CRYSTAL AND MOLECULAR-STRUCTURE OF PACLITAXEL (TAXOL)
CRYSTAL AND MOLECULAR-STRUCTURE OF PACLITAXEL (TAXOL)
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DOI：
10.1073/pnas.92.15.6920
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发表时间：
1995-07-18
影响因子：
11.1
通讯作者：
CAMERMAN, N
中科院分区：
文献类型：
--
作者：
MASTROPAOLO, D;CAMERMAN, A;CAMERMAN, N
紫杉醇（以前称为紫杉醇），一种重要的抗癌药物，通过结合并稳定微管聚合物来抑制细胞复制。由于药物-受体相互作用受两个参与者的三维立体化学控制，我们已经确定了紫杉醇的晶体结构以确定其可能与生物活性相关的构象偏好，单斜晶体在不对称单元中含有两个独立的紫杉醇分子以及几个水和二氧六环溶剂分子。两种紫杉醇分子中的紫杉烷环构象非常相似，并且与紫杉醇类似物多西他赛（以前称为泰索帝）晶体结构中发现的紫杉烷环构象相似。两个紫杉醇分子具有彼此不同并且与多西紫杉醇晶体结构中的相应侧链不同的碳-13侧链构象。一个紫杉醇分子的碳-13侧链构象与在极性溶剂中进行的NMR研究中提出的相似，而另一个紫杉醇分子的碳-13侧链构象不同并且迄今未观察到。紫杉醇分子通过广泛的氢键网络彼此相互作用并与溶剂原子相互作用。氢键网络的分析以及结构活性研究可能表明紫杉醇的哪些原子对于结合微管受体是重要的。
Paclitaxel (formerly called taxol), an important anticancer drug, inhibits cell replication by binding to and stabilizing microtubule polymers, As drug-receptor interactions are governed by the three-dimensional stereochemistries of both participants, we have determined the crystal structure of paclitaxel to identify its conformational preferences that may be related to biological activity, The monoclinic crystals contain two independent paclitaxel molecules in the asymmetric unit plus several water and dioxane solvent molecules. Taxane ring conformation is very similar in both paclitaxel molecules and is similar to the taxane ring conformation found in the crystal structure of the paclitaxel analogue docetaxel (formerly called taxotere). The two paclitaxel molecules have carbon-13 side-chain conformations that differ from each other and from that of the corresponding side chain in the docetaxel crystal structure, The carbon-13 sidechain conformation of one paclitaxel molecule is similar to what was proposed from NMR studies done in polar solvents, while that of the other paclitaxel molecule is different and hitherto unobserved, The paclitaxel molecules interact with each other and with solvent atoms through an extensive network of hydrogen bonds. Analysis of the hydrogen-bonding network together with structure-activity studies may suggest which atoms of paclitaxel are important for binding to microtubule receptors.