Total synthesis of enzyme inhibitor spirastrellolide A--stereochemical confirmation.
Total synthesis of enzyme inhibitor spirastrellolide A--stereochemical confirmation.
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DOI：
10.1002/anie.200800486
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发表时间：
2008-04
影响因子：
--
通讯作者：
M. Perkins
中科院分区：
文献类型：
--
作者：
M. Perkins
对具有对抗有丝分裂中的癌细胞周期进展的活性的新型化合物的搜索已经导致了用于检测有丝分裂停滞以筛选天然产物提取物的基于细胞的测定的发展。Andersen及其同事在2003年进行的一项此类研究[1]导致从海绵Spirastrellacoccus中分离出螺旋藻A（1）作为其甲酯2（方案1）。螺环内酯A（1）是一种有效的蛋白磷酸酶2A抑制剂（IC 50 = 1 nm），但与其他抗有丝分裂海绵大环内酯类药物（如spongistatin）不同，它不影响体外微管蛋白聚合。相反，它会加速细胞从细胞周期的其他阶段进入有丝分裂，然后以与冈田酸类磷酸酶抑制剂类似的方式导致有丝分裂停滞。[2]最初提出的spirastrelllastrin A（1）的结构缺乏立体化学细节，但在2004年发表了修订的结构。[2]从结构的角度来看，螺环内酯A（1）具有47个碳主链，含有约21个立构中心，其中除1个以外的所有立构中心均包含在含有三个环醚亚基（A、BC和DEF环）的38元大环内。环A是简单的四氢吡喃，而BC环系统是6，6-螺缩酮，
The search for novel compounds with activity against cancer cell-cycle progression in mitosis has led to the development of cell-based assays for the detection of mitotic arrest for the screening of natural product extracts. One such investigation by Andersen and co-workers in 2003 [1] led to the isolation of spirastrellolide A (1) as its methyl ester 2 (Scheme 1) from the marine sponge Spirastrella coccinea. Spirastrellolide A (1) is a potent protein phosphatase 2A inhibitor (IC50= 1 nm), but unlike other antimitotic sponge macrolides, such as spongistatin, it does not effect tubulin polymerization invitro. Instead, it accelerates the entry of the cells into mitosis from other stages of the cell cycle, prior to bringing about mitotic arrest in a similar manner to the okadaic acid class of phosphatase inhibitors.[2]The structure initially proposed for spirastrellolide A (1) was lacking in stereochemical detail, but a revised structure was published in 2004.[2] From a structural perspective, spirastrellolide A (1) has a 47-carbon backbone containing some 21 stereocenters, of which all bar one are contained within a 38-membered macrocycle that contains three cyclic ether subunits (A, BC, and DEF rings). Ring A is a simple tetrahydropyran, while the BC ring system is a 6, 6-spiroketal,