TOTAL SYNTHESIS OF THE CYTOTOXIN UCS1025A AND DERIVATIVES THEREOF FOR USE AS ANT

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。端粒酶抑制剂是一类独特的细胞毒性化合物，最近在化疗中取得了成功。UCS1025A是这类化合物的最新成员之一，它是一种五环聚酮，含有独特的糠吡咯利西啶亚基。这种化合物已被确定为端粒酶抑制剂和抗生素。然而，其氧化衍生物UCS1025B在这些检测中显示出最小的活性。这使药物化学家对这些分子的结构-活性关系有了独特的见解，值得进一步探索。因此，本提案的主要目标将是开发一种实用的合成序列，可用于生产克量的UCS1025A。此外，该序列将允许母体化合物的简单衍生物的容易生产，因此结构-活性关系可以确定。一旦合成，UCS1025A及其衍生物将在体外和体内测试其抑制端粒酶的能力。这个项目的最终目标将是开发一种新的端粒酶抑制剂，可以用作化疗药物。

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. Telomerase inhibitors are a distinctive class of cytotoxic compounds that have found recent success as chemotherapies. One of the newest members of this class, UCS1025A, is a pentacyclic polyketide that contains a unique furropyrrolizidine subunit. This compound has been identified as both a telomerase inhibitor and an antibiotic. However, its oxidized derivative, UCS1025B, shows minimal activity in each of these assays. This presents the medicinal chemist with a unique insight into the structure-activity relationship of these molecules and merits further exploration. Therefore, the primary objective of this proposal will be the development of a practical synthetic sequence that can be used to produce gram quantities of UCS1025A. Furthermore, the sequence will allow for the facile production of simple derivatives of the parent compound, so structure-activity relationships can be determined. Once synthesized, UCS1025A and its derivatives will be tested for their ability to inhibit telomerase both in vitro and in vivo. The ultimate goal of this project will be the development of a novel telomerase inhibitor that could be used as a chemotherapeutic agent.