Studies in peptide chemistry

Thesis



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 ROCH₂-, 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.

Authors: Thomas, D; Thomas, D. W.

• Publication date: 1988
• DOI: 10.5287/ora-zo0q0jry9
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Synthesis; Peptides; Arginine