The long term objective of this proposal is to develop an efficient, economical means of producing the polyketide (+)-discodermolide. This compound shows promising anticancer activity, having a similar mode of action as paclitaxel and epothilone, but is available only in minute quantity from its natural source, the deep-water marine sponge Discodermia dissolute. Total synthesis is the only option at present for producing sufficient quantities for clinical testing. Several total syntheses have been reported, yet all are lengthly and expensive. The most concise synthesis to date (Smith et al.) divides discodermolide into three segments. Each segment is elaborated from a common precursor, itself prepared via a multi-step route using expensive reagents. The PI proposes to develop a process to prepare an equivalent of this common precursor by fermentation, using genetically engineered polyketide synthases. In Phase 1, we will develop the methods to prepare this material and demonstrate its utility by conversion to the Smith common precursor. In Phase 2, we will develop the methodology to incorporate our fermentation product directly into the synthesis of (+)-discodermolide. The researchers will also explore the use of other natural polyketides as more advanced synthetic intermediates to decrease the number of steps required to produce discodermolide. The PI anticipates that this use of engineered enzymes will dramatically reduce the cost of preparing (+)-discodermolide, and facilitate the commercial development of this anticancer agent.
Discodermolide is a potential successor to paclitaxel (Taxol). The current market for paclitaxel is quite large, yet there are many problems associated with this drug. Discodermolide has many favorable aspects, including greater water solubility and activity against Taxol-resistance cells, and so could take over a large portion of the Taxol market. The present proposal should overcome the supply problem of discodermolide, thus facilitating it commercial development.
