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

立体化学作为开发抗癌药物的工具 - 新型紫杉醇类微管稳定剂劳利马利特的合成和功能研究

• 批准号: 5261518
• 负责人: Professor Dr. Ulrich Koert
• 金额: --
• 依托单位: Laboratoire de Synthèse et Réactivité des Substances Naturelles (SRSN) UMR 6514 FR 2703 (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2000
• 资助国家: 德国
• 起止时间: 1999-12-31 至 2004-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5261518?language=en
• 关键词: Stereochemistry; Tool; Developing; Anticancer; Agents

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.

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。生物活性构象是非常重要的。洛利马利是一种具有良好生物活性的天然产物。与紫杉醇或埃坡酮一样，它能稳定微管的形成，具有很大的抗癌潜力。我们建议在微管稳定的背景下研究劳利马利的拓扑化学与其生物活性构象之间的关系。为此，我们首先合成了劳利马利。必须制定的综合战略将是模块化和灵活的。在该项目的第二阶段，将对天然产物的结构进行修改，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。盖森教授的实验室将为分子的北部提供合成模块，而科尔特教授的实验室将为分子的南部合成分子模块。这两个部分将在最终的合成序列中放在一起。特别是，立体化学与优选构象的作用将通过核磁共振和X射线进行研究。合成化合物的生物活性测试将在索姆韦伯教授的实验室通过免疫荧光方法进行。像紫杉醇、埃普西隆和劳利马利这样的化合物是“热门”合成靶标。过去，美国大型集团曾成功地掌握了紫杉醇等复杂靶标的合成。如果我们作为欧洲化学家想要竞争，我们必须联合起来。通过法国和德国集团的联合合成努力，应该可以非常快地开发出一种合成进入洛利马利的药物。这类抗癌剂的合成途径具有很大的制药和生物技术潜力。欧洲共同体将从这个项目中受益。