SYNTHESIS OF THE TEDANOLIDES, CYTOTOXIC POLYPROPIONATES

描述：(申请人摘要)这项拟议研究的目的 方案是制定新的通用施工方法的几个 具有生物活性的聚丙酸酯天然产物。关键的一步是 这些化合物的合成涉及路易斯酸促进的协同作用 光学活性环氧醇的重排以生成 2-甲基-3-三烷基硅氧烷，即由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很容易地制备出来 该方法具有光学纯度高、产率高等优点。我们计划延长这一期限 制备不同绝对数聚丙酸链的研究 立体化学。特别是，为了说明这一点的效率 过程中，我们将完成两个极强的细胞毒性的合成 13-脱氧萜内酯1和萜内酯2及其紧密结构 类似物，通过将这一新方法应用于聚丙酸酯。 13-脱氧戊二内酯具有极强的细胞毒性(IC50为94 pg/ml(P388))，并具有很高的 抗肿瘤活性(T/C 189%(P388)，125微克/公斤) 对肿瘤也有极强的抑制作用(ED50‘S 250pg/ml(KB)和16pg/ml(PS)) 并在极低浓度(10%)下导致S期细胞积累 Ng/ml)。因此，它们作为癌症治疗的新药物是非常有希望的线索。 为它们的合成开发良好的一般路线不仅将 提供可能有用的它们的制剂(两者都是从 海绵和数量非常少的海绵)，但也允许 一是制备几种天然来源无法获得的结构类似物 这可能显示出增强的化疗特性。我们还将开展 重要抗菌药红霉素A_3和红霉素的全合成 齐墩果霉素4.所有先进的合成材料在替丹内酯 将对该系列药物进行抗肿瘤活性测试。通过这种方式，我们希望能够计算出 弄清楚这些复杂分子的哪些部分是有效的 活动，并希望准备一些更简单的结构，仍然显示 合理的活动。同样，红霉素和红霉素的合成类似物 奥兰霉素将接受抗生素活性测试。成功者 完成本建议中所述的研究--即 开发一种真正有用的合成聚丙酸酯的路线和 萜类内酯、红霉素A和油兰霉素的合成及其性能 类似物-将对药物化学具有重要意义。因为 靶标的药用价值，键构筑的效率 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是相当大的 很高。

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.