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

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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.