SYNTHETIC STUDIES OF PREPARATION OF 24-MEMBERED MACROCYCLIC POLYOXAZOLES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 我的研究重点是有机合成应用于生物活性分子的制备。我对有机金属化学在合成中的应用所带来的可能性特别感兴趣。利用有机金属试剂快速和立体选择性地合成适合于结构活性研究的高级中间体是我实验室的一个活跃研究领域。第二个感兴趣的领域是利用小环化合物中所含的能量来驱动生物重要化合物的合成。 最近，这些合成研究的目标是制备24元大环聚恶唑。这些化合物，由于它们的大小和功能，具有精确的选择性稳定DNA已采取G-四链体构象，而没有这样的亲和力双链体DNA。选择性G-四链体稳定剂作为一类新型抗癌药物引起了人们的极大兴趣。这种活性与抑制端粒酶有关，端粒酶在癌细胞的永生化中起作用，但在大多数正常细胞中不表达。在各种癌基因的启动子区域中形成的G-四链体的稳定化与这些癌基因的表达降低有关。因此，我实验室目前正在开发的化合物具有作为双重作用抗癌剂的潜力。 Satyanarayana，M.，Rzuczek，S.G.，LaVoie，E.J.，Pilch，D.S.，Liu，A.，Liu，L.F.，赖斯，J.E.用于合成具有增强的细胞毒性效力的高G-四链体选择性大环六恶唑的闭环复分解。Bioorg.医学化学快报，18（13），3802-3804，2008.

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.