Toward the total synthesis of spirastrellolide A.: Part 1:: Strategic considerations and preparation of the southern domain
Toward the total synthesis of spirastrellolide A.: Part 1:: Strategic considerations and preparation of the southern domain
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DOI：
10.1002/anie.200601654
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Radkowski, Karin
中科院分区：
文献类型：
--
作者：
Fuerstner, Alois;Fenster, Michael D. B.;Radkowski, Karin
加勒比海海绵Spirastrella coccacarium。[1]与许多其他海洋来源的抗有丝分裂大环内酯类药物不同，1在体外不影响微管蛋白聚合，但被证明是一种非常有效的（IC 50 = 1 nm）和令人惊讶的蛋白磷酸酶PP 2A的选择性抑制剂，具有在引起细胞周期停滞之前将细胞从S期直接驱动到有丝分裂的能力。[1，2]鉴于PP 2A的中心调节作用，螺旋霉素A代表了开发用于治疗癌症以及各种神经和代谢疾病的新型治疗剂的潜在先导。[3]基于对其甲酯衍生物1a（R= Me）的广泛NMR研究，对这种有趣的天然产物的最初归属[1]在出版后不久就得到了纠正。[2]即使是修改后的结构1仍然是试验性的;尽管它确实描述了螺旋藻A的正确构成和嵌入复杂大环框架中的各个结构域内的适当相对立体化学，但必须强调的是，方案2中颜色编码的片段之间的立体化学关系尚未确定。此外，1的绝对立体化学仍然未知。[二]《中国日报》
Caribbean sponge Spirastrella coccinea.[1] Unlike many other antimitotic macrolides of marine origin, 1 does not affect tubulin polymerization in vitro but was shown to be a very potent (IC50= 1 nm) and surprisingly selective inhibitor of protein phosphatase PP2A, with the ability to drive cells directly from the S phase into mitosis before causing cellcycle arrest.[1, 2] In view of the central regulatory role of PP2A, spirastrellolide A represents a potential lead for the development of novel therapeutic agents for the treatment of cancer as well as various neurological and metabolic disorders.[3]The initial assignment [1] of this intriguing natural product, based on extensive NMR studies of its methyl ester derivative 1a (R= Me), was corrected shortly after publication.[2] Even the revised structure 1 remains tentative; although it certainly depicts the correct constitution of spirastrellolide A and the proper relative stereochemistry within the individual domains embedded into the complex macrocylic frame, it must be emphasized that the stereochemical relationships between the segments color-coded in Scheme2 have yet to be determined. Moreover, the absolute stereochemistry of 1 is still unknown.[2]