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dc.contributor.authorMeng, Zhanchao
dc.contributor.authorSouillart, Laetitia
dc.contributor.authorMonks, Brendan
dc.contributor.authorHuwyler, Nikolas
dc.contributor.authorHerrmann, Jennifer
dc.contributor.authorMüller, Rolf
dc.contributor.authorFürstner, Alois
dc.date.accessioned2018-11-01T14:02:24Z
dc.date.available2018-11-01T14:02:24Z
dc.date.issued2018-07-06
dc.identifier.issn1520-6904
dc.identifier.pmid29265814
dc.identifier.doi10.1021/acs.joc.7b02871
dc.identifier.urihttp://hdl.handle.net/10033/621530
dc.description.abstractThe 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.en_US
dc.rightsAttribution-NonCommercial-ShareAlike 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/us/*
dc.titleA "Motif-Oriented" Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues.en_US
dc.typeArticleen_US
dc.contributor.departmentHIPS, Helmholtz-Institut füt Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
refterms.dateFOA2018-11-01T14:02:24Z
dc.source.journaltitleThe Journal of organic chemistry


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