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Issue 32, 2019
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Total synthesis of griseusins and elucidation of the griseusin mechanism of action

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Abstract

A divergent modular strategy for the enantioselective total synthesis of 12 naturally-occurring griseusin type pyranonaphthoquinones and 8 structurally-similar analogues is described. Key synthetic highlights include Cu-catalyzed enantioselective boration–hydroxylation and hydroxyl-directed C–H olefination to afford the central pharmacophore followed by epoxidation–cyclization and maturation via diastereoselective reduction and regioselective acetylation. Structural revision of griseusin D and absolute structural assignment of 2a,8a-epoxy-epi-4′-deacetyl griseusin B are also reported. Subsequent mechanistic studies establish, for the first time, griseusins as potent inhibitors of peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3). Biological evaluation, including comparative cancer cell line cytotoxicity and axolotl embryo tail inhibition studies, highlights the potential of griseusins as potent molecular probes and/or early stage leads in cancer and regenerative biology.

Graphical abstract: Total synthesis of griseusins and elucidation of the griseusin mechanism of action

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Publication details

The article was received on 10 May 2019, accepted on 26 Jun 2019 and first published on 27 Jun 2019


Article type: Edge Article
DOI: 10.1039/C9SC02289A
Chem. Sci., 2019,10, 7641-7648
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Total synthesis of griseusins and elucidation of the griseusin mechanism of action

    Y. Zhang, Q. Ye, Larissa V. Ponomareva, Y. Cao, Y. Liu, Z. Cui, S. G. Van Lanen, S. R. Voss, Q. She and J. S. Thorson, Chem. Sci., 2019, 10, 7641
    DOI: 10.1039/C9SC02289A

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