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Synthesis of New Peptide Mimetics University of Bath PHD Synthesis of new peptide mimetics Hackett, Anne Award date: 1996 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 Synthesis of New Peptide Mimetics Submitted by Anne Hackett for the degree of PhD of the University of Bath 1996 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may not be consulted, photocopied or lent to other libraries without the permission of the author from three years from the date of acceptance of the thesis. MocM UMI Number: U60169B 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. Dissertation Publishing UMI U601693 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 To Mum, Dad and Geraldine for their love, support and encouragement Acknowledgements I would like to thank my supervisors, Professor Malcolm Campbell, Professor Malcolm Sainsbury and Dr. Nigel Vicker for all their help, encouragement and enthusiasm throughout this project. I would also like to thank Mr. Harry Hartnell, Mr. Dave Wood, Mr. Alan Carver, Mr. Chris Cryer, Mr. John Bradley and Mr. Russell Barlow. A special thank you to Dr. Dave Brown, Dr. Ali Ninan and Dr. Richard Kinsmann for their help and advice along the way. Thank you too, to June, Freda and Angie for their help and good cheer. A big thank you to all at Rhone-Poulenc Rorer in Dagenham and to all my friends in Bath over the past three years, especially: Derradji Boumrah, Dave Corser, Simon Diston, Stuart Firth-Clark, Matt Fletcher, Barry Hayter, Lawrence Ho, Cida Kawamoto, Max Liu, Chris Rodriquez, Neil Smith and Jon Swift And finally, to Wilson - for his constant love and support Summary This project is concerned with the synthesis of a new family of peptide mimetics, 1: R3 T H PN H-V0^ R2 o 1 P = amino protecting group R l - R3 = amino acid sidechains R4 = alkyl It was aniticipated that a compound such as 1 would be resistant to enzymatic degradation, since incorporation of a reduced amide bond in place of an amide at a point of cleavage in a biologically active peptide is known to produce a protease enzyme inhibitor by mimicking the tetrahedral transition state for amide bond hydrolysis, which is itself resistant to hydrolysis. The conformation of such a compound was also of interest since molecular modelling studies suggest that reduction of certain amide bonds in a peptide chain causes the peptide to adopt a P turn structure. Synthetic routes to compound 1 via amide reduction, Mitsunobu alkylation, reductive amination of N-(t-butoxycarbonyl)amino aldehydes and tosylate displacement reactions are described. Contents Abbreviations i Nomenclature and terminology iii 1. Introduction 1.1 The history of peptide chemistry 1 1.2 Bioactive peptides 2 1.3 Why modify? 4 1.4 Modifications 5 1.5 Modification of the peptide backbone 6 1.6 A new family of peptide mimetics 8 1.7 The methyleneamino link as an amide bond isostere 9 1.8 Conformational studies on reduced peptides 13 1.9 Synthesis of reduced peptides 15 1.10 Aims 21 Results and discussion 2. Reduction 24 3. Mitsunobu alkylation 36 4. Reductive animation 49 5. Tosylate displacement 62 Conclusion 80 6. Experimental 81 References 108 Abbreviations Ac: acetyl ACE: angiotensin converting enzyme AcOH: acetic acid ADDP: 1, l'-(azodicarbonyl)dipiperidine Boc: N-(f-butoxycarbonyl) br: broad Bu: butyl *Bu: f-butyl Bzl: benzyl CD: circular dichroism d: doublet DCC: 1,3-dicyclohexylcarbodiimide DCU: 1,3-dicyclohexylurea DEAD: diethyl azodicaiboxylate DEPT: distortionless enhancement by polarisation transfer DIBAL-H: diisobutylaluminium hydride DIEA: N, N-diisopropylethylamine DMF: N, N-dimethylfomiamide DMSO: dimethylsulphoxide EDC: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride El: electron impact FAB: fast atom bombardment HOBt: 1-hydroxybenzotriazole hydrate HOSu: N-hydroxysuccinimide Me: methyl m: multiplet NBA: m-nitrobenzyl alcohol Pht: phthalimide PMA: phosphomolybdic acid py: pyridine q: quartet Red-Al: sodium bis(2-methoxyethoxy)aluminium hydride s: singlet t: triplet TFA: trifluoroacetic acid