Identifying the cellular components involved in viral infection, cancer, atherosclerosis, diabetes, arthritis, and neurodegenerative disease will generate new opportunities to combat these afflictions. Molecular events of the cell membrane play pivotal roles in a variety of these health concerns. In many cases, the identify of cellular machinery involved is not known. Through the use of structurally modified variants of biologically active natural products, the research objective is to (i) reveal important cellular interactions involved in membrane signaling and trafficking, (ii) provide a better understanding of the structure, function, and regulation of these cellular components, and (iii) identify new cellular entities that are useful targets fro controlling a number of diseases. (-)-Ilimaquinone, a sponge metabolite, has been used to gain a better understanding of vesicular trafficking. Ilimaquinone inhibits vesicle- mediated secretion through its interference with S- adenosylhomocysteinase. An enzyme in the activated methyl cycle. The proposed studies explore the ilimaquinone's interact with this important antiviral target, as well as to determine the specific methylation events regulating vesicle-mediated secretion. Similarly, the cellular interactions of the cacospongionolids will be determined to help understand their potent anti-inflammatory action. Likewise, insight into the physiological role of the icoprostanes, a newly discovered. class of membrane metabolites, will be achieved using functionalized derivatives of these endogenous molecules. These interdisciplinary studies will help identify interactions responsible for regulating various aspects of membrane trafficking and signaling. With a better description of these events, fundamentally new approaches for controlling disease through the selective interference of trafficking and signaling functions should become feasible. Inhibitors of trafficking could provide a new means of lowering cholesterol levels, inhibiting the first steps in viral infection, or regulating the secretion of the beta- amyloid protein. In a related matter, treatments for a wide range of other illnesses potentially could benefit from selective inhibitors of endocytosis. For instance, patients that are desensitized to ascertain drug therapy could benefit from compounds that inhibit the endocytotic down- regulation of the drug's receptor. For these reasons, further knowledge of the details of ligand interactions with membrane compounds should be of substantial benefit.
| Pandya, Bhaumik A; Snapper, Marc L (2008) A cross-metathesis route to the 5-F(2)-isoprostanes. J Org Chem 73:3754-8 |
| Murelli, Ryan P; Cheung, Atwood K; Snapper, Marc L (2007) Conformationally restricted (+)-cacospongionolide B analogues. Influence on secretory phospholipase A2 inhibition. J Org Chem 72:1545-52 |
| Shizuka, Manami; Schrader, Thomas O; Snapper, Marc L (2006) Synthesis of isoprostanyl phosphatidylcholine and isoprostanyl phosphatidylethanolamine. J Org Chem 71:1330-4 |
| Cheung, Atwood K; Murelli, Ryan; Snapper, Marc L (2004) Total syntheses of (+)- and (-)-cacospongionolide B, cacospongionolide e, and related analogues. Preliminary study of structural features required for phospholipase a2 inhibition. J Org Chem 69:5712-9 |
| Cheung, Atwood K; Snapper, Marc L (2002) Total syntheses of (+)- and (-)-cacospongionolide B: new insight into structural requirements for phospholipase A(2) inhibition. J Am Chem Soc 124:11584-5 |
