Laulimalide and Derivatives

The project aims for an efficient and stereocontrolled total synthesis of the antitumor agent laulimalide. This compound is a marine metabolite which resembles the venerable paclitaxel in stabilizing microtubules of eucaryotic cells and thus inhibiting cell division. Laulimalide is much more active than paclitaxel even against tumor cell lines which show multidrug resistance against paclitaxel. Laulimalide is not available in sufficient quantities from the natural source and can thus be best procured by total synthesis. However, the routes described so far are relatively long (in general around 50 steps and more), employ toxic reagents and are not fully stereocontrolled. Thus we plan a synthesis in which no more than about 32 steps should be required, the number of chromatographic separations should be minimized and no toxic reagents should be employed. The synthesis should be applicable to a larger scale and should be versatile enough to provide a sufficient diversity of analogs for biological testing. In this way the pharmacophoric parts of the molecule should be identified and the original lead compound should be so modified as to optimize the biological properties. Moreover, the binding of the compound to the microtubules, the conformation in solution and the active conformation with respect to microtubule binding shall be investigated.

The project aims for an efficient and stereocontrolled total synthesis of the antitumor agent laulimalide a cytotoxic 20-membered macrolide that was isolated from various marine sponges and from nudibranch Chromodoris lochi.[1,2] This compound is a marine metabolite which resembles the venerable paclitaxel in stabilizing microtubules of eucaryotic cells and thus inhibiting cell division. Laulimalide is much more active than paclitaxel even against tumor cell lines which show multidrug resistance against paclitaxel. Laulimalide is not available in sufficient quantities from the natural source and can thus be best procured by total synthesis. However, the routes described so far are relatively long (in general around 50 steps and more), employ toxic reagents and are not fully stereocontrolled. Thus we plan a synthesis in which no more than about 32 steps should be required, the number of chromatographic separations should be minimized and no toxic reagents should be employed. The synthesis should be applicable to a larger scale and should be versatile enough to provide a sufficient diversity of analogs for biological testing. Isolaulimalide (2) is an isomer of 1 which is formed by acid catalyzed SN2-type attack of the C- 20 hydroxyl group on C-17 of the expoxide.[1,2] Both 1 and 2 are potent inhibitors of cancer cell proliferation and are recognized as members of the MSAA (microtubule-stabilizing antitumor agents) family, which share a similar mechanism of action as the anticancer drug Taxol.[3] Another interesting tumor active natural derivative we synthesized is neolaulimalide (3). Whereas there are numerous approaches to 1,[4] 2 and 3 have not yet been synthesized. In the end our project was completely successful: 1. We developed an unprecedentedly short and efficient approach to laulimalide (1). 2. Besides, 2 and 3 were prepared for the first time. 3. Two additional non- natural derivatives 4 and 5 were synthesized. 4. All derivatives were tested for their antitumor activity. 1 and 3 were highly active, 2 much less and the other two not at all. [1] Corley, D. G., Herb, R., Moore, R. E.; Scheuer, P. J., Paul, V. J., J. Org. Chem. 1988, 53, 3644 - 3646. [2] Quinoa, E., Kakou, Y., Crews, P., J. Org. Chem. 1988, 53, 3642 - 3644. [3] Mooberry, S. L., Tien, G., Hernandez, A. H., Plubrukran, A., Davidson, B. S. Cancer Res. 1999, 59, 653. [4] Mulzer, J., Öhler, E., Chem. Rev. 2003, 103, 3753 - 3786