The principle objectives of this proposal are to develop syntheses of several complex marine-derived natural products that possess potent pharmacological activity, and that are currently available only in limited amounts. Specific target molecules include norhalichondrin B, E7389, and spirastrellolide B. Norhalichondrin B is a complex marine-derived polyether that displays remarkably potent in vitro and in vivo anti-cancer activity (GI50 values of <1nM vs. a range of cell lines). It is not available from the natural source at the present time, and a concise synthesis of this target that employs new methods for the construction of subunits and new strategies for the assembly of these subunits will be developed. The chemistry developed for this purpose will also be applied to a concise 25 step synthesis of the structurally related clinical candidate E7389, which is currently prepared by an ~35 step route. The third major target is spirastrellolide B, a very complex macrolide that displays nanomolar IC50 values against protein phosphatases of relevance to cancer therapy. A concise, potentially gram-scale, synthesis of this compound is proposed that will provide material for further biological study.
The marine environment is a prolific source of pharmacologically interesting molecules that have potential as drugs. However there are number of obstacles the prevent this from become a routine reality, the two most significant being the often high level of complexity among molecules produced by marine organisms and the fact that they are usually produced in only tiny amounts. The goals of the research described in this proposal are to provided new synthetic chemistry routes to two important classes of highly complex marine-derived molecules with potent anti-cancer activity: the halichondrins and the spirastrellolides
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