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Design and Synthesis of a Highly Simplified Pateamine Analogue

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posted on 15.11.2021, 20:31 by Brown, Sarah

Pateamine (1) is a natural product from the marine sponge Mycale hentscheli that exhibits potent anticancer properties, and has potential as an antiviral agent, and in preventing the muscle wasting disorder cachexia. This biological activity of pateamine is due to its ability to inhibit the eukaryotic initiation factor eIF4A, which leads to the formation of stress granules, the inhibition of protein synthesis, and ultimately cell death. Unfortunately, pateamine is obtained in very small amounts from Mycale hentscheli; thus, it is necessary to synthesise pateamine and novel structural analogues in the laboratory. Previously a separate binding and scaffolding domain of pateamine was proposed, which led to the synthesis of a simplified des-methyl des- amino analogue that reduced the number of synthetic steps compared to pateamine while retaining its biological activity. This was followed by the synthesis of a simplified triazole- containing analogue 9 6 ; unfortunately, this exhibited substantially reduced bioactivity compared to pateamine, and it is therefore necessary to determine if the reduction in bioactivity was due to the replacement of the thiazole ring with a triazole ring, or due to the removal of key methyl groups of pateamine. Thus, the thiazole-containing analogue of 96 is deemed to be an important synthetic target.  In this Master’s project a highly simplified side chain-free analogue 130 was synthesised, which laid the groundwork for future synthesis of a thiazole-containing analogue of 96. The synthesis of 130 was achieved through a convergent synthesis with one commercially available and two prepared fragments. Particular attention was paid to the development of an efficient thiazole formation methodology, as well as optimising fragment synthesis and coupling reactions. Determination of the binding of analogue 130 with eIF4A using a competitive bioactivity assay in the presence of pateamine was then undertaken, which showed that either 130 does not bind to eIF4A or that it binds non-covalently and is then displaced by pateamine.

History

Copyright Date

01/01/2016

Date of Award

01/01/2016

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Biomedical Science

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Masters

Degree Name

Master of Biomedical Science

Victoria University of Wellington Unit

Centre for Biodiscovery

ANZSRC Type Of Activity code

3 APPLIED RESEARCH

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Alternative Title

The Simplification of Pateamine

Victoria University of Wellington School

School of Biological Sciences

Advisors

Teesdale-Spittle, Paul; Harvey, Joanne