Design and Synthesis of Peptide Mimetic Heterocycles as Potential Glycogen Phosphorylase Inhibitors

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Loughlin, Wendy

Jenkins, Ian

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2011
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Abstract

This thesis reports the synthesis, and biological activity of a series of peptide mimetic heterocycles designed as potential glycogen phosphorylase inhibitors. Structural studies (NMR, CD, and modeling) on synthetic PEWPSYLGYEKLGPYY-NH2 (70, representing the C-terminus end of GL) revealed that the novel 70 is a random coil structure in the solution state. Twenty four di- to penta-peptides fragments of 70 were synthesised using solid phase and solution phase peptide synthesis. Screening of the peptide fragments against GPa showed that key residues involved in GPa inhibition (not binding) were Lys279, Leu280, and Gly281. Modeling of the EKL sequence of 70 led to the design of a morpholine scaffold. A library of morpholine derivatives were synthesised by solution phase chemistry involving direct coupling of amino acids onto a morpholine scaffold. The derivatives 130, 134, 139, and 144 were inactive, with derivatives 131 (20 % at 222) and 146 (25 % at 222) displaying low inhibition and the Leu morpholine derivative 135 (IC50 of 6.5 mM) being the most active against GPa. In a de novo approach, a novel spiro[4.5] lactam scaffold was designed from the Pro-Ser sequence of 70. Synthesis of spiro[4.5] lactams 186/187 was achieved from proline via a key intermediate hydantoin 183 in nine steps and in an overall yield of 7.2 %. A key step involved finding a very mild procedure to ring-open the normally extremely robust hydantoin to give the corresponding amino acid 185, which was then converted into the target spiro[4.5] lactam scaffold, obtained as a mixture of diastereomers 186/187. Only one of the diastereomers was active with 187 giving an IC50 of 241 M and 186 displaying no inhibition against GPa. Diastereomer 187 was identified as the lead spiro[4.5] lactam. A second de novo approach involved a previously developed pyridone scaffold.1 A series of pyridone derivatives were synthesised with 2 aryl groups attached by different length carbon chains. The aryl groups also contained various degrees of chlorination. The derivatives 201-202, 206-207, 211-215, 220-221, 225, 230-231, and 236 were screened against GPa and structure activity relationship (SAR) determined. For example, it was found that elongating only one side of the compound over the other side, as in the cases of 195, 212, 230, activity against GPa was lost. Similarly, 3,4-dichlorophenyl substitution was found to result in much higher activity than 2,4-dichlorophenyl substitution, or no chloro substitution, suggesting that the 3,4-dichlorophenyl substituent has a strong hydrophobic interaction with the GPa enzyme.

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Thesis (PhD Doctorate)

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Doctor of Philosophy (PhD)

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Eskitis Institute for Cell and Molecular Therapies

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The author owns the copyright in this thesis, unless stated otherwise.

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Subject

synthesis

peptide

mimetic

heterocycles

glycogen

phosphorylase

inhibitors

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