Efficient synthesis of discodermolide

discodermolide的高效合成

• 批准号: 6737067
• 负责人: DAVID C MYLES
• 金额: $ 37.5万
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737067
• 关键词: Myxococcus; Porifera; Streptomyces; alkaloids; analog; antineoplastics; chemical synthesis; experimental designs; heterocyclic compounds; lactones; method development; neoplasm /cancer chemotherapy; polyketide synthase

DESCRIPTION (provided by applicant): The objective of this Phase II proposal is the development of an efficient means of producing 14-normethyl discodermolide, a totally synthetic analog of the sponge metabolite (+)-discodermolide 3ossessing exciting anticancer activity. The natural product is available only in minute quantities from its endogenous source, and costly total synthesis is, at present, the only effective means of obtaining this compound or a biologically and commercially attractive analog such as 14-normethyl discodermolide. We have developed (Phase I) a synthesis of key precursors used in an established synthesis of (+)-discodermolide using genetically engineered polyketide synthase (PKS) genes operating on functionalized substrates to furnish functionally and stereochemically rich materials that were converted to the desired intermediates. Phase II builds on the successful discoveries of Phase I but avoids the need for the use of precursor directed biosynthesis. Phase II will provide large polyketide fragments that may be disassembled and then reassembled via very short sequences to gain access to 14-normethyl discodermolide. The specific aims of Phase II are: 1. We will produce in Myxococcus xanthus a truncated and modified analog of soraphen A that will be used for the synthesis of an advanced precursor of 14-normethyl discodermolide. 2. We will produce in Streptomyces coelicolor (2R,3S,4R,5S)-2,4-dimethyl-3,5-dihydroxyhexoate lactone at high titers. 3. We will use the products of Aims 1 and 2 to produce 14-normethyl discodermolide. Successful development of this methodology will reduce the extent, difficulty, and cost of the synthetic chemistry required, making large-scale commercial production of 14-normethyl discodermolide feasible and affordable.

描述(申请人提供)：这项第二阶段提案的目标是开发一种有效的方法来生产14-去甲基盘状分子，这是一种完全合成的海绵代谢物(+)-盘状分子3具有兴奋的抗癌活性的类似物。这种天然产物只能从其内源性来源获得微量，而昂贵的全合成是目前获得这种化合物或具有生物和商业吸引力的类似物(如14-去甲基盘状软糖)的唯一有效手段。我们利用在功能化底物上操作的基因工程聚酮合成酶(PKS)基因，开发了(第一阶段)用于(+)-盘状化合物合成的关键前体的合成，以提供功能和立体化学丰富的材料，这些材料被转化为所需的中间体。第二阶段建立在第一阶段成功发现的基础上，但避免了使用前体定向生物合成的需要。第二阶段将提供大的聚酮片段，这些片段可以被分解，然后通过非常短的序列重新组装，以获得14-去甲基盘状聚醚。第二阶段的具体目标是：1.我们将在黄色粘球菌中生产一种截短和修改的山梨烯A类似物，用于合成先进的14-去甲基盘状糖胺前体。2.我们将在天蓝色链霉菌中生产高滴度的(2R，3S，4R，5S)-2，4-dimethyl-3，5-dihydroxyhexoate内酯。3.我们将利用AIMS 1和AIMS 2的产品来生产14-去甲基盘状胺。这一方法的成功开发将降低合成化学所需的范围、难度和成本，使14-去甲基盘状化合物的大规模商业生产变得可行和负担得起。