Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a biotin tag at the oxazole.
Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a biotin tag at the oxazole.
复制标题
DOI：
10.1016/j.bmc.2010.10.055
复制
发表时间：
2011
影响因子：
3.5
通讯作者：
Yuri Yamazaki;Y. Kido;K. Hidaka;H. Yasui;Y. Kiso;F. Yakushiji;Y. Hayashi
中科院分区：
文献类型：
--
作者：
Yuri Yamazaki;Y. Kido;K. Hidaka;H. Yasui;Y. Kiso;F. Yakushiji;Y. Hayashi
通过CuI催化的Huisgen环加成反应合成了一种新的生物活性光亲和探针KPU-252-B1（4），该探针在有效的普那布林衍生物KPU-244（2）的恶唑环上具有生物素标签，以了解基于二酮哌嗪的抗微管剂普那布林与微管蛋白的精确结合模式。探针4显示出对微管蛋白的显著结合亲和力和对HT-29细胞的细胞毒性。一项光亲和标记研究表明，探针4在与普那布林或秋水仙碱结合的结合位点特异性识别微管蛋白，最有可能在秋水仙碱结合位点附近或秋水仙碱结合位点处，秋水仙碱结合位点位于α-和β-微管蛋白结合形成的界面区域。结果还表明，探针4可以作为一个有用的普那布林化学探针，以研究抗微管二酮哌嗪衍生物的分子机制。
A new bioactive photoaffinity probe KPU-252-B1 (4) possessing a biotin tag on the oxazole ring of a potent plinabulin derivative KPU-244 (2) was synthesized via the CuI-catalyzed Huisgen’s cycloaddition reaction to understand the precise binding mode of the diketopiperazine-based anti-microtubule agent plinabulin on tubulin. Probe 4 showed significant binding affinity toward tubulin and cytotoxicity against an HT-29 cells. A photoaffinity labeling study suggested that probe 4 specifically recognizes tubulin at a binding site that binds plinabulin or colchicine, most likely near or at the colchicine binding site, which is located at the interfacial region formed by α-and β-tubulin association. The results also demonstrated that probe 4 may serve as a useful plinabulin chemical probe to investigate the molecular mechanism by which anti-microtubule diketopiperazine derivatives operate.