SYNTHESIS OF WS9885B, A NOVEL CYTOTOXIC TUBULIN BINDER

描述：（主要研究者摘要）来自藤泽的科学家 制药公司最近描述的结构，相对 WS 9885 B是一种细菌衍生的， 具有前所未有的六环结构的天然产物， 桥头烯烃和12个立构中心。针对几种癌细胞系， 在体外，WS 9885 B显示出与紫杉醇（Taxol）一样强的细胞毒性， 治疗卵巢癌和乳腺癌的成熟药物。像 紫杉醇WS 9885 B在体外稳定细胞微管， 作为一种潜在的化疗药物， 癌 WS 9885 B结合了结构新颖和高生物活性的重要元素， 活性，因此是有机研究的一个有吸引力的目标。 合成.这项研究计划描述了一个假设的生物起源和一个 WS 9885 B的对映选择性化学合成 从丰富和廉价的起始材料。拟议的研究旨在 来挑战一个假设， WS 9885 B的复杂结构可以从基本上不那么复杂的 分子内自发重组。对映选择性 WS 9885 B的化学合成将建立其绝对立体化学， 允许系统研究其宪法与 微管稳定特性和细胞毒性。这一长期目标 研究内容包括：（1）确定WS 9885 B的活性桥头烯烃 引起微管或其他细胞组分的共价修饰;和 (2)化学的应用是在全面综合的过程中发展起来的。 WS 9885 B在类似物结构的合成中， 结构-活性概况这迷人的细胞毒性天然产物。

DESCRIPTION: (Principal Investigator's Abstract) Scientists from the Fujisawa Pharmaceutical Company recently described the structure, relative stereochemistry, and pronounced cytotoxicity of WS9885B, a bacterial-derived natural product possessing an unprecedented hexacyclic architecture, a reactive bridgehead alkene, and 12 stereocenters. Against several cancer cell lines in vitro, WS9885B displays cytotoxicity as potent as paclitaxel (Taxol), an established drug for the treatment of ovarian and breast cancers. Like paclitaxel, WS9885B stabilizes cellular microtubules in vitro and warrants serious attention as a potential chemotherapeutic agent for the treatment of cancer. WS9885B combines the important elements of novel structure and high biological activity, and is thus an attractive objective for research in organic synthesis. This research proposal describes a hypothetical biogenesis and a novel strategy to achieve an enantioselective chemical synthesis of WS9885B from abundant and inexpensive starting materials. The proposed research seeks to challenge the hypothesis that the architecturally and stereochemically complex structure of WS9885B could evolve from a substantially less complex substance by spontaneous intramolecular reorganization. An enantioselective chemical synthesis of WS9885B would establish its absolute stereochemistry and permit a systematic study of the relationship between its constitution and microtubule-stabilizing properties and cytotoxicity. Long term goals of this research include: (1) to determine if the reactive bridgehead alkene of WS9885B causes covalent modification of microtubules or other cellular components; and (2) the employment of chemistry developed in the course of a total synthesis of WS9885B in syntheses of analogue structures in an effort to define a structure-activity profile for this fascinating cytotoxic natural product.