This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The focus of my research is organic synthesis as applied to the preparation of biologically-active molecules. I am particularly intrigued by the possibilities presented by the use of organometallic chemistry in synthesis. The utility of organometallic reagents for the rapid and stereoselective synthesis of advanced intermediates suitable for structure-activity investigations is an area of active research in my laboratory. A second area of interest is to employ the energy contained within small-ring compounds to drive the synthesis of biologically-important compounds. Recently, the object of these synthetic studies has been the preparation of 24-membered macrocyclic polyoxazoles. These compounds, due to their size and functionality, have exquisite selectivity for stabilizing DNA that has assumed a G-quadruplex conformation, while having no such affinity for duplex DNA. There is considerable interest in selective G-quadruplex stabilizers as a novel class of anticancer agent. This activity has been associated with inhibiting telomerase, which plays a role in the immortalization of cancer cells, but is not expressed, to any great extent, in most normal cells. Stabilization of G-quadruplexes that form in the promoter region of various oncogenes is associated with the decreased expression of such oncogenes. The compounds that are currently under development in my laboratory therefore have potential as dual-acting anticancer agents. Satyanarayana, M., Rzuczek, S.G., LaVoie, E.J., Pilch, D.S., Liu, A., Liu, L.F., and Rice, J.E. Ring-closing metathesis for the synthesis of a highly G-quadruplex selective macrocyclic hexaoxazole having enhanced cytotoxic potency. Bioorg. Med. Chem. Lett., 18(13), 3802-3804, 2008.
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