Unprecedented immunosuppressive polyketides from Daldinia eschscholzii, a mantis-associated fungus
Unprecedented immunosuppressive polyketides from Daldinia eschscholzii, a mantis-associated fungus
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来自螳螂相关真菌 Daldinia eschscholzii 的前所未有的免疫抑制聚酮化合物
DOI：
10.1002/anie.200801284
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Tan, Ren Xiang
中科院分区：
文献类型：
--
作者：
Zhang, Ying Lao;Ge, Hui Ming;Tan, Ren Xiang
免疫抑制剂用于一系列医疗目的，如器官移植和自身免疫相关疾病的治疗。[1-2]然而，目前大多数可用的免疫抑制药物不可避免地具有严重的不良反应，如肝毒性、肾毒性和高血压诱导因此，迫切需要新的治疗药物来调节自身免疫反应。一些微生物是免疫损害化合物的可靠来源，如环孢菌素（CsA）、[3]、雷帕霉素、[4]和FK506.[5]的发现共生体是存在于植物、昆虫和哺乳动物中的一种多样的微生物群落，不会产生任何可检测到的症状，由于它们产生具有化学激励作用和生物效力的代谢物而重新受到关注，这可能是它们与宿主长期共同进化的结果特别是，一些与昆虫相关的真菌可能已经获得了从最初的微生物-宿主相互作用到最终定植的合成免疫缓解代谢物的本能能力。[7-9]在我们对内生菌培养物中新的生物活性代谢物进行表征的基础上，[10-12]这一观察结果促使我们探索寄生在健康昆虫器官（如螳螂肠道）中的真菌可能产生的新的免疫抑制代谢物，螳螂肠道显然是共生体（包括静止病原体[13]）和食物携带的“外来”微生物的重要入口和庇护所正如预期的那样，初步筛选发现在螳螂种Tenodera aridifolia的肠道中存在免疫抑制物质或免疫抑制物质Daldinia eschscholzii IFB-TL01的培养物中存在免疫抑制物质，Tenodera aridifolia是许多昆虫的常见捕食者，以携带内生菌的植物为食。随后，对真菌放大发酵提取的提取物进行了生物测定指导分离，得到了两种聚酮，dalesconols A(1)和B(2)，它们具有前所未有的碳骨架，以及与生物合成相关的中间体5[15]和8[16]1和2在手性相上的高效液相色谱拆分得到对应的对映体(+)-dalesconol a（(+)-1）和（À）-dalesconol a （（À）-1）、(+)-dalesconol B（(+)-2）和（À）-dalesconol B （（À）-2）。本文报道了对映体聚酮的分离、结构和立体化学解析、免疫抑制活性以及它们的生物合成细节。第一个分离物dalesconol A(1)为红色结晶。在其高分辨率ESI质谱中，质子化的分子离子位于m/z 463.1180处，其分子式与1H和13C核磁共振波谱数据一致（C29H19O6的m/z calcd为463.1176；见配套资料中的表1和表S3）。1的1H NMR谱表明存在一个α， β不饱和羰基，以及一个1,2,3,4 -四取代和两个1,2,3 -三取代的苯核。13C核磁共振谱证实了这一假设，还发现了另外两个酮基和一个完全取代的乙烯基，以及一个季碳原子、一个甲基和两个亚甲基碳原子。这些被分配的片段总共有17个不饱和指数，其余的片段必须在分子中再编辑成4个环。对1的二维核磁共振谱的详细解释允许构建最可能的dalesconol A的平面结构(1)。
Immunosuppressants are required for an array of medical purposes, such as organ transplantations and the treatment of autoimmune-associated diseases.[1–2] However, most of the currently available immunosuppressive drugs have been shown to inevitably possess severe adverse effects, such as hepatotoxicity, nephrotoxicity, and hypertension induction.[2] Therefore, there is an urgent need for new therapeutic agents for modulating the autoimmune response. Some microorganisms are a reliable source of immunocompromising compounds, as exemplified by the discovery of cyclosporinA (CsA),[3] rapamycin,[4] and FK506.[5] Symbionts, a diverse microbial community present in plants, insects, and mammals without the generation of any detectable symptoms, are receiving renewed attention for their production of chemically inspiring and biologically potent metabolites, presumably as a result of their long coevolution with hosts.[6] In particular, some insect-associated fungi might have acquired instinctlike capabilities for synthesizing immunoalleviating metabolites from their initial microbe–host interaction through to the final colonization.[7–9] In continuation of our characterization of new bioactive metabolites from endophyte cultures,[10–12] this observation tempted us to explore novel immunosuppressive metabolites that could be produced by fungi inhabiting healthy insect organs, such as the mantis gut, which is clearly an important entrance and shelter for symbionts (including quiescent pathogens [13]) and meal-carried “foreign” microbes.[14] As expected, a preliminary screen recognized the presence of an immunosuppressive substance or immunosuppressive substances in a culture of Daldinia eschscholzii IFB-TL01 residing in the gut of the mantis species Tenodera aridifolia, a common predator of many insects that feed on plants harboring endophyte. Subsequent bioassay-guided fractionation of the extract derived from the scaled-up fermentation of the fungus afforded two polyketides, dalesconols A (1) and B (2), which share an unprecedented carbon skeleton, together with the biosynthetically related intermediates 5 [15] and 8.[16] Optical resolution of 1 and 2 by HPLC on a chiral phase gave the corresponding enantiomers (+)-dalesconol A ((+)-1) and (À)-dalesconol A ((À)-1),(+)-dalesconol B ((+)-2) and (À)-dalesconol B ((À)-2). We report herein the isolation, structural and stereochemical elucidation, and immunosuppressive activity of the enantiomeric polyketides, as well as details of their biosynthesis.The first isolate, dalesconol A (1), was obtained as red crystals. A protonated molecular ion at m/z 463.1180 in its high-resolution ESI mass spectrum indicated a molecular formula that was in accordance with the 1H and 13C NMR spectroscopic data (m/z calcd for C29H19O6: 463.1176; see TablesS1 and S3 in the Supporting Information). The 1H NMR spectrum of 1 suggested the presence of an α, βunsaturated carbonyl group as well as one 1, 2, 3, 4-tetrasubstituted and two 1, 2, 3-trisubstituted benzene nuclei. This assumption was confirmed by the 13C NMR spectrum, which revealed additionally the existence of two further ketone groups and a fully substituted vinyl group, as well as a quaternary, a methine, and two methylene carbon atoms. These assigned fragments accounted in total for seventeen indices of unsaturation, with the rest having to be edited into four more rings in the molecule. Detailed interpretation of the 2D NMR spectra of 1 allowed the construction of the most likely planar structure of dalesconol A (1).