SYN MODELS FOR ELUCIDATING PACLITAXEL BINDING

描述：紫杉醇是一种新的二萜类化合物，现已被公认为具有临床活性的抗癌药物。由于分子的复杂性，创造紫杉醇类似物以获得机制信息的尝试一直受到限制。因此，关于这种天然激动剂在微管蛋白结合部位的生化基础的信息相对较少。利用晶体结构和核磁共振数据，我们(和其他几个基团)成功地在水环境中对紫杉醇分子进行了计算机模拟。与其他已被模拟的结构相反，大部分在有机溶剂中，我们发现在水中紫杉醇分子在某种程度上会自行坍塌。在这种折叠形式中，在传统的非水模型中不太可能相邻的几个功能在空间上变得非常接近。由于在人体的水环境中，紫杉醇分子很可能存在于某种形式的坍塌结构中，我们推测坍塌的紫杉醇结构很可能是具有药理活性的形状的极佳模型。因此，我们建议合成几种紫杉醇的同系物，它们被“捆绑”起来，以模拟分子崩溃的各个阶段。根据我们的计算机模拟数据，我们期望这些衍生物对微管蛋白结合位点显示出高度的结合特异性。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Paclitaxel is a novel diterpenoid which is now well established as a clinically active anticancer agent. Due to the complexity of the molecule, attempts to create paclitaxel analogs to obtain mechanistic information have been limited. Thus, there is relatively little information on the biochemical basis of this natural agonist at the tubulin binding site. Using crystal structure and NMR data, we have (along with several other groups) successfully computer-modeled the paclitaxel molecule in an aqueous environment. Contrary to other structures that have been modeled, for the most part in organic solvent, we have found that in water the paclitaxel molecule, to some degree, collapses upon itself. In this collapsed form, several functionalities, which are not likely neighbors in the traditional non-aqueous models, become extremely close to each other in space. Since in the body's aqueous environment, the paclitaxel molecule is most likely found in some form of the collapsed structure, we have postulated that the collapsed paclitaxel structure is likely to be an excellent model for the pharmacologically active shape. Thus, we are proposing the synthesis of several paclitaxel congeners that are "tied down" to mimic various stages of molecular collapse. Base on our computer-modeling data, we would expect these derivatives to show a high degree of binding specificity to the tubulin binding site.