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Toward the Development of Γ-Lactones and Γ-Lactams As Toward the Development of -Lactones and -Lactams as Protease Inhibitors Thesis presented for the award of Ph.D degree by Nessa S. Mullane BSc. Supervisor: Dr. Timothy Smyth Submitted to the University of Limerick October 2012 Declaration The work presented in this thesis is the original work of the author and due reference has been made, when necessary, to the work of others. No part of this thesis has previously been submitted to this or any other university. ____________________________ Nessa Mullane i Abstract A select set of -lactones, -lactams and related bicyclic -lactams - pyrrolothiazole[2,1b]thiazoles - were designed, synthesised and evaluated enzymatically as inhibitors of the serine proteases, elastase, and (to a very limited extent) thrombin. Computational docking was used to predict the suitability of substituent groups on the -lactone and -lactam scaffolds for occupancy of the primary binding pockets that border the enzyme active site. Weak activity against thrombin was observed for one of the pyrrolothiazoles (108 showed a 40% reduction in enzyme activity when incubated for 40 min at 1 mM), however, the levels of inhibition of elastase were considerably lower for all the structures examined. It was considered that the inherent reactivity of the -lactone and -lactam scaffolds studied here was too low for effective acylation of the active-site serine of elastase. The synthetic methodology that was used was based on mucohalic acid chemistry that allowed for a modular synthesis of the various scaffolds. For both the mono and bicyclic structures, the C-3 vinylic halogen of mucohalic acid was initially replaced using a 1,4-addition-elimination process to give a muco-derivative which, when reacted with D-penicillamine lead to the pyrrolothiazole core structure, and when treated with diphenyldiazomethane was converted to a ring-opened ester that proved to be a key unit for formation of -lactams bearing an electron-withdrawing group tosyl group on the lactam nitrogen atom. The formation of a sulfonylimine from the ring- opened ester proceeded smoothly when treated with a tellurodiimide reagent, prepared by reaction of tellurium powder and chloramine-T. Reaction of the sulfonylimine with a hydride reagent generated the monocyclic -lactam. Reaction of the ring-opened ester with a hydride reagent proved to be an effective method for formation of the monocyclic -lactones, while reaction of this ester with a methyl Grignard reagent led to a monocyclic -lactam with a methyl group in the 5-poistion. In the case of each of these monocyclic units, and the pyrrolothiazole core structure, the remaining vinyl halide was then replaced so as to complete the installation of the desired substituents. This last displacement was effected both by azide ion and via Suzuki-Miyaura coupling using aromatic boronic acid or ester reagents. A Click reaction with the azide derivatives allowed for installation of a phenyltriazole group. ii Publication Part of the work completed in this thesis has been published by: Emma E. O’Dwyer, Nessa S. Mullane and Timothy P. Smyth Journal of Heterocyclic Chemistry, 2011, 48, 286 Modular Synthesis of Pyrrolo[2,1-b]thiazoles and Related Monocyclic Pyrrolo Structures iii Acknowledgements I would like to express my gratitude to: o My supervisor, Dr. Tim Smyth. My sincerest thanks for your constant support, guidance and enthusiasm all the way through this project. “It’s good to talk”. o My research colleague, Emma O’Dwyer. For all your help and encouragement, I sincerely thank you. o All the technical staff of the CES department, especially Brian, Leo and Peter. o All the final year project students: Lorraine, Pat, Dervla, Tadhg, Andy, Joe, Shane, Jen and Rónán for their help with various aspects of the project. o All the UL ladies who always had time for tea and a chat, especially Corinna, Rosaleen, Jenny, Ali, Caroline, Sarah, Lijana, Ciara and Laura, you made the days go faster. o My grandmother, Margaret Mullane, whose support has always been unwavering and prayers endless. o Eoin. For everything you have done, I could not have done it without you. o My parents, Dan and Emily, and sister, Íde. For your boundless enthusiasm and support and for showing an interest, even when you had no idea what I was talking about. iv Funding I am very grateful to the Chemical and Environmental Sciences Department of the University of Limerick for Departmental funding. v Table of Contents Chapter 1 Introduction .................................................................................................... 1 1.1 Serine proteases ..................................................................................................... 1 1.2 Kinetic description of an enzyme-catalysed reaction ......................................... 