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Design and Synthesis of Simplified Analogues of Pateamine A

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posted on 2021-12-08, 11:09 authored by Cumming, Hemi

Pateamine A (14) is a natural product that was extracted from a marine sponge off the coast of the South Island of New Zealand. It exhibits potent biological activity, mediated by a number of protein targets. The most sensitive of these towards pateamine are the eIF4A isoforms, which have roles in translation of RNA into proteins and in nonsensemediated decay. The inhibition of these enzymes may be beneficial in the treatment of cancer or certain types of genetic diseases. Unfortunately, the naturally available supply of pateamine is very limited and its total synthesis is complex. This provides an imperative for the design of a synthetic strategy that would allow the preparation of simplified analogues of pateamine to gain further insight into the necessary features for activity and selectivity of the eIF4A isoforms. Based on the principles of pharmacophore modification, chemical synthesis and the structure-activity relationships (SARs) reported by Romo and co-workers, a simplified analogue of pateamine, 107, was targeted that lacked a number of pendant methyl groups and contained a triazole in place of the thiazole. Synthesis of the target analogue 107 was achieved through preparation of four fragments, followed by an investigation of suitable coupling reactions and the optimal order of connectivity. This included the preparation of two macrocycles that lacked the trienecontaining sidechain, and of simplified model substrates that allowed investigation of two olefination reactions (namely, the Wittig and Julia-Kocienski reactions) for the attachment of the sidechain fragment. After substantial optimisation of the fragment preparation and connectivity, the complete synthesis of the target pateamine analogue 107 was achieved. The synthesis features: 1) a Julia Kocienski olefination between a highly functionalised three-carbon sulfone and a conjugated aldehyde to attach the sidechain; 2) copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction to form the triazole; 3) ring opening of a δ-substituted α,β-unsaturated lactone to access the Z,E-dienoate moiety; and 4) Yamaguchi macrolactonisation. This synthesis represents a convergent strategy with 11 steps in the longest linear sequence, which utilises easily accessible starting materials (i.e. furan (or cis-butenediol), epichlorohydrin, ε-caprolactone and 1,3-propanediol) and reagents. The approach is also broadly applicable to the preparation of a range of analogue variants. The simplified analogue (107) was found to have significantly lower activity, in comparison to pateamine A (14), in a growth inhibitory assay. Presuming this loss of bioactivity is at least partially caused by the incorporation of the triazole (in place of the thiazole), this raises an interesting question as to the role of the thiazole moiety in the bioactivity of pateamine A. The adaptation of the synthetic strategy devised in this thesis to the preparation of future analogues will enable study of the mechanism of action of pateamine and related compounds, and probe the requirements for effective binding to the eIF4A isoforms.


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Date of Award



Te Herenga Waka—Victoria University of Wellington

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Author Retains Copyright

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Degree Grantor

Te Herenga Waka—Victoria University of Wellington

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Degree Name

Doctor of Philosophy

ANZSRC Type Of Activity code

970103 Expanding Knowledge in the Chemical Sciences

Victoria University of Wellington Item Type

Awarded Doctoral Thesis



Victoria University of Wellington School

School of Chemical and Physical Sciences


Teesdale-Spittle, Paul; Harvey, Joanne