Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin.
Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin.
复制标题
用于 β-微管蛋白光亲和标记的 22-(3-叠氮基苯甲酰氧基)甲基埃坡霉素 C 的全合成和评价。
DOI：
10.1016/j.bmcl.2009.04.077
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发表时间：
2009
影响因子：
2.7
通讯作者：
Georg,GundaI
中科院分区：
文献类型：
--
作者：
Hutt,OliverE;Inagaki,Jun;Reddy,BolluS;Nair,SajivK;Reiff,EmilyA;Henri,JohnT;Greiner,JackF;VanderVelde,DavidG;Chiu,Ting-Lan;Amin,ElizabethA;Himes,RichardH;Georg,GundaI
22-（3-叠氮基苯甲酰氧基）甲基埃博霉素C的全合成被描述为一种潜在的光亲和探针，以阐明β-微管蛋白结合位点。采用一种新的衍生化C1-C6片段的顺序Suzuki-aldol-Yamaguchi大环内酯化策略。C22-官能化的类似物在微管组装测定中表现出良好的活性，但细胞毒性显著降低。分子模型模拟表明，在C22位置的空间体积过大的结合位点的大疏水口袋容纳。光亲和标记研究不确定，表明非特异性标记。
The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1–C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.