SYNTHETIC STUDIES OF PREPARATION OF 24-MEMBERED MACROCYCLIC POLYOXAZOLES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我的研究重点是有机合成，用于制备具有生物活性的分子。我特别感兴趣的是在合成中使用有机金属化学所带来的可能性。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的实验室中一个活跃的研究领域。第二个令人感兴趣的领域是利用小环化合物中包含的能量来驱动具有生物重要性的化合物的合成。 最近，这些合成研究的目标是制备24元大环多恶唑。由于它们的大小和功能，这些化合物对稳定已呈G-四链构象的DNA具有极好的选择性，而对双链DNA没有这种亲和力。选择性G-四链稳定剂作为一类新型抗癌药物备受关注。这种活性与抑制端粒酶有关，端粒酶在癌细胞永生化中发挥作用，但在大多数正常细胞中不在很大程度上表达。在各种癌基因的启动子区域形成的G-四联体的稳定与这些癌基因表达的减少有关。因此，我的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.和Rice，J.E.闭环复分解合成具有增强细胞毒活性的高G-四链选择性大环六恶唑。生物组织。地中海医院。化学。2008年，18(13)，3802-3804。

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.