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Development of Novel Heterocyclic Compounds As Vascular Targeting Agents

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Development of Novel Heterocyclic Compounds As Vascular Targeting Agents Development of Novel Heterocyclic Compounds as Vascular Targeting Agents Patrick Killoran School of Environment & Life Sciences, University of Salford, Salford, UK Submitted in partial fulfilment of the requirements of the Degree of Doctor of Philosophy, July 2015 Acknowledgement This research project would not have been possible without the support of many people. I wish to express my gratitude to my supervisor Dr John (Hadders) Hadfield for his patience and advice. A big thanks to Prof A McGown and Kidscan (Holly, Chris X 2, James, Jane and Lowri) for the funding and enthusiasm that made this happen. I would like to thank Guillaume Mossand and Mellisa Rosell for their help with the synthesis of dibenzo(b,d)oxepines. My thanks also extend to Tiabauld Peuden and Dr Nick Hirst for their invaluable help in the development of the Ziegler-Ullman biaryl coupling methodology and Pd catalysed o arylation respectively. Lots of thanks also to the lovely Kamila Schmidt for her help with biological testing and her heavy metal melodies! Along with being the biggest wind-up artist in Salford, Kirit Amin is a true wizard of NMR, I would be lost without his assistance and I thank him greatly! A letter should be sent to the Vatican to get the ball rolling on Mark Parlby’s sainthood, thanks for everything. I also extend my thanks to all of the technicians, who have helped and given me cake over the years, I am very grateful. Dr Steve Rossington is a true gent and a friend. If you substitute the L.A underground for the University of Salford in the opening sequence of the A-Team, that sums up what a great guy he is. Without his wise words and encouragement I would be sorely stuck! Many thanks to thank the man, the myth, the chemist Dr Jim Wilkinson for sharing his priceless wisdom on everything from organic chemistry to the carry on movies! An especially big thank you goes to my good pal Ryan and his lovely girlfriend Becky for taking me into their home and extending me great generosity and friendship, it saddens me greatly that there will be no more handsome haircut Fridays! Thanks to Andrew McGowsling and Natalie Barnes for the support and fun memories in lab. I pass the torch to you guys; don’t hold it beside the stills! To all of the placement/project students that I have worked with/tortured thank you and good luck! (Lewis, Amjad, Chris “Sir Donksalot” Lawson and many more!). The lovely Iustina Slabu has been and always will be my chemistry buddy, thanks for your support! On a more serious note I have to thank my two personal physicians Dr Evin Winters and Dr Gavin Callaghan for keeping me safe through some treacherous expeditions… A tip of the hat to you both! Many thanks to my consigliere Kerill Winters for his wise (guy) words. To the members of Whiskey Dust thanks for the memories, give it a few years, someone will make an offer we can’t refuse!! 2(Dr) Alex Mastin has been a great friend and often a voice of reason, I will miss our Friday think tank! Manisha Patel is also a great pal but she messed up badly by feeding me and will have to suffer the consequences… Gemma Lace Costigan is a hip lady, thanks for all the advice! Thanks to all of the Staff who make Salford such a friendly place to work. I fondly remember some great “extracurricular” adventures during my PhD with some lovely people. Kathrin and Tom, that rendition of “I would do anything for love” still haunts me! Dr Robert Coles is a dance champion! I never told Soran Baban this, in Gaelic his name means means “A wild man”. Firozeh…….. ? I extend a special thanks to Geoff and Cath Hide for all of the kindness they have shown over my time at Salford. I have to thank my family for their support throughout this process, I love you all dearly in spite of the school boy jokes! Thanks to my dad, brother, Paula and Ian for all your love and support. Thanks to my beautiful girlfriend Helen for putting up with me for so long I love my mum, she is an inspiration to me every day, it couldn’t have been easy bringing up two bad boys on your own! I dedicate this to you. "A scientist in his laboratory is not a mere technician: he is also a child confronting natural phenomena that impress him as though they were fairy tales." Marie Curie Abstract In chapter one the biology of cancer is introduced along with a brief history of drug treatment and the status quo of cancer therapeutics. This includes a general overview of cancer prevalence, carcinogenesis, and biochemistry. The main targets for cancer therapeutics are introduced along with in-depth look at cancer vasculature, tubulin binding agents and their mechanisms of action. In chapter two the development of the routes to the dibenzo[c,e]oxepine target compounds are described. The optimisation of a key biaryl precursor molecule for these analogues is described. This includes a brief overview of palladium catalysed coupling chemistry and a screen for suitable catalytic systems. In chapter three the development of an intramolecular ring closing process for dibenzo[b,d]oxepine is described. This includes investigation into non-phenolic oxidative coupling and a screen for oxidants. Palladium/phosphine catalysed intramolecular arylation is also discussed. In chapter four the synthesis of the target compounds is described along the development of routes to further analogues. In chapter five the biological testing of compounds is discussed. This features an introduction to biological evaluation methods for anti cancer compounds. The results for all of the MTT and tubulin binding assays (MA) are presented, revealing a fluorinated dibenzo[c,e]oxepine analogue with cytotoxicity within the nanomolar range (MTT K562 - IC50 60 nm, MA - 1.2 µM). Furthermore a link has also been established between the cytotoxic activity profiles of a series of simple biaryl compounds and Combretastatin A-4. Table of Contents Chapter 1: Introduction ........................................................................................................................... 1 What is cancer?- .................................................................................................................................. 2 Cancer causes and metastasis .......................................................................................................... 6 Cancer cell cycle ............................................................................................................................. 7 Types of cancer ............................................................................................................................... 9 Cancer chemotherapy .................................................................................................................... 10 Antimetabolites ............................................................................................................................. 11 Alkylating agents .......................................................................................................................... 12 DNA intercalating agents .............................................................................................................. 13 Angiogenesis and tumour vasculature .............................................................................................. 14 Anti-angiogenic Agents ................................................................................................................ 17 Tubulin and microtubules ................................................................................................................. 19 Tubulin as a drug target ................................................................................................................ 22 Microtubule stabilizing agents ...................................................................................................... 24 Taxoid binding site ....................................................................................................................... 24 The Laulimalide/Peloruside Binding Site ..................................................................................... 26 Binding at the vinca binding region .............................................................................................. 29 Colchicine binding site ................................................................................................................. 31 Vascular Targeting Agents ............................................................................................................... 33 Podophyllotoxin ............................................................................................................................ 33 Combretastatin A-4 ....................................................................................................................... 34 ZD6126 ......................................................................................................................................... 38 Oxepines ....................................................................................................................................... 42 Project aims ....................................................................................................................................... 44 Design rationale ............................................................................................................................ 45 Chapter 2: Development of a route to the desired oxepine analogues .................................................. 49 Introduction ......................................................................................................................................
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