The objectives of the proposal include total synthesis and biomechanistic studies of the marine natural products pateamine A, palau'amine, gymnodimine, and phakellin which possess novel structures and exhibit potent physiological effects. Natural products that have strong and specific cellular effects have proven to be powerful biochemical probes for dissecting molecular mechanisms of signal transduction pathways involved in various cellular functions. Pateamine A and palau'amine are potent immunosuppressive agents that promise to be useful biochemical probes for elucidating cellular events involved in the immune response. Thus, these natural products may potentially lead to new therapeutic targets for not only organ transplantation therapy, but also diabetes, multiple sclerosis, and rheumatoid arthritis. Gymnodimine is a potent marine toxin that possesses an unusual spirocyclic imine moiety. Its precise molecular mechanism of toxicity has not been elucidated although it appears to be unique. Marine toxins have proven useful for the study of ion channels, protein phosphatases, and neurotransmitter receptors. Thus, gymnodimine promises to be a useful biochemical probe for studies of neuronal function. Phakellin has been proposed to be responsible for the powerful antibiotic effects observed in extracts from the marine sponge Phakellia flabellata. Considering the rise in antibiotic resistance in recent years, the search for novel antibiotics has intensified. The utility of the tetracylic guanidine structure in phakellin and congeners as new antibiotics will be assayed. A naturally conjoined objective in our total synthesis efforts is the development of new synthetic methods and strategies for the concise synthesis of these targets. In this regard, several new methods and strategies including formylation of vinyl halides, Hantzsch thiazole synthesis with unactivated bromoketones, Diel-Alder reactions of alpha-exomethylene lactams and vinyl imidazolidinones, a single pot lactam to cyclic imine synthesis, an intramolecular chlorination/1,2 shift sequence, and the use of latent pyrroles will be studied. The synthetic products resulting from this research will enable us and our collaborators Prof. Jun Liu (MIT) and Dr. Chris Miles (AgResearch) to address questions of biological and thus health significance.
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