SYNTHESIS OF TEDANOLIDES CYTOTOXIC POLYPROPIONATES

这项拟议的研究计划的目的是开发新的通用 聚丙酸酯天然产物的构建方法。钥匙 在这些化合物的合成步骤中，涉及一种一致的Lewis酸- 促进光学活性环氧醇重排生成 2-甲基-3-三烷基硅氧基-烷烃，即由 非Aldol路线。我们已经证明，所有四种可能的对映体都可以是 该方法制备简单，光学纯度高，产率高。 我们计划将这项研究扩展到制备聚丙酸链 各种绝对的立体化学。特别是，为了说明 这个过程的效率，我们将把两者综合到极致 强细胞毒剂，13-脱氧萜内酯1和萜内酯2，以及 它们的紧密结构类似物和非对映异构体，通过应用 这种聚丙酸酯的新方法。13-脱氧戊二内酯是非常 细胞毒性[IC50 94 pg/ml(P388)]，具有较高的抗肿瘤活性[T/C 125mug/kg时189%(P388)，而tedanolide也是极具肿瘤性质的 抑制作用[ED50‘S 250 pg/ml(KB)和16 pg/ml(PS)]及其原因 极低浓度(10%)下S期细胞的积累 Ng/ml)。因此，它们是非常有希望成为治疗癌症的新药物的线索。 治疗。发展良好的合成路线 不仅提供了它们(两者)的潜在有用的准备 是从海绵中分离出来的，存在于非常小的 数量)，但也将允许一个人准备几个结构 天然来源无法获得的类似物，可能会显示出增强的 化疗特性。我们打算制作几个类似物(例如， 2的13-同分异构体，侧链较短的类似物和带有 不同的群体和/或立体化学)。所有先进的合成材料 材料将进行抗肿瘤活性测试。通过这种方式，我们希望 找出这种复杂分子的哪些部分是 强大的抗肿瘤活性，希望能制备出一些更简单的 仍然显示出合理活动的结构。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 高效细胞毒剂13-脱氧戊二内酯1和2的合成 Tedanolide 2及其类似物-将具有重要意义 药物化学。因为靶子的药用价值， 在合成中键的构筑效率高， 新方法本身的内在价值，一种 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.