Charalambous, Mario Andreas; (1990) The synthesis of peptide and lipid analogues incorporating very hydrophobic α-aminoalkanoic acids. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The application of a series of α-aminoalkanoic acids to the synthesis of a novel phospholipase A2 analogue and a new class of very hydrophobic LHRH peptides is described. The racemic α-aminodecanoic α-aminotetradecanoic and α-aminoeicosanoic acids were synthesised and resolved with the chiral ketol (-)-(1S,2S,5S)-2-hydroxypinan-3-one as the methyl ester hydrochlorides. In addition, the two lower homologues were enzymatically resolved with renal acylase I and leucine aminopeptidase respectively. These enzymes could not resolve the higher homologue. Designation of the absolute configuration of the resolved amino acid derivatives was made with CD spectroscopy by comparison with enzymatically resolved amino acid. Both N and C protected DL-α-aminoalkanoic acids were used to synthesise phospholipids in an attempt to obtain non-hydrolysable substrate analogues of phospholipase A2 for active site protection. The design of the synthesis permitted the resolution of phosphorylated intermediates with the chiral ketol. Several very hydrophobic LHRH analogues were also synthesised incorporating the very hydrophobic α-aminoalkanoic acids. These peptides were synthesised as part of our studies in peptide drug delivery of analogues with enhanced membrane adhesion and permeability. These properties could ultimately determine the design of analogues for oral administration.

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