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Dicarba mimetics of cystine-containing peptides

thesis
posted on 22.03.2017, 01:41 by van Lierop, Bianca Jane
Peptide-based therapeutic agents represent a significant category in the pharmaceutical market. Problems associated with their poor stability and oral availability, however, necessitates the use of chemical engineering to design and synthesise novel peptidomimetics possessing improved physicochemical properties. Our interest in homogeneous catalysis led to the development of a toolbox of generic strategies for the construction of structurally enhanced peptides (Chapter 2). These strategies were ultimately used to create dicarba analogues of cystine-containing peptide targets, including complex examples that possess multiple disulfide bridges (Chapters 3 and 4). Peptide aggregation can hamper the synthesis of cyclic dicarba peptides via on-resin ring closing metathesis (RCM). Chapter 2 investigated the use of microwave-based heating to disrupt undesirable secondary structures, and was successfully used to generate a library of cystino-dicarba hybrids of the α-conotoxin family. For the construction of medium to large rings, the combined utility of microwave-irradiation and pseudoproline insertion was found to deliver a high yielding synthesis through localisation of reacting termini. This strategy was used to generate a cyclic human growth hormone fragment. A novel route to stable pseudoproline residues was also investigated in this chapter. Towards this end, a tandem metathesis-cyclisation strategy was used to deliver a high yielding and enantioselective synthesis of 5,5-dimethylproline dipeptides for direct incorporation into peptide sequences. At the close of Chapter 2, regioselective construction of multiple dicarba bridges was investigated via a tandem metathesis-hydrogenation approach. Here, microwave-accelerated RCM provided an expedient synthesis of bis-dicarba analogues belonging to the α-conotoxin family. Metathesis was also used to achieve macrolactamisation, N→C (head-to-tail) cyclisation, through the use of metathesis-labile tethers. Chapter 3 applied some of the preceding strategies to construct intrachain dicarba analogues of insulin superfamily molecules via on-resin, microwave-accelerated RCM. Cyclisation of the relaxin-3 A-chain peptide gave moderate conversion (50%) to the carbocyclic product without the inclusion of a turn-inducing residue. The primary sequence of INSL3, however, was modified to include a pseudoproline residue, and cyclised in higher yield (70%). Biological evaluation of the dicarba relaxin-3 and INSL3 analogues demonstrated equipotent binding and activity profiles, and conclusively showed, for the first time, that the intrachain bridge in these two peptide targets plays a structural role in maintaining a biologically active conformation. Significantly, both geometric isomers of each peptide were equipotent, which suggests that the relaxin-3 and INSL3 receptors are able to accommodate structural changes in this bridge region.

History

Campus location

Australia

Principal supervisor

Andrea Jane Robinson

Year of Award

2011

Department, School or Centre

Chemistry

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Science