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Synthesis of w-conotoxin GVIA inspired small molecules in the search for relief of neuropathic pain

thesis
posted on 15.05.2017, 06:54 authored by Graham, Janease Erin
This thesis describes the synthesis and biological evaluation of non-peptide mimetics of the potent Cav2.2 inhibitor ro-Conotoxin GVIA towards the development of novel analgesics. These mimetics explored and optimised the potency of existing anthranilamide and benzathiazole lead compounds that display the functional groups of three amino acid residues, Lys2, Tyr13 and Arg17, key for the potency of ro-Conotoxin GVIA. A series of ten analogues 49 and 50 based on a lead anthranilamide lead Cav2.2 binder were synthesised to explore the effect of the changing the linker length connecting the Lys2 and Arg17 side chain functional groups to the central anthranilamide scaffold and the functionalisation of the Lys2 and Arg17 moieties. Synthesis of these mimetics was achieved by the stepwise and selective addition of Lys2, Tyr13 and Arg17 mimics to a central aryl core. Functional group interconversion and deprotection steps completed the functionalisation of the target compounds 49 and 50. All anthranilamide targets showed micromolar ICso values and stronger binding was demonstrated when the Lys2 and Arg17 positions were functionalised with guanidinium groups 49. The propyl and octyllinked diguanidinium compound 49c showed the strongest binding to the Cav2.2 channel with an ICso value of 12 ~M. Second generation anthranilamide compounds were then synthesised. These compounds included fuctionalisation of the 4-position of the Tyr 13 phenoxy group to further improve the Cav2.2 affinity of these compounds. The fluoro functionalised anthranilamide compound 49f recorded the strongest binding affinity for this series of compounds exhibiting an ICso value of 6.2~M. In attempt to improve the Cav2.2 affinity of a benzathiazole based lead compound, six benzimidazole analogues 80-83 were synthesised and the synthesis of indole based analogues 130-133 was attempted. The benzimidazole based Cay2.2 binders 80-83 were synthesised with structural diversity in the Tyr13 and Argl7 groups as well as the linker functionality. These compounds were produced by synthesising a 2-aminobenzimidazole key intermediate 107 by addition of cyanamide to a dianiline 113. The amidobenzimidazole 109 and aminobenzimidazole cores 117 were synthesised via key acyl coupling and reductive amination reactions using the 2-aminobenzimidazole intermediate 107. Functional group interconversions of these core benzimidazoles 109 and 117 produced the target compounds 80-83. The strongest affinity for Cay2.2 was shown by the amide linked benzimidazole compound 83b that was fluorinated at the Tyrl3 position and guanidinium functionalised at the Argl7 position. This compound 83b bound to Cay2.2 channels with an ICso value of 0.9 11M. As observed for the anthranilamide series compounds functionalised with a guanidinium moiety at the Arg17 position 83 showed stronger binding than those compounds with an amine functionality at this position 80 and 82 and the fluorinated guanidinium benzimidazole 83b showed stronger Cay2.2 binding than the unfuctionalised guanidinium benzimidazole 83a. The synthesis of indole based mimetics was attempted. An indole 155 was synthesised via a Liemgruber-Batcho indole synthesis and directed lithiation of this precursor 155 followed functional group interconversions produced a 2-aminoindole key intermediate 144. The novel 2- amidolinked indole and 2-aminolinked compounds 156 and 161 were then produced by the acyl coupling and reductive amination of this common 2-aminoindole precursor 144. The benzimidazole 83b exhibited the strongest Cay2.2 affinity (lCso = 0.9 11M) of all compounds synthesised in this thesis. Leading on from the original non-peptide lead compounds, the benzimidazole 83b is the most potent Cay 2.2 binder of this type to date and is also the first to have higher Cay2.2 affinity than the original mimetics.

History

Campus location

Australia

Principal supervisor

Kellie Tuck

Additional supervisor 1

Peter Duggan

Year of Award

2010

Department, School or Centre

Chemistry

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Science