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.

该建议的研究计划的目的是开发新的一般一般 建造聚占天然产品的方法。钥匙 进入这些化合物的合成涉及一致的刘易斯酸 - 促进光学活性环氧醇的重排以产生 2-甲基-3-雄烷基氧甲羟基烷基，即A藻类产物 非醛固路线。我们已经表明，所有四个可能的对映异构体都可以 通过这种方法可以轻松以高光纯度和良好的收率制备。 我们计划扩展这项研究，以准备与 各种绝对的立体化体。特别是为了说明 这个过程的效率，我们将极端合成这两个 强烈的细胞毒性剂，13-脱氧胆碱1和Tedanolide 2，以及 它们通过应用 这种新方法的新方法。 13-脱氧烷酚非常非常 细胞毒性[IC50 94 pg/ml（p388）]，具有高抗肿瘤活性[T/C 125杯/千克的189％（P388），而Tedanolide也是极端肿瘤 抑制性[ED50的250 pg/ml（kb）和16 pg/ml（ps）] 在非常低的浓度下，在S相中积累细胞的积累（10 ng/ml）。因此，作为癌症的新药物，它们是非常有前途的铅 治疗。开发良好的一般路线以供其合成 不仅会为它们提供潜在有用的准备 从海绵中分离出来，很小 数量），但也可以使一个人准备几个结构 从天然来源无法获得的类似物可能会显示出增强的 化学治疗特性。我们打算做几个类似物（例如， 13个EPIMER 2，类似于侧链较短的类似物 不同的小组和/或立体化学的组合）。所有高级合成 材料将进行抗肿瘤活性的测试。这样，我们希望 弄清楚该复合物分子的哪些部分需要 有效的抗肿瘤活动，希望准备一些简单的 仍然显示合理活动的结构。成功 在本提案中描述的研究的完成 - 即 开发真正有用的合成途径到多丙酸和 有效的细胞毒性剂的合成13-脱氧胆碱1和 Tedanolide 2及其类似物 - 对 药物化学。由于目标的重要性， 合成中的键构建效率，高 新方法本身的内在价值， 对与健康相关的科学的重要贡献很高。