Towards Synthesis of Simplified Analogues of Pateamine A

Pateamine A (22) is a natural product that was isolated from a marine sponge inhabiting the coast of New Zealand. It exhibits potent inhibition of protein synthesis and nonsense-mediated mRNA decay through binding with eIF4A isoforms. Due to the scarcity of pateamine A (22) in the natural source and the low yield of total synthesis of pateamine A, it is necessary to prepare structurally simplified analogues which would allow further research on structure-activity relationships (SAR) of pateamine A (22). Based on the structure-activity relationship studies reported by Romo and co-workers, a simplified triazole analogue 182 lacking methyl groups was synthesized by Hemi Cumming, a previous Ph.D. student who studied at Victoria University of Wellington. The antiproliferative activity of this analogue was found to be significantly lower than that of pateamine A, suggesting that the thiazole embedded within the molecule or the excised methyl groups are crucial for its potency. Therefore, to further explore the necessary features for its selective activity for eIF4A isoforms, new thiazole analogues 183 – 186 and triazole analogues (10S)-and (10R)-analogue 187 were targeted in this project. The preparation of the thiazole-containing macrocyclic core of analogues 183 and 184 was achieved. It features: (1) gold-catalysed thiazole formation through coupling between an alkyne fragment and a thioamide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of a δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. The synthesis of the triazole-containing macrocyclic core of (10S)-analogue 187 was completed. It features: (1) a copper-catalysed triazole formation through 1,3-dipolar cycloaddition between an alkyne fragment and an azide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. Studies on the preparation of a side-chain fragment with suitable functionalities to allow coupling with the various macrocycles through olefination reactions were also conducted. The attachment of the side-chain fragment onto the macrocyclic cores for the synthesis of the targeted analogues 183 and 184 and (10S)-analogue 187 will be investigated in future work. These experimental results will inform the synthesis of new generation analogues to further study the key structures required for effective binding to the protein target eIF4A and selectivity between isoforms.