TRADITIONAL AND FLUOROUS SYNTHESIS APPROACHES TO DICTYOSTATIN ANTICANCER AGENTS

盘菌素抗癌剂的传统合成方法和氟合成方法

• 批准号: 6928831
• 负责人: DENNIS P CURRAN
• 金额: $ 17.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928831
• 关键词: antineoplastics; biological products; chemical models; chemical structure function; conformation; drug design /synthesis /production; lactones; macrolide antibiotics; microtubules; stereoisomer

The overarching aims of this Project are to synthesize the microtubule stabilizing natural product dictyostatin-1 and its analogs, and to evaluate the potential of these compounds as anticancer agents. In addition to the tight collaborative medicinal chemistry aspects of the work, the use of the new technique of fluorous mixture synthesis is also featured. The specific aims are: 1) Assignment of the structure of dictyostatin by total synthesis. Aim 1 is well advanced. We have recently completed the total synthesis of dictyostatin 1, and we now know its full structure, including absolute and relative configurations. It turns out that dictyostatin and discodermolide have the same configurations at all ten shared stereocenters. This structure determination has removed a major roadblock to development of dictyostatin as a potential anti-cancer agent. However, we still would like to learn how similar (spectroscopically, biologically) the isomers are with the same relative configurations at the three main fragments but coupled together in different pairings. This question will be answered by making multiple isomers by fluorous mixture synthesis. We have also nearly completed synthesis of the original Pettit structures, so this work will be finalized. 2) Synthesis of 0.35-1.0 g of dictyostatin for in vivo characterization. To accomplish this goal, the current synthesis must be improved, and a plan to streamline it by increasing convergency is outlined. 3) Synthesis of stereoisomers and analogs of dictyostatin for SAR studies. We will use the recently established synthetic route to make analogs by fluorous mixture synthesis. We plan to make stereoisomers, and to make simplified analogs with the goal of beginning to elucidate the structure/activity relationship. 4) Conformational modeling of dictyostatin and key stereoisomers. Multiconformational searching coupled with MM3 calculations in Macromodel will be used to predict conformational minima of key isomers. Initially, this data will be used to help interpret NMR experiments, and will serve as a basis for analog design as well as for more sophisticated modeling and docking experiments.

该项目的总体目的是合成微管稳定天然产物dictyostatin-1及其类似物，并评估这些化合物作为抗癌剂的潜力。除了工作的紧密协作化学方面外，还使用新的混合物合成技术的使用。具体目的是：1）通过总合成来分配Dictyostatin的结构。 AIM 1非常先进。我们最近完成了dictyostatin 1的总合成，现在我们知道了它的完整结构，包括绝对和相对配置。事实证明，dictyostatin和dincodermolide 在所有十个共享的立体中心方面具有相同的配置。这种结构的确定已消除了dictyostatin作为潜在抗癌剂的发展的主要障碍。但是，我们仍然想了解异构体在三个主要片段上具有相同的相对配置，但在不同的配对中耦合在一起的相对相对构型如何相似。通过通过荧光混合物合成制作多个异构体来回答这个问题。我们还几乎完成了原始Pettit结构的合成，因此这项工作将被敲定。 2）合成0.35-1.0 g dictyostatin用于体内表征。为了实现这一目标，必须改进当前的合成，并概述通过增加收敛性来简化它的计划。 3）用于SAR研究的立体异构体和类似物的合成。我们将使用最近建立的合成途径通过荧光混合物合成来制作类似物。我们计划制作立体异构体，并制作简化的类似物，以开始阐明结构/活动关系。 4）DICTYOSTATIN和关键立体异构体的构象建模。多形式搜索以及大分子模型中的MM3计算将用于预测关键异构体的构象最小值。 最初，这些数据将用于帮助解释NMR实验，并将作为模拟设计以及更复杂的建模和对接实验的基础。