The Dolastatins, A Family of Promising Antineoplastic Agents

The dolastatins and some related compounds are antineoplastic pseudopeptides isolated from the sea hare Dolabella auricularia by the groups of G. R. Pettit and K. Yamada. Several groups including ours have contributed to the development of synthetic routes to most of these compounds. We recently described the synthesis of dolatrienoic acid, the lipidic component of dolastatin 14. Among all these metabolites, dolastatin IO and dolastatin 15 exhibit the most promising antiproliferative properties and are currently under evaluation in clinical trials. These antimitotic agents seem to exert their activity by interacting with tubulin and inducing apoptosis. Research in this domain could greatly benefit from the recent elucidation of the atomic structure of tubulin. However, other targets cannot be excluded. Elucidation of the structure-activity relationships is an important step in the development of therapeutic agents. Parallel to the studies developed by other groups, our approach to exploring structural requirements for the antineoplastic activity of these compounds involved the determination of their preferred conformations in solution. Our study showed that dolastatin IO exists in two different conformations corresponding to a cis-trans isomerization of a central amide bond. Such a situation was not demonstrated in the case of dolastatin I 5. In view of elucidating the biological relevance of these findings, we elaborated hybrid molecules constituted of parts of both compounds. We also synthesized a cyclic analogue of dolastatin 10 which locked this compound in its cis conformation. Our results as well as those of others could be interpreted in terms of an existing structural model.