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Issue 22, 2016
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Synthesis of a simplified triazole analogue of pateamine A

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Abstract

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.

Graphical abstract: Synthesis of a simplified triazole analogue of pateamine A

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Publication details

The article was received on 13 Jan 2016, accepted on 04 May 2016, published on 04 May 2016 and first published online on 04 May 2016


Article type: Paper
DOI: 10.1039/C6OB00086J
Citation: Org. Biomol. Chem., 2016,14, 5117-5127
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    Synthesis of a simplified triazole analogue of pateamine A

    A. Hemi Cumming, S. L. Brown, X. Tao, C. Cuyamendous, J. J. Field, J. H. Miller, J. E. Harvey and P. H. Teesdale-Spittle, Org. Biomol. Chem., 2016, 14, 5117
    DOI: 10.1039/C6OB00086J

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