Total Synthesis of Bioactive Compounds

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DESCRIPTION (provided by applicant): The principle objectives of this science described in this proposal are to develop the chemistry and biology of two complex marine-derived natural products that possess potent pharmacological activity, and that are either unavailable, or available only in minute amounts from their natural sources. The first 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. Structural biology information, along with analysis of the chemical features of a number of compounds related to spirastrellolide will also be used to try and identify molecules that modulate protein phosphatases in an selective fashion. The second target is adriatoxin, a decacyclic 'ladder' polyether that has been implicated in diarrhetic shellfish poisoning and is a close analog of compounds that have remarkable anti-cancer activity. A concise, 30 step synthesis, that employs new chemistry is described for adriatoxin, and material obtained by the synthesis will be used to identify adriatoxin's molecular target. The marine environment is a prolific source of pharmacologically interesting molecules that have potential both as drugs and as probes for biological systems. However there are a number of obstacles that prevent this potential from becoming 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 only produced in miniscule amounts. The primary goals of the research in this proposal are to develop new synthetic chemistry routes to two important classes of complex marine natural products that have potent biological activity and to use material produced by this endeavor to study their biology.