The thesis discusses the design of potential inhibitors of Angiotensin Converting Enzyme (ACE). The synthesis of pep tide inhibitors containing arginine and histidine-type residues is described. Successful incorporation of these residues during peptide synthesis requires the use of protecting groups on the side-chains* and new developments in this area are described. Ch. 1 reviews the currently available protecting groups for histidine. A methodology for regiospecific introduction of protecting groups of type ROCH<sub>2</sub>-, via their corresponding chloromethyl ethers, is described. A convenient synthesis of these reagents (specifically t-Butoxymethylchloride, Dum-Cl and 2,4,6-TrimethyIbenzyloxymethyl- chloride, Tom-Cl) is given. Ch. 2 demonstrates that a knowledge of the location of histidine protecting groups has become mandatory, both in peptide synthesis and elsewhere. Two methods) a), nuclear Overhauser enhancement measurements and b), a procedure involving methylation, deprotection and amino-acid analysis are presented, which have allowed the differentiation of ? and ? derivatised histidines. Ch. 3 reviews the currently available protecting groups for arginine. Using 2-phenylethyIguanidine as a model for arginine, a number of haloacylguanidines and 5,5-disubstituted pyrimidinones wBe synthesised, and this chapter describes their structures, and the potential use of the corresponding reagents in protecting arginine during peptide synthesis. Ch. 4 describes the synthesis of his tidyIphenylalanylarginine and several variants on this structure. Biological data showing the level of inhibition both of A.C-E- and of Renal ^ndopeptidase by these compounds is presented. The syntheses also provide a further demonstration of the efficacy of the recently introduced benzyloxymethyI, (Bom)protecting group.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:329965 |
| Date | January 1988 |
| Creators | Thomas, David William |
| Contributors | Jones, J. H. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:8cf7679d-1a0b-4163-b9dd-87363c9bf806 |
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