(Principal Investigator's) The objective of this research program is to invent and/or discover efficient chemical synthesis methods that will allow structurally complex nitrogen-containing molecules to be prepared in a practical way from commercially-available building blocks. Our ultimate goal i to develop sufficiently versatile and efficient synthesis tools so that any desired molecule could be synthesized in a commercially viable manner. In this endeavor we target structurally novel, complex chemical structures for which there is no existing road map, or obvious strategy, for their synthesis. Our intent is not just to make the target compounds, but to evolve new synthesis strategies and to learn about the chemical peculiarities of novel chemical structures. In the long term, the availability of these new organic synthesis tools will facilitate the future development of new chemical agents for treating cardiovascular and other diseases. Many of our current natural produc synthesis targets exhibit promising medicinal properties, yet are not sufficiently accessible for in vivo evaluation. In these areas, our proposed investigations could have immediate practical application by making these compounds, and analogs, available for biomedical investigation. A variety of complex guanidine and polyamine alkaloids have been selected for investigation. These structures are targeted for two reasons: (1) guanidine an polyamine functional group arrays are found in a high percentage of recently-isolated, pharmacologically-active, natural products, and (2) methods for chemical synthesis of compounds containing many nitrogen atoms are less developed than other organic synthesis tools. Among our synthesis targets are (a) the crambescidin alkaloids, for which a variety of pharmacological activities have been reported, most significantly in vitro anticancer activity inhibition of calcium channels, inhibition of Na(+), K(+) and Ca(2+)-ATPases, (b) the batzelladine alkaloids, which inhibit protein-protein interactions tha are important for immunological responses, (c) palau'amine, a relatively non-toxic immunomodulator, (d) styloguanidine, a chitinase inhibitor, and (e) aloperine, an active component of traditional Chinese medicines used for treating heart arrhythmias and inflammatory disorders. The proposed investigations are founded on discoveries made during the current project period of new strategies for preparing complex guanidine alkaloids by cyclocondensation and cycloaddition reactions.
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