CRYSTAL STRUCTURES OF TAXOL AND TAXOL ANALOGUES

虽然紫杉醇的抗肿瘤活性和毒性机制是 在分子水平上不被理解，它们必须涉及相互作用 在三维水平上药物和各种受体之间的关系。 因此，获得更具选择性的紫杉醇类似物的合理方法是 确定紫杉醇的三维立体化学，以及 紫杉醇衍生物具有不同程度的抗癌活性和 毒性；然后可以比较这些结构和不同的 导致不同活动的立体化学特征可能是 可辨认的。为此，我们已经获得了紫杉醇的样本，并 成功地获得了用于结构测定的单晶 通过X射线衍射法。 紫杉醇晶体具有晶胞尺寸a=9.67，b=28.24，c=19.83A，和 含有两个独立的紫杉醇分子和一些溶剂分子 单元格。它们的衍射率为1.05A，提供了可能的5000 可收集独立的X射线数据。我们将确定三个- 紫杉醇的空间立体化学，包括空间位置 和所有官能团的构象。我们也会明晰 并阐明了已知的几个紫杉醇类似物的结构。 活动；然后将对立体化学进行比较 确定影响疗效的立体化学参数， 毒性、运输等。这些信息将对 更具选择性的紫杉醇类似物的合理设计。

Although the mechanisms of taxol antitumor activities and toxicity are not understood at the molecular level, they must involve interactions between the drug and various receptors on a three-dimensional level. Therefore, a rational way to achieve more selective taxol analogues would be to determine the three-dimensional stereochemistry of taxol, and of taxol derivatives with differing degrees of anticancer activity and toxicity; the structures could then be compared and the different stereochemical features responsible for the different activities may be identifiable. To this end we have procured a sample of taxol and have been successful in obtaining single crystals for structure determination by x-ray diffraction. Taxol crystals have cell dimensions a=9.67, b=28.24, c=19.83A, and contain two independent taxol molecules plus some solvent molecules in the unit cell. They diffract to 1.05A, affording a possible 5000 independent x-ray data collectable. We shall determine the three- dimensional stereochemistry of taxol, including the locations in space and conformations of all functional groups. We shall also crystallize and elucidate the structures of several taxol analogues of known activities; comparisons of stereochemistries will then be made to determine the stereochemical parameters responsible for efficacy, toxicity, transport, etc. This information will be very beneficial for the rational design of more selective taxol analogues.