Synthesis of a simplified triazole analogue of pateamine A.

Org Biomol Chem 2016 Jun 16;14(22):5117-27. Epub 2016 May 16.

School of Chemical and Physical Sciences and Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.

Pateamine A is a naturally occurring metabolite extracted from the marine sponge Mycale hentscheli. It exhibits potent cytotoxicity towards cancer cell lines and has been shown to target protein translation initiation via inhibition of the function of eukaryotic initiation factor 4A proteins. We have synthesised a simplified analogue of pateamine A, consisting of the skeletal core of the natural product but with the thiazole heterocycle replaced by a triazole. The convergent design of the synthesis features a base-induced opening of a δ-valerolactone to access the Z,E-dienoate moiety, Julia-Kocienski olefination and copper-catalysed azide-alkyne cycloaddition. Bioactivity testing of the simplified pateamine A analogue (3) indicated a significant reduction in cytotoxicity, compared to natural pateamine A. We propose that this reduced activity is due mainly to the substitution of the thiazole for the triazole heterocycle. This supports the hypothesis that the thiazole of pateamine A is important for binding to its biological target.

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http://dx.doi.org/10.1039/c6ob00086jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5166979PMC
June 2016
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