Stereochemistry as a Tool for Developing Anticancer Agents - Synthetic and Functional Studies on Laulimalide, a new Paclitaxel-Like Microtubule-Stabilizing Agent

分子的拓扑立体化学和手性可以导致化合物的一种或多种优选的手性构象。高度重要的是生物活性构象。萝莉酸是一种具有良好生物活性的天然产物。像紫杉醇或埃博霉素一样，它稳定微管的形成，并具有作为抗癌剂的巨大潜力。我们建议在微管稳定化的背景下研究laulimalide的拓扑化学和其生物活性构象之间的关系。为此，我们将首先合成laulimalide。必须开发的合成策略将是模块化和灵活的。在该项目的第二阶段，天然产物的结构将被修改，目的是寻找立体化学，构象和生物作用的变化。模块化合成策略将允许目标结构的快速组装。Gesson教授的实验室将为分子的北方部分提供合成模块，而Koert教授的实验室将为南方部分合成分子模块。这两个部分将在最后的合成序列中组合在一起。特别是，将通过NMR和X-射线研究与优选构象有关的立体化学的作用。在Saumweber教授的实验室中，将通过免疫荧光方法对合成的化合物进行生物活性测试。像紫杉醇、埃博霉素和laulimalide这样的化合物是“热门”的合成目标。过去，美国的大型集团曾成功地掌握了紫杉醇等复杂目标化合物的合成。如果我们这些欧洲化学家想要竞争，我们就必须联合起来。通过法国和德国小组的联合合成努力，应该有可能非常快地开发出一种进入laulimalide的合成物。这类抗癌剂的合成途径具有巨大的制药和生物技术潜力。欧洲共同体将从这一项目中受益。

The topological stereochemistry and the chirality of a molecule can lead to one or more preferred chiral conformations of the compound. Highly important are bioactive conformations. Laulimalide is a natural product with a promising bioactivity. Like taxol or epothilone it stabilizes microtubule formation and has a great potential as an anticancer agent. We propose to study the relationship between the topological chemistry of laulimalide and its bioactive conformation in the context of microtubule stabilization. Towards this end, we will first synthesize laulimalide. The synthetic strategy, which has to be developed, will be modular and flexible. In a second phase of the project the structure of the natural product will be modified with the goal to look for changes in the stereochemistry, the conformation and the biological action. The modular synthetic strategy will allow the fast assembly of the target structures. Prof. Gesson's lab will provide synthetic modules for the northern part of the molecule, while Prof. Koert's lab will synthesize molecular modules for the southern part. Both parts will be put together in the final synthetic sequence. In particular, the role of stereochemistry in relation to the preferred conformations will be studied by NMR and X-ray. The bioactivity tests of the sythetic compounds will be done by immunofluorescence methods in Prof. Saumweber's lab. Compounds like taxol, epothilone and laulimalide are 'hot' synthetic targets. In the past, big US american groups have succeeded in mastering the synthesis of complex targets like taxol. If we as european chemists want to compete, we have to join forces. By a joint synthetic effort of the french and the german group it should be possible to develop a synthetic entry into laulimalide very fast. The synthetic access to this class of anticancer agents has a great pharmaceutical and biotechnological potential. The european community will benefit from this project.