Total synthesis and evaluation of C26-hydroxyepothilone D derivatives for photoaffinity labeling of beta-tubulin.
Total synthesis and evaluation of C26-hydroxyepothilone D derivatives for photoaffinity labeling of beta-tubulin.
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用于 β-微管蛋白光亲和标记的 C26-羟基埃坡霉素 D 衍生物的全合成和评价。
DOI：
10.1021/jo901752v
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Georg,GundaI
中科院分区：
文献类型：
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作者：
Reiff,EmilyA;Nair,SajivK;Henri,JohnT;Greiner,JackF;Reddy,BolluS;Chakrasali,Ramappa;David,SunilA;Chiu,Ting-Lan;Amin,ElizabethA;Himes,RichardH;VanderVelde,DavidG;Georg,GundaI
采用全合成法制备了三种光亲和标记的埃坡霉素 D 衍生物，采用高效的新型不对称合成方法来制备两种重要的合成结构单元。 (S,E)-3-(叔丁基二甲基硅氧基)-4-甲基-5-(2-甲基噻唑-4-基)戊-4-烯醛不对称合成的关键步骤涉及用(R)-Me-CBS-恶唑硼烷进行酮还原。为了合成(5S)-5,7-二[(叔丁基二甲基甲硅烷基)氧基]-4,4-二甲基庚烷-3-酮，采用了β-酮酯的不对称Noyori还原。 C26 羟基埃坡霉素 D 衍生物是按照完善的全合成策略构建的，并将光亲和标记附着在 C26 羟基上。在微管蛋白组装测定中测试了光亲和类似物以及针对 MCF-7 和 HCT-116 癌细胞系的细胞毒性。在微管蛋白组装测定中，发现 3- 和 4-叠氮基苯甲酸类似物与埃坡霉素 B 一样具有活性，但与埃坡霉素 B 相比，其细胞毒性显着降低。二苯甲酮类似物在两种测定中均无活性。进行的对接和评分研究表明，叠氮化物类似物可以与埃坡霉素结合位点结合，但二苯甲酮类似物会经历空间驱动的配体重排，从而中断所有氢键合，从而中断蛋白质结合。 3-叠氮基苯甲酸衍生物的光亲和标记研究没有鉴定出任何共价标记的肽片段，这表明苯基叠氮基侧链主要以结合构象暴露于溶剂中。
Three photaffinity labeled derivatives of epothilone D were prepared by total synthesis, using efficient novel asymmetric synthesis methods for the preparation of two important synthetic building blocks. The key step for the asymmetric synthesis of (S,E)-3-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal involved a ketone reduction with (R)-Me-CBS-oxazaborolidine. For the synthesis of (5S)-5,7-di[(tert-butyldimethylsilyl)oxy]-4,4-dimethylheptan-3-one an asymmetric Noyori reduction of a β-ketoester was employed. The C26 hydroxyepothilone D derivative was constructed following a well-established total synthesis strategy and the photoaffinity labels were attached to the C26 hydroxyl group. The photoaffinity analogues were tested in a tubulin assembly assay and for cytotoxicity against MCF-7 and HCT-116 cancer cell lines. The 3- and 4-azidobenzoic acid analogues were found to be as active as epothilone B in a tubulin assembly assay, but demonstrated significantly reduced cellular cytotoxicity compared to epothilone B. The benzophenone analogue was inactive in both assays. Docking and scoring studies were conducted that suggested that the azide analogues can bind to the epothilone binding site, but that the benzophenone analogue undergoes a sterically driven ligand rearrangement that interrupts all hydrogen bonding and therefore protein binding. Photoaffinity labeling studies with the 3-azidobenzoic acid derivative did not identify any covalently labeled peptide fragments, suggesting that the phenylazido side chain was predominantly solvent-exposed in the bound conformation.
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
S. Ali;S. M. A. Hashmi;M. N. Siddiqui;I. Mohammed;M. Wazeer
通讯作者：
S. Ali;S. M. A. Hashmi;M. N. Siddiqui;I. Mohammed;M. Wazeer