Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria.
Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria.
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DOI：
10.1002/chem.201600674
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发表时间：
2016-06-06
期刊：
影响因子：
--
通讯作者：
Luesch H
中科院分区：
文献类型：
--
作者：
Gunasekera SP;Li Y;Ratnayake R;Luo D;Lo J;Reibenspies JH;Xu Z;Clare-Salzler MJ;Ye T;Paul VJ;Luesch H
从海洋蓝藻Symploca sp.中分离得到一个新的二聚体大环内酯木吡喃糖苷cocosolide（1）。通过NMR、HRMS、X-射线衍射研究和碱水解产物的Mosher分析的组合确定结构。其碳骨架与从海绵Myriastra clavosa中分离的clavosolides A-D非常相似，但其生物活性未知。我们首次全合成了椰油酸内酯（1）沿着[α，α]-端基异构体（26）和大环核（28），从而确认了天然1的结构。聚合反应主要包括Wadsd-Emmons环丙烷化反应、Sakurai成环反应、Yamaguchi大环化/二聚化反应、α-选择性糖苷化反应和β-选择性糖苷化反应。化合物1和26以T细胞受体依赖性和非依赖性方式有效抑制IL-2产生。完全活性需要糖部分以及完整的二聚体结构的存在。可可脂（1）也以剂量依赖性方式抑制抗CD 3刺激的T细胞的增殖。从海洋蓝藻中分离得到一个新的二聚体大环内酯木吡喃糖苷--椰子内酯。其结构通过光谱方法的组合进行了鉴定，并通过全合成进一步证实。沿着其[α，α]-端基异构体和大环核心，椰油固体在各种生物测定中进行了评价，揭示了其在免疫抑制中的作用。SAR研究表明，糖部分和完整的二聚体结构的存在下，需要实现充分的活性。
A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR, HRMS, X-ray diffraction studies and Mosher’s analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [α,α]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α-selective glycosidation and β-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide (1) also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner. A new dimeric macrolide xylopyranoside, cocosolide, was isolated from marine cyanobacteria. Its structure was elucidated by a combination of spectroscopic methods and further confirmed by total synthesis. Along with its [α,α]-anomer and macrocyclic core, cocosolide was evaluated in various bioassays, which unveiled its role in immunosuppression. SAR study indicated the presence of the sugar moiety and the intact dimeric structure was required to achieve full activity.