Total synthesis of a biotinylated rocaglate: Selective targeting of the translation factors eIF4AI/II

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Abstract

The total synthesis of a biotinylated derivative of methyl rocaglate is described. This compound was accessed from synthetic methyl rocaglate (2) via formation of the propargyl amide and subsequent click reaction with a biotin azide. Affinity purification revealed that biotinylated rocaglate (8) and methyl rocaglate (2) bind with high specificity to translation factors eIF4AI/II. This remarkable selectivity is in line with that found for the more complex rocaglate silvestrol (3).

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Acknowledgments

We thank the Australian Research Council-Discovery Grants Scheme for funding. LML holds an NHMRC Peter Doherty Early Career Fellowship (1035502). Research on this subject is supported by the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS to WEHI (LML).

References and notes (21)

  • Meurer-Grimes, B. M.; Yu, J.; Vario, G. L. WO 2002002566, A1 20020110, 2004,...
  • B.Y. Hwang et al.

    J. Org. Chem.

    (2004)
  • B. Gerard et al.

    J. Am. Chem. Soc

    (2004)
    B. Gerard et al.

    J. Am. Chem. Soc.

    (2006)
  • S.G. Stewart et al.

    Org. Biomol. Chem.

    (2010)
  • C.M. Pannell
    (1992)
  • S.S. Ebada et al.

    Prog. Chem. Org. Nat. Prod.

    (2011)
    L. Pan et al.

    Nat. Prod. Rep.

    (2014)
    S.S. Ebada et al.

    Prog. Chem. Org. Nat. Prod.

    (2011)
  • M.L. King et al.

    J. Chem. Soc., Chem. Commun.

    (1982)
  • F.N. Ko et al.

    Eur. J. Pharmacol.

    (1992)
  • F. Ishibashi et al.

    Phytochemistry

    (1993)
  • M. El Sous et al.

    Angew. Chem., Int. Ed.

    (2007)
    T.E. Adams et al.

    J. Am. Chem. Soc.

    (2009)
    B. Gerard et al.

    Angew. Chem., Int. Ed.

    (2007)
    J.M. Chambers et al.

    J. Nat. Prod.

    (2012)
There are more references available in the full text version of this article.

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    Whereas Phe163Leu-Ile199Met mutations clearly rendered human eIF4A1 resistant to RocA in vitro (Figure 5), their in vivo effects were still modest (Figure 4). This difference was probably caused by the presence of a highly homologous eIF4A1 paralog, eIF4A2, which has been also reported as a target of rocaglates (Chambers et al., 2013, 2016). Although its expression is relatively low compared to eIF4A1 in the HEK293 cells used in this study (Figure S5F), the potent dominant-negative effect of RocA (Iwasaki et al., 2016) could be induced via the minor paralog of eIF4A.

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