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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。端粒酶抑制剂是一类独特的细胞毒性化合物，最近在化疗方面取得了成功。这一类的最新成员之一，UCS1025A，是一种五环多酮，其中含有一个独特的呋喃并吡咯烷亚基。该化合物已被鉴定为端粒酶抑制剂和抗生素。然而，其氧化衍生物UCS1025B在每一种检测中都显示出极低的活性。这为药物化学家对这些分子的构效关系提供了独特的见解，值得进一步探索。因此，该提案的主要目标将是开发一种实用的合成序列，该序列可用于生产克量的UCS1025A。此外，该序列将允许容易地产生母体化合物的简单衍生物，因此可以确定结构-活性关系。一旦合成，UCS1025A及其衍生物将在体外和体内测试它们抑制端粒酶的能力。该项目的最终目标将是开发一种可用作化疗药物的新型端粒酶抑制剂。

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.