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

用作ANT的细胞毒素UCS1025A及其衍生物的全合成

• 批准号: 7381366
• 负责人: Brenton L. DeBoef
• 金额: $ 1.79万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381366
• 关键词: TOTAL; SYNTHESIS; CYTOTOXIN; UCS1025A; DERIVATIVES

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，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，最近在化疗方面取得了成功。 UCS1025A 是此类最新成员之一，是一种五环聚酮化合物，含有独特的呋喃并吡咯里西啶亚基。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 在这些测定中均显示出最小的活性。这为药物化学家提供了对这些分子的构效关系的独特见解，值得进一步探索。因此，该提案的主要目标是开发可用于生产克级数量的 UCS1025A 的实用合成序列。此外，该序列将允许轻松生产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其抑制端粒酶的能力。该项目的最终目标是开发一种可用作化疗药物的新型端粒酶抑制剂。