Tandem aldol-allylation approach to discodermolide analogs

Taxol? could arguably be considered one of the most successful anticancer compounds ever developed. Despite this success, Taxol has severe limitations, in that, it is difficult to administer to the patient and that certain cancers have become resistant to its effects. Discodermolide is a potential solution to these problems. Not only has it been shown to be as effective as Taxol both in the test-tube and in animal models, but this drug candidate is also more easily administered and is less susceptible to acquired drug resistance. However, the current supply of discodermolide is limited by its chemical synthesis. Additionally, this has also hampered the ability to effectively study this potent anticancer agent. Unfortunately,

discodermolide is isolated in very small quantities from a sponge that can only be obtained by the use of manned submersibles making chemical synthesis the only viable route to this powerful anticancer agent. Therefore, a newer streamlined synthesis is required that addresses the limitations of the existing routes. As a consequence of a more efficient approach to this molecule comes the ability to generate many discodermolide analogs quickly, which will directly affect its development as a drug.

The studies in this proposal focus on a more efficient approach to discodermolide analogs that addresses shortcomings of the currently used synthetic sequences. The successful development of the proposed route will allow for faster production of discodermolide-like molecules, which could facilitate the identification of clinically effective drugs. Additionally, this proposal puts forth a discodermolide analog (made through the proposed synthesis) that will answer questions as to the orientation of the molecule when bound to its target. The information obtained from such a study will direct medicinal chemists efforts to design better discodermolide analogs. The ultimate end scenario could result in a more potent anticancer agent that is more easily administered and potentially less toxic.