SYNTHESIS OF THE TEDANOLIDES, CYTOTOXIC POLYPROPIONATES

描述：（申请人摘要）本研究的目的 计划是开发新的一般方法，用于构建几个 生物活性聚丙酸酯天然产物。的关键步骤 这些化合物的合成涉及协同的刘易斯酸促进的 光学活性环氧醇的重排以产生 2-甲基-3-三烷基甲硅烷基氧基烷醛，即非羟醛缩合反应的羟醛产物， 路线我们已经证明了所有四种可能的对映体都可以很容易地制备 该方法具有高的光学纯度和良好的产率。我们计划把这个 研究制备具有不同绝对分子量的聚丙酸酯链 立体化学特别是，为了说明这种方法的效率， 过程中，我们将完成两个极强的细胞毒性的合成 药物，13-脱氧tedanlavin 1和tedanlavin 2，以及它们的接近结构， 类似物，通过应用这种新的方法聚丙酸酯。 13-脱氧替丹诺具有极强的细胞毒性（IC 50 94 pg/ml（P388））， 抗肿瘤活性（125 μ g/kg时T/C 189%（P388））， 也具有极强的肿瘤抑制作用（ED 50为250 pg/ml（KB）和16 pg/ml（PS）） 并在极低浓度下引起S期细胞的积累（10 ng/ml）。因此，他们是非常有前途的领导作为新的药物用于癌症治疗。 开发良好的一般合成路线不仅 提供了它们的潜在有用的制备物（两者均分离自 海洋海绵和目前在非常少量），但也将允许 一个是制备几种天然来源无法获得的结构类似物 其可显示增强的化疗性质。我们还将开展 主要抗菌药物红霉素A_3、 竹桃霉素4.所有的先进合成材料在tedanecraft 将测试系列的抗肿瘤活性。通过这种方式，我们希望能够 这些复杂分子的哪一部分才是 活动，并希望准备一些更简单的结构， 合理的活动。同样，红霉素的合成类似物和 将测试竹桃霉素的抗生素活性。成功 完成这项建议中所描述的研究，即， 开发了一种真正有用的聚丙酸酯合成路线， 替丹内酯、红霉素A和竹桃霉素的合成及其应用 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 综合，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相当大。 高

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.