TRADITIONAL AND FLUOROUS SYNTHESIS APPROACHES TO DICTYOSTATIN ANTICANCER AGENTS

本项目的首要目标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。除了紧密合作的药物化学方面的工作，氟混合物合成的新技术的使用也是特色。具体目标是：1）通过全合成方法确定其结构。目标1已经很先进了。我们最近完成了dictyostatin 1的全合成，我们现在知道了它的完整结构，包括绝对和相对构型。事实证明， 在所有十个共享立构中心处具有相同的构型。这种结构的确定消除了一个主要的障碍，发展的dictyostatin作为一个潜在的抗癌剂。然而，我们仍然想知道在三个主要碎片上具有相同相对构型但以不同配对偶联在一起的异构体有多相似（光谱学上，生物学上）。这个问题将通过用氟混合物合成法制备多种异构体来回答。我们也几乎完成了原始Pettit结构的合成，因此这项工作将最终完成。2)合成0.35-1.0 g用于体内表征的网丝抑素。为了实现这一目标，目前的合成必须加以改进，并计划通过增加收敛精简它的概述。3)构效关系研究用的网状物抑制素立体异构体和类似物的合成。我们将使用最近建立的合成路线，通过氟混合物合成来制备类似物。我们计划制作立体异构体，并制作简化的类似物，目的是开始阐明结构/活性关系。4)网壳抑素及其关键立体异构体的构象模拟。将使用Macromodel中的多构象搜索与MM 3计算相结合来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。

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.