SYNTHESIS OF THE TEDANOLIDES, CYTOTOXIC POLYPROPIONATES

细胞毒性聚丙酸酯泰丹内酯的合成

• 批准号: 6475903
• 负责人: MICHAEL E JUNG
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-16 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475903
• 关键词: analog; antineoplastics; biological products; chemical synthesis; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; propionates; stereochemistry

DESCRIPTION: (Applicant's Abstract) The purpose of this proposed research program is to develop new general methods for the construction of several biologically active polypropionate natural products. The key step in the syntheses of these compounds involves a concerted Lewis acid-promoted rearrangement of an optically active epoxy alcohol to generate a 2-methyl-3-trialkylsilyloxyalkanal, namely an aldol product by a non-aldol route. We have shown that all four possible enantiomers can be easily prepared in high optical purity and good yields by this approach. We plan to extend this research to prepare polypropionate chains with various absolute stereochemistries. In particular, in order to illustrate the efficiency of this process, we will finish the synthesis of two extremely strongly cytotoxic agents, 13-deoxytedanolide 1 and tedanolide 2, and their close structural analogues, by an application of this new approach to polypropionates. 13-Deoxytedanolide is extremely cytotoxic (IC50 94 pg/ml (P388)) and has high antitumor activity (T/C 189 percent (P388) at 125 microg/kg) while tedanolide is also extremely tumor inhibitory (ED50's 250 pg/ml (KB) and 16 pg/ml (PS)) and causes accumulation of cells in the S phase at very low concentrations (10 ng/ml). Thus they are very promising leads as new agents for cancer treatment. The development of good general routes for their synthesis would not only provide a potentially useful preparation of them (both were isolated from marine sponges and are present in very small quantities) but also would allow one to prepare several structural analogues unavailable from natural sources which may show enhanced chemotherapeutic properties. We will also carry out total syntheses of the important antibacterial agents, erythromycin A 3 and oleandomycin 4. All of the advanced synthetic materials in the tedanolide series will be tested for antitumor activity. In this way, we hope to figure out just what parts of these complex molecules are required for the potent activity and hopefully to prepare some simpler structures which still show reasonable activity. Likewise the synthetic analogues of erythromycin and oleandomycin will be tested for antibiotic activity. The successful accomplishment of the research described in this proposal-namely, the development of a really useful synthetic route to polypropionates and the synthesis of the tedanolides, erythromycin A and oleandomycin and their analogues-would be of great significance to medicinal chemistry. Because of the medicinal importance of the targets, the efficiency of bond construction in the syntheses, and the high intrinsic value of the new methods themselves, the likelihood of an important contribution to health-related science is quite high.

描述：（申请人的摘要）这项拟议研究的目的 计划是开发新的通用方法来建造几个 具有生物活性的聚丙酸酯天然产物。其中关键的一步是 这些化合物的合成涉及协同路易斯酸促进 光学活性环氧醇的重排生成 2-甲基-3-三烷基甲硅烷氧基链烷醛，即非羟醛生成的羟醛产物 路线。我们已经证明所有四种可能的对映体都可以轻松制备 通过这种方法可以得到高光学纯度和良好的产率。我们计划延长这个时间 制备各种绝对值聚丙酸酯链的研究 立体化学。特别地，为了说明此方法的效率 过程中，我们将完成两种极强细胞毒性的合成 药物，13-脱氧泰那内酯 1 和泰那内酯 2，以及它们的紧密结构 通过将这种新方法应用于聚丙酸酯，可以得到类似物。 13-Deoxytedanolide 具有极高的细胞毒性（IC50 94 pg/ml (P388)），并且具有高 抗肿瘤活性（T/C 189% (P388) at 125 microg/kg），而泰那内酯 还具有极强的肿瘤抑制作用（ED50 为 250 pg/ml (KB) 和 16 pg/ml (PS)） 并导致细胞在极低浓度（10 纳克/毫升）。因此，它们是非常有前途的癌症治疗新药。 开发良好的通用合成路线不仅可以 提供了它们的潜在有用的制备（两者都是从 海洋海绵并且存在量非常小），但也允许 一种用于制备几种天然来源无法获得的结构类似物的方法 这可能显示出增强的化疗特性。我们还将开展 重要抗菌剂红霉素A 3 和的全合成 竹桃霉素 4. 泰诺内酯中的所有先进合成材料 系列将进行抗肿瘤活性测试。通过这种方式，我们希望能够弄清楚 找出这些复杂分子的哪些部分是有效的 活动并希望准备一些仍然显示的更简单的结构 合理的活动。同样，红霉素的合成类似物和 将测试夹竹桃霉素的抗生素活性。成功者 本提案中描述的研究成果，即 开发一种真正有用的聚丙酸酯合成路线以及 泰那内酯、红霉素A和竹桃霉素的合成及其 类似物——对药物化学具有重要意义。因为 目标的医学重要性、债券建设的效率 合成，以及新方法本身的高内在价值， 对健康相关科学做出重要贡献的可能性是相当大的 高的。