Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90.
Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90.
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DOI：
10.1021/jo1000109
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发表时间：
2010-05-07
影响因子：
3.6
通讯作者：
Panek, James S.
中科院分区：
文献类型：
--
作者：
Wrona, Iwona E.;Gozman, Alexander;Taldone, Tony;Chiosis, Gabriela;Panek, James S.
报道了不对称合成瑞布拉菌素(1)，首次全合成自溶菌素(2)及相关结构化合物。这些合成扩大了一个高度区域和非对映选择性的氢化金属化醛加成序列的用途，以组装天然产物的完全功能化的ANSA链。还记录了分子内铜介导的酰胺化反应，以关闭19个成员的大环内酰胺类药物。酰胺化反应也被用于生成酚类阿萨霉素的结构衍生物(6-9)。安山霉素天然产物和选定的结构类似物在与乳腺癌细胞裂解物的竞争结合试验和细胞毒性试验中进行了评估。与17-烯丙氨基-17-去甲氧基格尔达霉素(17-AAG，4)相比，瑞布拉菌素(1)和自溶霉素(2)与HSP90蛋白的结合活性均增强(~25 nM)，17-烯丙氨基-17-去甲氧基格尔达霉素(17-AAG，4)是目前正在评估的用于癌症治疗的格尔达霉素(3)衍生物(~100 nm)。
A full account of an asymmetric synthesis of reblastatin (1), the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio-and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6–9) of phenolic ansamycins. Ansamycin natural products and selected structural analogs were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the Hsp90 protein with enhanced binding activity (~25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (~100 nM).
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