SYNTHESIS OF THE ANTITUMOR AGENT (+)-SUPERSTOLID

抗肿瘤剂 ( )-Superstolid 的合成

• 批准号: 2429893
• 负责人: GREGORY K FRIESTAD
• 金额: $ 2.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-06 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2429893
• 关键词: Diels Alder reaction; X ray crystallography; analog; antineoplastic antibiotics; biological products; chemical structure; conformation; cytotoxicity; drug design /synthesis /production; macrolide antibiotics; stereochemistry

The proposed research is a convergent, enantiospecific synthesis of the highly cytotoxic macrolide antitumor agent (+)-superstolide A (1). Isolated from a marine sponge, 1 has very high in vitro cytotoxicity toward various cancer cell lines. A synthetic route is necessary to obtain sufficient quantities of 1 and analogs for further testing. The essential first steps in exploring the potential of 1 and analogs as clinically useful cancer therapeutics are the following specific aims of this proposed research: * A convergent, enantiospecific synthesis of 1, adaptable to synthesis of analogs, will be developed. * The structure and absolute configuration of 1 will be verified by synthesis and X- ray crystallography. The synthetic strategy proposed includes a) an intramolecular Diels-Alder reaction to define the configuration of four stereocenters of the functionalized decalin system and b) iterative double asymmetric crotylboronation to form the C19-C26 propionate-derived segment. An additional benefit of this research is the likelihood of significant new insights regarding the synthesis of complex macrolide natural products.

拟议的研究是一种收敛的、对映体特异性的合成 高细胞毒性大环内酯类抗肿瘤药(+)--超级内酯A(1)。 从海绵中分离出来的1具有很高的体外细胞毒性 不同的癌细胞系。需要一条合成路线才能获得 足够数量的1和类似物，以供进一步测试。最重要的 探索1及其类似物临床应用潜力的第一步 有用的癌症疗法是这个项目的以下具体目标 建议的研究： *1的一种收敛的、对映体特异的合成，适用于合成 类似的，将被开发出来。 *1的结构和绝对配置将由 合成和X射线结晶学。 所提出的合成策略包括a)分子内Diels-Alder 反应，以确定四个立体中心的配置 功能化十氢林系和b)迭代双不对称 巴豆基硼化形成C19-C26丙酸衍生链段。一个 这项研究的另一个好处是有可能出现重大的新 关于合成复杂大环内酯类天然产物的见解。