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Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti‐Cancer Properties
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Philipp Krastel Silvio Roggo Markus Schirle Nathan T. Ross Francesca Perruccio Peter Aspesi Jr. Thomas Aust Kathrin Buntin David Estoppey Brigitta Liechty Felipa Mapa Klaus Memmert Howard Miller Xuewen Pan Ralph Riedl Christian Thibaut Jason Thomas Trixie Wagner Eric Weber Xiaobing Xie Esther K. Schmitt Dr. Dominic Hoepfner 《Angewandte Chemie (International ed. in English)》2015,54(35):10149-10154
Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti‐fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF‐1α) as the primary target for this compound class. Nannocystin A ( 1 ) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti‐cancer compound didemnin B on EF‐1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1. 相似文献
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Mono‐, di‐ and trimethylated homologues of isoprenoid tetraether lipid cores in archaea and environmental samples: mass spectrometric identification and significance
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Chris Knappy Daniela Barillà James Chong Dominic Hodgson Hugh Morgan Muhammad Suleman Christine Tan Peng Yao Brendan Keely 《Journal of mass spectrometry : JMS》2015,50(12):1420-1432
Higher homologues of widely reported C86 isoprenoid diglycerol tetraether lipid cores, containing 0–6 cyclopentyl rings, have been identified in (hyper)thermophilic archaea, representing up to 21% of total tetraether lipids in the cells. Liquid chromatography‐tandem mass spectrometry confirms that the additional carbon atoms in the C87‐88 homologues are located in the etherified chains. Structures identified include dialkyl and monoalkyl (‘H‐shaped’) tetraethers containing C40‐42 or C81‐82 hydrocarbons, respectively, many representing novel compounds. Gas chromatography‐mass spectrometric analysis of hydrocarbons released from the lipid cores by ether cleavage suggests that the C40 chains are biphytanes and the C41 chains 13‐methylbiphytanes. Multiple isomers, having different chain combinations, were recognised among the dialkyl lipids. Methylated tetraethers are produced by Methanothermobacter thermautotrophicus in varying proportions depending on growth conditions, suggesting that methylation may be an adaptive mechanism to regulate cellular function. The detection of methylated lipids in Pyrobaculum sp. AQ1.S2 and Sulfolobus acidocaldarius represents the first reported occurrences in Crenarchaeota. Soils and aquatic sediments from geographically distinct mesotemperate environments that were screened for homologues contained monomethylated tetraethers, with di‐ and trimethylated structures being detected occasionally. The structural diversity and range of occurrences of the C87‐89 tetraethers highlight their potential as complementary biomarkers for archaea in natural environments. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
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Torsten Roth Vladislav Vasilenko Callum G. M. Benson Hubert Wadepohl Dominic S. Wright Lutz H. Gade 《Chemical science》2015,6(4):2506-2510
A simple, “click” synthetic approach to a new type of hybrid phosph(III)azane/NHC system is described. The presence of the phosphazane P2N2 ring unit, with P atoms flanking the NCN fragment and with this ring perpendicular to the binding site of the NHC, provides unique opportunities for modifying the electronic and steric character of these carbenes. 相似文献
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