THF: tetrahydrofuran Tic: 1 ,2 ,3 ,4-tetrahydroisoquinoline-3-carboxylic acid TIPA: N, N, N\ N’-tetraisopropylazodicarboxamide TMAD: N, N, N', N’-tetramethylazodicarboxamide TMSQ: chlorotrimethylsilane Tpi: 2 ,3 ,4 ,9-tetrahydro-1 H-pyrido-[3,4-6]indole-3-carboxylic acid Ts: p-toluenesulphonyl TsCl: p-toluenesulphonyl chloride Z: N-benzyloxycarbonyl Nomenclature and terminology IUPAC nomenclature for peptides and peptide analogues is used. The backbone of a homomeric, homodetic peptide is composed of three repeating units: the amide nitrogen, the a-carbon and the amide carbonyl (Figure 1). The unit in Figure 1 is referred to as an amino acid residue. R O Figure 1, The symbol "y" signals the absence of the amide bond. Within the brackets that follow is specified the structure that replaces the amide group, e.g. Figure 2. The replacing unit for the amide bond is "CH 2 NH"; the nomenclature symbol is "y[CH2NH]". O Figure 2. Alay[CH2NH]Ala The following terms are used in this thesis: agonist: a molecule that binds to a receptor and produces an effect; antagonist or inhibitor a molecule that binds to a receptor and prevents the receptor from transmitting a signal; IC5 0 : the concentration (of inhibitor) at which 50% inhibition of the enzyme is achieved. Turns A host of bioactive peptides have been discovered in the last 20 years. Turn structures have been proposed and implicated in the bioactivity of several of these naturally occurring peptides. Turns are intrinsically polar structures with backbone groups that pack together closely and sidechains that project outward. In peptides, turns are the conformations of choice for simultaneously optimising both backbone- chain compactness (intramolecular nonbonded contacts) and sidechain clustering (to facilitate intermolecular recognition). A turn is defined as a site where the peptide chain reverses its overall direction. A p turn contains four amino acid residues. The carbonyl of residue i is hydrogen bonded to the NH of residue i+3 (Figure 3). Figure 3. A p turn. Table 1 defines the dihedral angles for the eight types of p turns. 1 Table 1. Dihedral angles in p turns. i + 1 i + 2 P turn ♦ V ♦ V Type I -60 -30 -90 0 T ypel’ 60 30 90 0 Typell -60 120 80 0 Type IT 60 -120 -80 0 Type HI -60 -30 -60 -30 Type nr 60 30 60 30 Type IV -60 120 -90 0 Type IY' -120 120 -60 0 Chapter 1 Introduction 1. Introduction 1.1 The history of peptide chemistry 'To Emil Fischer we owe the systematic attack on a field of natural substances that had previously been avoided by chemists. "2 Emil Fischer is generally regarded as the father of peptide chemistry and this quote from Wieland and Bodanszky sums up his place in its history. Peptide chemistry had its beginnings early this century with the production of peptides containing simple amino acids by Fischer and his contemporaries. Without the coupling reagents and protecting groups available nowadays, syntheses were laborious. In former times the synthetic difficulties were alleviated somewhat by the discovery of the benzyloxycarbonyl protecting group by Bergmann and Zervas in 1932,3 allowing the use of polyfunctional amino acids. The synthesis of small peptides was now feasible and glutathione, a naturally occurring small peptide was synthesised by Harington and Mead in 1935.4 The synthesis, eighteen years later, of the octapeptide hormone, oxytocin by du Vigneaud et al$ is regarded as a major breakthrough in peptide chemistry. The next formative step occurred when Bodanszky and his co-workers, in 1967, now with a vast array of protecting groups and reagents at hand, synthesised the 27-residue sectretin peptide by solution phase stepwise addition methodsA? Wieland described the advances in peptide chemistry in the following way: "... the synthesis of glutathione opened the door to peptide synthesis a crack, and the synthesis of oxytocin pushed the door wide open."8 Grant^ extends this analogy, saying that the development of solid phase peptide synthesis by Merrifield in 1963 ^ "blew the door off its hinges".
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