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A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2017-12-21 00:00:00 , DOI: 10.1021/acs.joc.7b02871 Zhanchao Meng 1 , Laetitia Souillart 1 , Brendan Monks 1 , Nikolas Huwyler 1 , Jennifer Herrmann 2 , Rolf Müller 2 , Alois Fürstner 1
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2017-12-21 00:00:00 , DOI: 10.1021/acs.joc.7b02871 Zhanchao Meng 1 , Laetitia Souillart 1 , Brendan Monks 1 , Nikolas Huwyler 1 , Jennifer Herrmann 2 , Rolf Müller 2 , Alois Fürstner 1
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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.
中文翻译：
Nannocystin Ax的“面向主题”的全合成。类似物的制备和生物学评估
已知nannocystin家族具有高度细胞毒性的环二肽与真核翻译延伸因子1α（EF-1α）结合。如先前的计算机研究中所建议的，对接姿势的分析表明，三取代的烯烃部分和相邻的甲醚形成了一个域，该域可能与生物活性紧密相关。该假设赞助了旨在“以基序为导向”的合成运动：具体来说，构想了一系列闭环炔烃复分解（RCAM），然后对所得环炔烃进行羟基定向的反式氢化取代，这使得该潜在的锚固亚结构得以实现。在后期进行系统处理。这种固有的灵活方法使人们可以使用Nannocystin Ax（1）本身以及10种非天然类似物。虽然生物学数据证实了这类化合物的显着功效，并表明所讨论的域确实是药效团的固有部分，但其特定的结构/活性关系只能部分与最初的计算机对接研究相一致；因此，我们得出结论，该模型需要仔细地重新审视。
更新日期：2017-12-21
中文翻译：
Nannocystin Ax的“面向主题”的全合成。类似物的制备和生物学评估
已知nannocystin家族具有高度细胞毒性的环二肽与真核翻译延伸因子1α（EF-1α）结合。如先前的计算机研究中所建议的，对接姿势的分析表明，三取代的烯烃部分和相邻的甲醚形成了一个域，该域可能与生物活性紧密相关。该假设赞助了旨在“以基序为导向”的合成运动：具体来说，构想了一系列闭环炔烃复分解（RCAM），然后对所得环炔烃进行羟基定向的反式氢化取代，这使得该潜在的锚固亚结构得以实现。在后期进行系统处理。这种固有的灵活方法使人们可以使用Nannocystin Ax（1）本身以及10种非天然类似物。虽然生物学数据证实了这类化合物的显着功效，并表明所讨论的域确实是药效团的固有部分，但其特定的结构/活性关系只能部分与最初的计算机对接研究相一致；因此，我们得出结论，该模型需要仔细地重新审视。
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