Spirocycles formed from formal oxidative cyclization onto indole or imidazole cores comprise a diverse family of naturally occurring alkaloids that exhibit a wide range of promising biological properties, including anticancer and antibiotic activity. Consequently, total synthesis studies may impact on these larger health concerns by providing the natural products in macroscopic quantities along with structural analogues for lead development as pharmaceutical agents. In this continuing project, the application of a new approach to these stereochemically challenging types of targets will be explored. This chemistry stems from recent advances in Pummerer oxidation chemistry developed during the former grant period. Targets include dibromoagelaspongin, palau'amine, and the axinellamines.
This award through the Organic and Macromolecular Chemistry Program of the National Science Foundation supports the research of Professor Ken Feldman in the Department of Chemistry at the Pennsylvania State University. Professor Feldman's research efforts focus on the development of new strategies and new chemical reactions for the efficient construction of complex, biologically active natural products. Successful prosecution of these research objectives may lead to new drug leads, which in turn will impact favorably on the pharmaceutical enterprise in the United States.
The search for new, effective, and safe pharmaceuticals relies on the field of organic chemistry to provide the means to identify and prepare new molecular structures that exhibit promising biological activities. One particularly productive thrust toward this goal involves organic synthesis; the ability to design and then execute the deliberate construction of molecules that might evince specific biological responses. When organic synthesis efforts are married to discovery efforts in natural products chemistry, a more direct path to pharmaceutical leads can be in hand. Thus, screening natural sources for promising biological leads, often collected in minute quantities, and then preparing useful quantities of these leads (and designed analogues) for further study, represents a tried and true approach to advancing human health through chemotherapy. Funding provided by NSF CHE 0808983 fueled studies focused on one particular class of naturally occurring compounds isolated from marine sponges; the oroidin derivatives. This large family of alkaloids has long held promise in chemotherapeutic disease intervention, with specific members showing activity as antivirals and antiproliferatives (= anticancer), among other activities. The chemical structures of these species span a broad range, but they all can be tied to a few structural motifs that feature elaborated versions of imidazole rings. Thus, progress in the understanding of how these marine alkaloids exert their biological effects, and in providing material for further studies, can be favorably impacted by the development of new and efficient approaches for their construction (and the construction of designed analogue structures). The research accomplishments under NSF CHE 0808983 include just such a development; the invention of a new approach to assemble several of these oroidin-derived species in a rapid, selective, and efficient manner. This chemistry exploited an unrecognized attribute of a venerable reaction in organic chemistry, the Pummerer reaction first reported in 1903! Thus, application of a modern version of this process to the imidazole structure (and indole also, a related species) led to much new chemistry, including formation of several new bonds to the core ring (imidazole or indole). This new bond formation was orchestrated to deliver specific oroidin alkaloid target structures, thus making good on the promise of efficient and effective synthesis in this natural products area. Synthesized oroidin targets include dibromophakellstatin, dibromophakellin, dibromoagelaspongin, and the core structure of palau'amine. These species have been implicated as inhibitors of the human 20S proteosome, a validated target in cancer chemotherapy. In collaboration with Dr. Jetze Tepe of the Chemistry Department of Michigan State University, synthetic dibromophakellstatin, synthetic dibromophakellin, and a few synthesized analogues of palau'amine were assayed for their 20S proteosome inhibitory activity. Reasonable (low-to-mid-micromolar) levels of inhibition were detected. Thus, the developmental synthesis efforts funded by NSF CHE 0808983 have led to the discovery of potential new leads for chemotherapeutic intervention in cancer therapy.
