the retinoid pathways. A protocol for docking scaffolds into the binding site of the retinoic acid receptor ~ (RAR~) was developed. These docking methodologies were used to identify novel scaffolds as potential RAR~ ligands, as well as probe the mechanisms behind the observed structure activity relationships (SAR) of the prepared compounds. A wide range of novel indole-benzothiazole acetamides were synthesized via PyBOP amide coupling of 3-indoleacetic acids and 2-aminobenzothiazoles. These scaffolds were investigated for their cytotoxic activity against neuroblastoma cells. Several analogues were found to have low micromolar IC50 values, demonstrated selectivity towards cells with high RAR~ expression and also were selective for cancerous cells over normal cells. Furthermore, the ability of these compounds to modulate RAR protein expression was demonstrated. Indole and quinoline-oxadiazoles were synthesized by the dehydrocyclization of bis-hydrazides by 4-toluenesulfonyl chloride. The cytotoxic activity of these scaffolds was investigated with their selectivity towards cells overexpressing different RAR subtypes (a, ~ . y) also investigated. Benzothiazole-thieno[2,3-c]pyrazole amides were also synthesized by the one-pot, single step alkylation-aldol condensation of methyl thioglycolate and formyl-halopyrazoles. The cytotoxicity and SAR of these scaffolds was also explored. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). - ~~~A1¥~t~!(?.ls.b.. : ........... ... ~.. Vf?J:S?.:PL?.. ........ ·u ·:-.-.:.{ 7 Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and ~e uire the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS CERTIFICATE OF ORIGINALITY I hereby declare that this submission is my own work and that, to the best of my knowledge and belief, it contains no material previously published or written by another person, nor material which to a substantial extent has been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged. Signed .. ..... .. ... .. ..... ....... .............. Date ...... 7.: 0 ~/?. Pl.?. ...... ii ABSTRACT Retinoids play a crucial role in the treatment of multiple human cancers, particularly neuroblaostoma and leukemia. However, their utility is often hampered by the inherent toxicities assosciated with the concentrations necessary for therapeutic benefit, as well as innate or acquired resistance to treatment. This thesis focuses on the discovery and development of novel scaffolds that possess cytotoxic activity mediated through the retinoid pathways. A protocol for docking scaffolds into the binding site of the retinoic acid receptor β (RARβ) was developed. These docking methodologies were used to identif y novel scaffolds as potential RARβ ligands, as well as probe the mechanisms behind the observed structure activity relationships (SAR) of the prepared compounds. A wide range of novel indole-benzothiazole acetamides were synthesized via PyBOP amide coupling of 3-indoleacetic acids and 2-aminobenzothiazoles. These scaffolds were investigated for their cytotoxic activity against neuroblastoma cells. Several analogues were found to have low micromolar IC 50 values, demonstrated selectivity towards cells with h igh RARβ expression and also were selective for cancerous cells over normal cells. Furthermore, the ability of these compounds to modulate RAR protein expression was demonstrated. Indole and quinoline-oxadiazoles were synthesized by the dehydrocyclization of bis- hydrazides by 4-toluenesulfonyl chloride. The cytotoxic activity of these scaffolds was investigated with their selectivity towards cells overexpressing different RAR subtypes (α, β, γ) also investigated. iii Benzothiazole-thieno[2,3-c]pyrazole amides were also synthesized by the one-pot, single step alkylation-aldol condensation of methyl thioglycolate and formyl- halopyrazoles. The cytotoxicity and SAR of these scaffolds was also explored. iv ACKNOWLEDGEMENTS My first words of thanks are offered to my supervisor Prof. Naresh Kumar. Through your guidance, support, encouragement and input, I have been able to overcome the many obstacles of post-graduate research. You have provided me with the opportunity not only to learn and develop as a scientist, but to develop the necessary skills for a career in research and teaching. But most of all, you have given me the opportunity and support to achieve one of my dreams. I wish to also offer the same sentiment to my co-supervisors Dr. Belamy Cheung and Prof. David StC. Black. Thank you Belamy for taking me on when I was just a chemist, with no understanding of the intricacies of molecular biology. You gave me every guidance, support and opportunity, allowing me to gain knowledge and skills I never thought I would. Thank you David for your enthusiastic encouragement, immeasurable knowledge, the stories you shared and our discussions about cricket. You have not only set an example, but challenged and encouraged me to reach it. Also, I must thank my other supervisors; Prof. Glenn Marshall and A/Prof. Renate Griffith. Thank you for your enthusiasm Glenn, your kindness and insight. You always reiterated the importance of doing good science, the Nature paper question and the reason we do this at all: to make someone’s lif e better. Thank you Renate for all of your assistance with my compoutational studies and the time you spent training me with the software and troubleshooting the issues I had along the way. Thank you also for guiding and supporting me with this new endeavour. Thanks also to the staff of the UNSW School of Chemistry, the Analytical Centre and Children’s Cancer Institute . You have taught, helped and befriended me since the time I v was a first year undergraduate student, providing a safe and enjoyable environment for me to study and work. Without your efforts to maintain the facilities, supply chemicals and equipment, run samples and the countless other duties you perform, there would not be a School of Chemistry for me to be at, let alone this thesis. To everyone in the Kumar-Black group, both past and present, thank you for your help and friendship. Thank you all for putting up with my questions (particularly in the early days), my OCD behaviour when it comes to random things, playing music (sometimes loudly) in the lab, my strange (possibly offensive) sense of humour and the random things I say and do. But I must single out a few people who deserve special thanks: Dr. Kasey Wood for being a friend, mentor and gym buddy; Dr. Renxun Chen for his friendship, advice and always wanting to get lunch, or at least coffee; Dr. Samuel Kutty for always providing help with all aspects of my project, being my friend and a fellow cricket enthusiast; Dr. Kitty Ho for her help, particularly in keeping the lab working, and her friendship; and Dr. Murat Bingul for his much appreciated assistance with chemistry, being my friend, gym buddy and coffee lover. Thank you also to all the members of the Molecular Carcinogenesis program. At some point or other I have come to you all with questions about what I was doing, or more accurately, what should I be doing, which were always met with kindness, understanding and thorough assistance. Without all your help, there would otherwise not be anywhere near the amount of biology that is in this thesis. Special thanks to Selina, Owen and Patrick for their continued help and friendship. But of course, the biggest thanks here must go to Jess Koach. Thank you for teaching me almost everything I know about how to do molecular biology, for putting up with my countless questions and constant interruptions, and still being my friend after it all.
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