Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core
Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core
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DOI：
10.1073/pnas.1001421107
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发表时间：
2010-04-06
影响因子：
11.1
通讯作者：
Overman, Larry E.
中科院分区：
文献类型：
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作者：
Schnermann, Martin J.;Beaudry, Christopher M.;Overman, Larry E.
报道了含有2，7-二氧杂双环[3.2.1]Octan-3-one部分的海绵二萜马法兰E(Mace)及其合成类似物t-Bu-Mace的高尔基修饰性质。天然产物筛选工作发现，Mace在高尔基体结构中诱导了一种新的形态变化，这种变化由条带断裂定义，并保持了产生的高尔基体片段在中央周围区域。采用化学合成法合成了含有取代的2，7-二氧二环[3.2.1]辛烷-3-酮的叔丁基取代了MACE的氢天青烯亚基的叔丁基。对Mace、t-Bu-Mace和几个相关结构的高尔基修饰特性的研究表明，整个富氧桥式双环片段是诱导这种独特的高尔基体组织表型所必需的。MACE诱导的高尔基体修饰的进一步表征表明，蛋白质分泌被抑制，而对肌动蛋白或微管细胞骨架没有影响。在常温下，在质子胺存在下，t-Bu-Mace和结构上相关的DES-乙酰氧基同系物转化为取代吡咯，表明共价修饰可能参与了MACE的高尔基改变活性。
Golgi-modifying properties of the spongian diterpene macfarlandin E (MacE) and a synthetic analog, t-Bu-MacE, containing its 2,7-dioxabicyclo[3.2.1]octan-3-one moiety are reported. Natural product screening efforts identified MacE as inducing a novel morphological change in Golgi structure defined by ribbon fragmentation with maintenance of the resulting Golgi fragments in the pericentriolar region. t-Bu-MacE, which possesses the substituted 2,7-dioxabicyclo[3.2.1] octan-3-one but contains a tert-butyl group in place of the hydroazulene subunit of MacE, was prepared by chemical synthesis. Examination of the Golgi-modifying properties of MacE, t-Bu-MacE, and several related structures revealed that the entire oxygen-rich bridged-bicyclic fragment is required for induction of this unique Golgi organization phenotype. Further characterization of MacE-induced Golgi modification showed that protein secretion is inhibited, with no effect on the actin or microtubule cytoskeleton being observed. The conversion of t-Bu-MacE and a structurally related des-acetoxy congener to substituted pyrroles in the presence of primary amines in protic solvent at ambient temperatures suggests that covalent modification might be involved in the Golgi-altering activity of MacE.