Efficient Synthesis of (+)-Discodermolide

( )-Discodermolide 的高效合成

• 批准号: 6417185
• 负责人: DAVID C MYLES
• 金额: $ 10万
• 依托单位: KOSAN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6417185
• 关键词: antineoplastics; chemical synthesis; drug design /synthesis /production; drug discovery /isolation; fermentation; lactones; method development; polyketide synthase

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.

描述（由申请人提供）：该提案的长期目标 开发一种高效、经济的聚酮化合物生产方法 (+)-discodermolide。该化合物显示出有前景的抗癌活性， 作用方式与紫杉醇和埃坡霉素相似，但仅适用于 来自其天然来源——深海海绵的微量 混乱的混乱。全合成是目前唯一的选择 生产足够数量用于临床测试。几种全合成 已有报道，但所有这些都冗长且昂贵。最简洁的 迄今为止的合成（Smith 等人）将 discodermolide 分为三个部分。 每个部分都是从一个共同的前体精心制作而成，其本身是通过 使用昂贵试剂的多步骤路线。 PI 建议开发一个流程 通过发酵制备这种常见前体的等价物，使用 基因工程聚酮合酶。在第一阶段，我们将开发 制备该材料的方法并通过转换来证明其实用性 史密斯共同先驱。在第二阶段，我们将开发方法 将我们的发酵产品直接加入到合成中 (+)-discodermolide。研究人员还将探索其他天然材料的使用 聚酮化合物作为更先进的合成中间体，可减少 生产 discodermolide 所需的步骤。 PI 预计这种使用 工程酶将大大降低制备成本 (+)-discodermolide，并促进该产品的商业开发 抗癌剂。 拟议的商业应用： Discodermolide 是紫杉醇 (Taxol) 的潜在替代品。 目前的市场为 紫杉醇的体积相当大，但该药物也存在很多问题。 Discodermolide 具有许多有利的方面，包括更大的水溶性和 对紫杉醇抗性细胞的活性，因此可以接管大部分 紫杉醇市场。 本提案应解决供应问题 discodermolide，从而促进其商业开发。