The objectives of this renewal proposal include synthetic and biomechanistic studies of the marine natural products axinellamine A, palau'amine, gymnodimine, phakellstatin, pateamine A and thiolyngbyan, which possess novel structure and exhibit potent biological effects. Natural products with potent and specific cellular effects continue to be useful biochemical probes for dissecting molecular mechanisms of signal tansduction pathways involved in various cellular functions. Pateamine A and palau'amine are potent immunosuppressive agents that promise to be useful biochemical probes for discovery of cellular events involved in cell signaling and continued collaborations with Jun Liu (John Hopkins) will continue to provide insights in this area. These natural products may potentially lead to new therapeutic targets for organ transplantation therapy, but also cancer, diabetes, multiple sclerosis, and rheumatoid arthritis. Gymnodimine is a potent marine toxin that possesses an unusual spirocyclic imine moiety and its molecular mechanism of toxicity has not been elucidated although it appears to be unique. Marine toxins have proven useful in the study of ion channels, protein phosphatases, and neurotransmitter receptors. Furthermore, the need to monitor harmful algal blooms in our oceans drives our interest in developing congener independent immunoassays for gymnodimine and this will be pursued in collaboration with an interdisciplinary team at Texas A&M including Lisa Campbell (TAMU-Oceanography). Phakellin has been proposed to be responsible for the powerful antibiotic effects observed in extracts from its sponge of origin while the closely related phakellstatin is a structurally novel antitumor agent. In collaborative efforts with Justin Du Bois' laboratory (Stanford), we seek to develop a C-H insertion strategy for the synthesis of these and related oroidin alkaloids. In collaborative efforts with Coran Watanabe (TAMU-Chemistry) we will screen for antitumor and other activities and, if warranted by activity, elucidate the mechanism of action of the phakellstatins and the axinellamines. In line with this latter interest, we will explore the potential of thermoresponsive polymers as soluble support for natural products. Thiolyngbyan is a novel antifungal agent with a proposed unique 5-membered cyclic disulfide moiety. Collaborative efforts with Bill Gerwick's laboratory (Oregon State) seek to confirm the structure and determine its absolute stereochemistry. A naturally conjoined objective in our total synthesis efforts is the development of new synthetic strategies for the concise synthesis of these targets. In this regard, several unique strategies are outlined for the synthesis of the natural product targets proposed. ? ?
Showing the most recent 10 out of 17 publications