6 1.3 Analysis of enzyme kinetics ................................................................................ 10 1.4 Kinetic analysis of enzyme inhibition ................................................................ 12 1.5 Binding of Serine Proteases ................................................................................ 17 1.6 Inhibition of serine proteases ............................................................................. 19 1.6.1 Elastase and α-1-Antitrypsin .......................................................................... 22 1.7 Synthetic inhibitors ............................................................................................. 23 1.7.1 Non-covalent mode of inhibition ................................................................... 24 1.7.2 Covalent mode of inhibition........................................................................... 26 1.8 Development aspects of trans-lactams as elastase inhibitors .......................... 36 1.9 Development aspects of 5,5-fused thiophene -lactams as elastase inhibitor . 38 1.10 Clinical status of elastase inhibitors ................................................................ 40 1.11 Previous Work in the Group ............................................................................ 41 1.11.1 Exploration of routes to substituted pyrrolothiazoles .................................. 46 1.12 Aims and Objectives ......................................................................................... 48 Chapter 2 Results and Discussion ................................................................................. 50 2.1 Results and Discussion – Part 1 ......................................................................... 50 Further exploration of pyrrolothiazole synthesis .................................................... 50 2.1.1 Bicyclisation reaction with L-cysteine ............................................................ 50 2.1.2 Complete functionalisation of mucohalic component prior to cyclisation .... 55 2.1.3 Partial functionalisation of the mucohalic component prior to cyclisation .... 61 2.1.4 Deprotection and salt formation ..................................................................... 67 2.1.5 Enzymatic evaluation ..................................................................................... 67 vi 2.1.6 Alternative to bicyclic scaffold ...................................................................... 72 2.2 Results and Discussion – Part 2 ......................................................................... 77 2.2.1 Computational docking .................................................................................. 78 2.2.2 γ-Lactone synthesis ........................................................................................ 83 2.2.3 γ-Lactam synthesis ......................................................................................... 92 2.2.4 Chemoselective Suzuki Reactions ............................................................... 103 2.2.5 Enzymatic Evaluation of γ-lactones and γ-lactams ...................................... 103 Chapter 3 Conclusions and Perspective ...................................................................... 107 Chapter 4 Experimental ............................................................................................... 118 Chapter 5 References ................................................................................................... 147 Appendix I - Publication……………………………………………………………..157 vii Abbreviations AAT -1-antitrypsin CF Cystic Fibrosis DIW De-ionised water (distilled water) DMSO Dimethyl sulfoxide DPM Diphenylmethyl ester (benzhydryl ester) EM Effective molarity ENZ Enzyme EWG Electron-withdrawing group HNE Human neutrophil elastase HRMS High resolution mass spectroscopy IR Infrared LG Leaving group PDB Protein Data Bank NMR Nuclear magnetic spectroscopy R.T. Room temperature STAB Sodium triacetoxyborohydride TBS tert-butyl dimethyl silyl TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride TMG Tetramethylguanidine UV Ultra-violet viii Figures, Schemes & Tables Scheme 1.1 Mode of action of serine proteases. ............................................................... 2 Figure 1.1 Schematic representation of the stereoelectronic aspects of a tetrahedral intermediate by addition of a nucleophile (Nu-) to an amide carbonyl group. ................. 3 Figure 1.2 Schematic representation of the breakdown of a tetrahedral intermediate involving protonation and departure of the nucleofuge along a Bürgi-Duitz trajectory. .. 4 Figure 1.3 Histidine “ring-flip” schematic for proton transfer from the His-57 imidazolium ion to the amine leaving group of a peptide substrate.
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