As the majority of small molecule drugs (and drug candidates) targeting the CNS are heterocycles, predominantly nitrogen and oxygen heterocycles, the focus of our NS program is the invention of new methods and synthesis strategies for preparing such molecules. The proposed research program has three components: total synthesis of structurally novel natural products, development of new chemical synthesis methods, and studies of the unique effect of oxygen heterocycles having the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system on the organization and function of the Golgi. The natural products targeted for enantioselective total synthesis-daphnipaxinin, aspergillin PZ, macfarlandin E, aplyviolene, norrlandin, chromodorolide A-have not been previously prepared;as a result, our investigations will define synthetic strategies for assembling these uncommon, bioactive, structural motifs. Moreover, the proposed studies will define the chemical peculiarities of these target molecules, develop chemistry for manipulating their structures, and provide analog structures for biological evaluation. Daphniphyllum alkaloids are neurotoxic and target directly the central nervous system, resulting in depression of voluntary movement as well as respiratory function;daphnipaxinin was isolated form an evergreen tree whose leaves and stems are used as antiinflammation herbs in Chinese folk medicine. Aspergillin PZ, also isolated in China, is reported to be an antitumor agent. Macfarlandin E, norrlandin, and chromodorolide A are rearranged spongian diterpenes that contain the rare 4,6-diacetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system. In collaboaration with the laboratory of Christine Sutterlin, we have recently shown that macfarlandin E and synthetic analogs containing the 4,6-diacetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system induce a unique modification of the Golgi ribbon in which the ribbon is fragmented with localization of the fragments in the pericentriolar region with concurrent block of protein transport out of the Golgi. As natural macfarlandin E is no longer available, synthetic macfarlandin E and analogs will allow cell biology studies to dissect the individual contributions of Golgi organization and position to the regulation of protein trafficking, cell polarization, centrosome organization, and cell division. If the purported neurotrophic properties of nankakurines A and B are confirmed, we will prepare analogue structures to enhance these properties and determine what aspects of their structures are important for neurotrophic activity;these rare alkaloids were first prepared during this project period and are currently undergoing pharmacological evaluation. Exploratory chemical synthesis studies are proposed that will: (a) develop new ways to initiate Prins cyclizations and explore the synthetic utility of O-acyloxonium ions, (b) continue our development of a new enantioselective method for preparing angularly substituted 1-azabicyclic molecules and unusual ?-amino acids in which dynamic kinetic resolution is achieved by combining a rapid tautomeric equilibration of diastereomeric iminium cations with a diastereoselective rearrangement, and (c) develop new cascade sequences that exploit oxocarbenium ions produced in a first cascade reaction to initiate a second C-C bond-forming process. In addition exploratory chemical biology studies will be undertaken to evaluate the utility of 6-acyloxy-2,7-dioxabicyclo[3.2.1]octan-3-ones to selectively tag lysine side chains and potentially directly introduce a fluorphore to allow in situ analysis of the modified biomolecule.
If the aims of this application are realized, biomedical researchers will have new tools for synthesizing and modifying the structure of complex nitrogen and oxygen heterocycles. The availability of the new organic synthesis methods that we are developing will facilitate discovery and production of improved chemical agents for treating neurological and other medical disorders. In addition, the proposed studies will enable collaborative studies of several cellular processes that are critical for cellular function.
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