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  A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues

Meng, Z., Souillart, L., Monks, B., Huwyler, N., Herrmann, J., Müller, R., et al. (2018). A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues. The Journal of Organic Chemistry, 83(13), 6977-6994. doi:10.1021/acs.joc.7b02871.

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 Creators:
Meng, Zhanchao1, Author              
Souillart, Laetitia1, Author              
Monks, Brendan1, Author              
Huwyler, Nikolas1, Author              
Herrmann, Jennifer2, Author
Müller, Rolf2, Author
Fürstner, Alois1, Author              
Affiliations:
1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              
2Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, 66123 Saarbrücken, Germany, ou_persistent22              

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 Abstract: The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1α (EF-1α). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be “motif-oriented”: specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited.

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Language(s): eng - English
 Dates: 2017-11-132017-12-212018-07-06
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acs.joc.7b02871
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Title: The Journal of Organic Chemistry
  Other : J. Org. Chem.
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 83 (13) Sequence Number: - Start / End Page: 6977 - 6994 Identifier: ISSN: 0022-3263
CoNE: https://pure.mpg.de/cone/journals/resource/954925416967_1