SYNTHESIS OF TEDANOLIDES CYTOTOXIC POLYPROPIONATES

这项研究计划的目的是开发新的通用 用于构建聚丙酸酯天然产物的方法。关键 这些化合物的合成步骤涉及协同的刘易斯酸- 促进了光学活性环氧醇的重排， 2-甲基-3-三烷基甲硅烷基氧基-烷醛，即通过 非醛醇途径。我们已经表明，所有四种可能的对映体都可以是 通过该方法容易地以高光学纯度和良好的产率制备。 我们计划将这项研究扩展到制备聚丙酸酯链， 各种绝对立体化学。特别是，为了说明 这个过程的效率，我们将综合这两个极端 强细胞毒性剂，13-脱氧替丹明1和替丹明2，和 其结构类似物和非对映体，通过应用 聚丙酸酯的新方法。13-去氧替旦诺是非常 细胞毒性[IC 50 94 pg/ml（P388）]，具有高抗肿瘤活性[T/C 125 μ g/kg时为189%（P388）]，而替丹替尼也是极高的肿瘤 抑制性[ED 50为250 pg/ml（KB）和16 pg/ml（PS）]， 在非常低的浓度（10 ng/ml）。因此，它们是非常有希望的癌症新药物 治疗开发良好的通用合成路线 不仅提供了一个潜在的有用的准备他们（两者）， 是从海绵中分离出来的， 数量），但也将允许一个准备几个结构 天然来源无法获得的类似物， 化疗性质。我们打算制作几种类似物（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。这样，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，并有望制备一些更简单的 结构仍然显示出合理的活性。成功 完成本提案中所述的研究-即， 开发了一种真正有用的聚丙酸酯合成路线， 有效的细胞毒性剂13-脱氧替丹明1和 tedanlavin 2及其类似物-将具有重大意义， 药物化学由于目标的医学重要性， 在合成中的键结构的效率，以及高的 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。

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.