Efficient Synthesis of (+)-Discodermolide

描述(由申请人提供)：本建议书的长期目标 是开发一种高效、经济的方法来生产聚酮 ()-Discodermolide。这种化合物显示出良好的抗癌活性，具有 作用模式与紫杉醇和埃博西酮相似，但仅在 从其天然来源--深水海绵中摄取的微量 顽固性盘皮病。全合成是目前唯一的选择 生产足够数量的用于临床测试的。几种全合成方法 已有报道，但所有这些都是漫长和昂贵的。最简明的 迄今为止的综合(Smith等人)将盘状物分成三段。 每一段都是由一个共同的前体精心制作的，它本身是通过一个 使用昂贵试剂的多步骤路线。PI建议开发一个流程 要通过发酵来制备这种常见前体的等价物，使用 基因工程聚酮合成酶。在第一阶段，我们会发展 方法来准备此材料，并通过转换为 史密斯的共同前驱。在第二阶段，我们将开发方法来 将我们的发酵产品直接用于合成 ()-Discodermolide。研究人员还将探索使用其他天然的 聚酮类化合物作为更高级的合成中间体，以减少 生产盘状分子筛所需的步骤。国际和平研究所预计，这种使用 基因工程酶将极大地降低制备成本 ()-Discodermolide，并促进这一技术的商业开发 抗癌剂。 建议的商业应用： Discodermolide是紫杉醇(Taxol)的潜在替代品。目前的市场 紫杉醇相当大，但与这种药物相关的问题很多。 Discodermolide有许多有利的方面，包括更好的水溶性和 对紫杉醇耐药细胞的活性，因此可能会占据很大一部分 紫杉醇市场。目前的建议应能克服#年的供应问题 Discodermolide，从而促进其商业化发展。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to develop an efficient, economical means of producing the polyketide (+)-discodermolide. This compound shows promising anticancer activity, having a similar mode of action as paclitaxel and epothilone, but is available only in minute quantity from its natural source, the deep-water marine sponge Discodermia dissolute. Total synthesis is the only option at present for producing sufficient quantities for clinical testing. Several total syntheses have been reported, yet all are lengthly and expensive. The most concise synthesis to date (Smith et al.) divides discodermolide into three segments. Each segment is elaborated from a common precursor, itself prepared via a multi-step route using expensive reagents. The PI proposes to develop a process to prepare an equivalent of this common precursor by fermentation, using genetically engineered polyketide synthases. In Phase 1, we will develop the methods to prepare this material and demonstrate its utility by conversion to the Smith common precursor. In Phase 2, we will develop the methodology to incorporate our fermentation product directly into the synthesis of (+)-discodermolide. The researchers will also explore the use of other natural polyketides as more advanced synthetic intermediates to decrease the number of steps required to produce discodermolide. The PI anticipates that this use of engineered enzymes will dramatically reduce the cost of preparing (+)-discodermolide, and facilitate the commercial development of this anticancer agent. PROPOSED COMMERCIAL APPLICATION: Discodermolide is a potential successor to paclitaxel (Taxol). The current market for paclitaxel is quite large, yet there are many problems associated with this drug. Discodermolide has many favorable aspects, including greater water solubility and activity against Taxol-resistance cells, and so could take over a large portion of the Taxol market. The present proposal should overcome the supply problem of discodermolide, thus facilitating it commercial development.