SYNTHESIS OF TEDANOLIDES CYTOTOXIC POLYPROPIONATES

泰丹内酯细胞毒性聚丙酸酯的合成

• 批准号: 2837715
• 负责人: MICHAEL E JUNG
• 金额: $ 15.66万
• 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 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2837715
• 关键词: antineoplastics; biological products; chemical synthesis; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; propionates; stereochemistry

The purpose of this proposed research program is to develop new general methods for the construction of 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 an 2-methyl-3-trialkylsilyloxy-alkanals, 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 synthesize the two extremely strongly cytotoxic agents, 13-deoxytedanolide 1 and tedanolide 2, and their close structural analogues and diastereomers, 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% (P388) at 125 mug/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 intend to make several analogues (e.g., the 13-epimer of 2, analogues with shorter side chain and ones with different groups and/or stereochemistries). All of the advanced synthetic materials will be tested for antitumor activity. In this way, we hope to figure out just what parts of this complex molecule are required for the potent antitumor activity and hopefully to prepare some simpler structures which still show reasonable 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 potent cytotoxic agents 13-deoxytedanolide 1 and tedanolide 2 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.

该拟议研究计划的目的是开发新的通用 聚丙酸酯天然产物的构建方法。关键 这些化合物的合成步骤涉及协同路易斯酸- 促进光学活性环氧醇的重排以生成 2-甲基-3-三烷基甲硅烷基氧基链烷醛，即羟醛产物 非羟醛途径。我们已经证明所有四种可能的对映体都可以 通过这种方法可以很容易地以高光学纯度和良好的产率制备。 我们计划扩展这项研究以制备聚丙酸酯链 各种绝对立体化学。特别地，为了说明 这个过程的效率，我们将两者综合起来 强细胞毒性剂，13-脱氧特那内酯 1 和特那内酯 2，以及 它们结构密切的类似物和非对映异构体，通过应用 这种聚丙酸酯的新方法。 13-脱氧丁内酯非常 细胞毒性 [IC50 94 pg/ml (P388)] 并具有高抗肿瘤活性 [T/C 189% (P388) at 125 mug/kg] 而泰那内酯也具有极强的肿瘤作用 抑制性 [ED50 为 250 pg/ml (KB) 和 16 pg/ml (PS)] 及其原因 细胞在 S 期以非常低的浓度（10 纳克/毫升）。因此，它们是非常有希望成为癌症新药的先导化合物 治疗。开发良好的通用合成路线 不仅会为它们提供潜在有用的准备（两者 是从海绵中分离出来的，并且以非常小的形式存在 数量），但也允许人们准备几种结构 天然来源中无法获得的类似物可能表现出增强 化疗特性。我们打算制作几个类似物（例如， 2的13-差向异构体，具有较短侧链的类似物和具有 不同的基团和/或立体化学）。所有先进的合成 将测试材料的抗肿瘤活性。通过这种方式，我们希望 弄清楚这个复杂分子的哪些部分是 有效的抗肿瘤活性并希望制备一些更简单的 仍然表现出合理活动的结构。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 强效细胞毒剂 13-deoxytanolide 1 的合成 tedanolide 2 及其类似物 - 对于 药物化学。由于目标的药用重要性， 合成中键构建的效率，以及高 新方法本身的内在价值， 对健康相关科学的重要贡献相当高。