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NOVEL BIS-QUINOLINIUM CYCLOPHANES AS Skca CHANNEL BLOCKERS

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NOVEL BIS-QUINOLINIUM CYCLOPHANES AS Skca CHANNEL BLOCKERS NOVEL BIS-QUINOLINIUM CYCLOPHANES AS SKca CHANNEL BLOCKERS A thesis presented in partial fulfilment of the requirements for the Doctor of Philosophy Degree of the University of London LEJLA ARIFHODZIC Department of Chemistry University College London September 2001 ProQuest Number: U153874 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U153874 Published by ProQuest LLC(2015). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ACKNOWLEDGMENTS I am grateful to my supervisor. Prof C.R. Ganellin, firstly, for giving me the opportunity to do this project and for all his support and invaluable advice thereafter. A very special thank you to Mr W. Tertuik for all his help and guidance during my time at UCL. Many thanks to Prof D.H. Jenkinson for performing the biological testing and for useful discussions and to Dr A. Vinter for his assistance in molecular modelling. My thanks go to many past and present members of UCL, in particular: T.Akinleminu, A.Alic, A.E.Aliev, J.E.Anderson, D.C.H.Benton, S.Corker, C.Escolano, J.Gonzales, K.J.Hale, J.Hill, F.Lerquin, J.Maxwell, F.L.Pearce, N.Penumarty, E.Power, S.Samad, A.Stones, S.Manaziar, M.Sachi, D.Yang, C.Yingiau and P.Zunszain. I thank Department of Chemistry, UCL for the financial support. Many thanks to Jared and Alex for their understanding and assistance. I am especially grateful to my Igor for his love, devotion and patience - this project could not have been completed without his help and understanding. I would like to thank my sister Sanja and my dearest friend Sanida for their love and support. Finally, thanks to Dianijela for her understanding. / thank my dearest mum and dad for their unconditional love and support. To them I dedicate this thesis. ABSTRACT Small conductance Ca^^ activated channels (SK^J are present in many cells and thought to be involved in some pathophysiological states, including myotonic muscular dystrophy. Some of these channels are potently and selectively blocked by the naturally occurring peptidic toxin apamin, with ICso-lnM. Previous research has led to the discovery of bis-quinolinium cyclophanes as the first nanomolar non-peptidic blockers of the apamin sensitive SK^a channel. The most active compounds discovered were UCL 1684 and UCL 1848, with their structures shown below: HN NH HN NH UCL 1848 UCL 1684 In order to further explore their activity, we have altered the structure of the two compounds by introducing various substituents at the 6 and 7 positions of their quinoline rings. Whereas all the substituents introduced in UCL 1684 resulted in some loss of potency, the same substituents introduced at the position 6 or 7 of the analogue UCL 1848 seemed to be well tolerated. The influence of the addition of two Cl atoms, at positions 5 and 7 of the two quinoline rings, has also been investigated. Furthermore, changes in the activity caused by varying one or both linkers between the two quinoline rings have been studied. Here, the most interesting finding was that UCL 1684 and UCL 1848 can behave very differently when subjected to the same alteration of one of their linkers. Novel Bis-Quinolinium Cyclophanes as SKca Channel Blockers It is of great interest to synthesise radioligand for the SK^j, channel and by synthesising a series of new compounds we were able to further explore the effect o f structure alterations, as well as to produce an iodine containing analogue. Finally, it is uncertain weather the protons attached to the exocyclic N atoms of these cyclophanes can be ionised at physiological pH. In order to explore this aspect, we have attempted the synthesis of structural analogues with more readily ionisable protons. The results obtained in this thesis are supported by molecular modeling studies. Novel Bis-Quinolinium Cyclophanes as SKq^ Channel Blockers 6 CONTENTS Page Abbreviations ...................................................................................................................... 8 Table 1 ................................................................................................................................. 16 Compounds Synthesised as Part of the Thesis............................................................ 21 Chapter 1 - Introduction................................................................................ 23 General Introuction..........................................................................................................23 1.1 Voltage-Dependent Potassium Channels..............................................................26 1.1.1 Delayed Rectifier fC Channel (K d b ) .................................................26 1.1.2 Transient Outward iC Channel (K a)................................................. 28 1.1.3 Inward (Anomalous) Rectifier iC Channel (Kir) .................................31 1.1.4 The Crystal Structure o fiC Channel......................................................33 1.2 Receptor-Coupled Potassium Channels............................................................... 36 1.2.1 G Protein-gated lC Channels (including Muscarinic-activated iC Channels (Kach).............................................................................36 1.2.2 Muscarinic-inactivated FC Channels (Km)...........................................37 1.2.3 Serotonin-sensitive FC Channels (K sr)..............................................38 1.2.4 cAMP-sensitive FC Channels (Kac ) ....................................................................38 1.3 Other FC Potassium Channels...............................................................................40 1.3.1 ATP-sensitive FC Channel (Katp) .......................................................... 40 1.3.2 Cell Volume-activated FC Channel........................................................43 1.3.3 Na^-activated FC Channel (K^a)............................................................43 1.3.4 Further Information About iC Channels ..............................................44 1.4 Calcium-Activated Potassium Channels.............................................................45 1.4.1 Large Conductance Ca^^-activated FC Channels (BK)..................... 45 1.4.2 Intermediate Conductance Ca^^-activated iC Channels (IK)...........53 7 1.4.2 Voltage-independent IK channels................................................ 53 1.4.2 Voltage-dependent IK channels....................................................57 1.4.3 Small Conductance Ca^^-activated K^ Channels (SK)).......................60 1.5 Previous Studies in Our Group.............................................................................. 79 Chapter 2 - Selection of Compounds...........................................................89 Chapter 3 - Synthesis and Characterisation of Compunds.................. 99 3.1 General Synthesis.....................................................................................................99 3.2 Preparation of Commercially Unavailable Starting Materials.......................100 3.3 Preparation of Intermediates............................................................................... 109 3.4 Synthesis of Final Bis-Quinolinium Cyclophanes................................ ...........119 3.5 Characterisation of Compounds........................................................................137 Chapter 4 - Results and Discussion...........................................................145 4.1 Series I - The Effect of Substituents in Cyclophane 1 ...................................... 146 4.2 Series II - The Effect o f Substituents in Cyclophane 2 ..................................... 153 4.3 Series III - Investigation of the Linkers in Cyclophane 1 (I)........................... 158 4.4 Series IV - Investigation of the Linkers in Cyclophane I (II).........................162 4.5 Series V- Towards the Introduction of^^^f ........................................................ 166 4.6 Series VI - Investigation of the Linkers in Compounds 1 and 2 ..................... 169 4.7 Conclusions and Future Work ............................................................................. 177 Chapter 5 - Experimental..............................................................................180 5.1 Chemistry ............................................................................................................... 180 5.2 Failed Chemistry...................................................................................................262 5.3 Biological Testing_ ................................................................................................ 266 5.4 Molecular Modelling ............................................................................................269 Chapter 6 - Refererences.............................................................................. 270 Abbreviations ABBREVIATIONS Â angstrom All angiotensin II Acc Mass accurate mass ACh acethylcholine ACTH adrenocorticotropic hormone ABC ATP binding cassette ABC region part of SK channel which binds CaM ADP adenosine 5’-diphosphate
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