SYNTHESIS OF THE TEDANOLIDES, CYTOTOXIC POLYPROPIONATES

细胞毒性聚丙酸酯泰丹内酯的合成

• 批准号: 6592046
• 负责人: MICHAEL E JUNG
• 金额: $ 3.41万
• 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/6592046
• 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 计划是开发新的一般方法，以构建几种 生物活性的聚丙烯天然产物。关键步骤 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- trialkylsilyloxyalkanal，即非醛醇的藻类产物 路线。我们已经表明，所有四个可能的对映异构体都可以轻松准备 通过这种方法，具有很高的光学纯度和良好的收率。我们计划扩展这一点 研究以各种绝对的准备链链制备链条 立体化学。特别是为了说明这一点的效率 过程，我们将完成两个极强细胞毒性的合成 代理，13-脱氧胆碱1和Tedanolide 2及其紧密结构 类似物，通过将这种新方法应用于多面化。 13-脱氧乙酰苯酚极为细胞毒性（IC50 94 pg/ml（p388）），并且具有高 抗肿瘤活性（T/C 189％（P388）为125 microg/kg），而Tedanolide 也是极度肿瘤抑制（ED50的250 pg/ml（kb）和16 pg/ml（ps）） 并在非常低的浓度下导致S相中的细胞积累（10 ng/ml）。因此，作为癌症治疗的新药物，它们是非常有前途的铅。 开发良好的综合途径不仅会 提供潜在有用的准备准备（两者都与 海海绵，数量很少），但也允许 一个可以从天然来源准备几个结构类似物 这可能显示出增强的化学治疗特性。我们还将执行 重要抗菌剂的总合成，红霉素A 3和 leandomycin 4。 系列将测试抗肿瘤活性。这样，我们希望能弄清楚 算出这些复合物分子的哪些部分才能有效 活动，希望准备一些仍然显示的简单结构 合理的活动。同样，红霉素和 珠霉素将用于抗生素活性。成功 在本提案中描述的研究的完成 - 开发真正有用的合成途径到多丙酸和 Tedanolides，红霉素A和leany霉素的合成及其合成 类似物将对药物化学具有重要意义。因为 靶标的药物重要性，债券建设的效率 合成以及新方法本身的高内在价值， 对与健康相关的科学做出重要贡献的可能性很大 高的。