Asymmetric Synthesis of Marcolide Antibiotics

Marcolide 抗生素的不对称合成

• 批准号: 8632159
• 负责人: JAMES L LEIGHTON
• 金额: $ 22.68万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632159
• 关键词: 3-hydroxybutanal; Alkynes; Antibiotics; Antibodies; Binding; Biological; Biological Factors; Cancer cell line; Clinic; Clinical; Complex; Cytotoxic agent; Development; Evaluation; Goals; Health; Human; Inhibitory Concentration 50; Macrolides; Malignant Neoplasms; Marines; Methods; Microtubules; Mitotic; Oxidation-Reduction; Pharmaceutical Preparations; Preparation; Reaction; Series; Site; Source; Staging; Synthesis Chemistry; Time; Tubulin; analog; chemical synthesis; chemotherapeutic agent; clinical efficacy; design; diketone; frontier; marine natural product; method development; operation; oxidation; pre-clinical; preclinical evaluation; research clinical testing; spongistatin 1; success

DESCRIPTION (provided by applicant): Non-aromatic polyketide natural products of marine origin are often characterized by both significant structural complexity and extraordinary biological activities. Because these exciting compounds are not typically available in any meaningful quantities from natural sources, total chemical synthesis is the only means by which sufficient amounts of material may be accessed for the full biological/preclinical evaluation of these compounds. No natural product better exemplifies this class of compound than spongistatin 1. This extraordinarily complex and precious marine natural product has an average IC50 value against the NCI panel of 60 human cancer cell lines of 0.12 pM. The ultimate goal of this proposal is to adapt spongistatin 1 for use in an antibody-drug conjugate (ADC) construct, by way of the design, synthesis and evaluation of a series of analogs of spongistatin 1 to identify appropriate linker sites for bioconjugation and to identify a significanly structurally simplified analog that retains the sub-nanomolar potency of the natural product. Our focus on an ADC approach derives mainly from two considerations: 1) this approach requires far less drug material than conventional approaches, rendering the synthesis of the kinds of amounts required for full clinical evaluation a significantly more realistic proposition, and 2) th low pM potency of spongistatin 1 renders it an ideal candidate for use in an ADC, as so little drug material makes it to the target that extraordinary potency is required for any meaningful clinical efficacy. In order to achieve these goals, we will continue to develop synthetic methods for the synthesis of polyketide natural products that are characterized by unprecedented levels of step-economy, efficiency, and scalability to continue to push the frontiers of efficiency in the chemical synthesis. We will then apply these methods to the development of a synthesis of spongistatin 1 that may easily be adapted for use in the preparation of the designed analogs. Finally, we will identify and synthesize significant quantities of the most significantly structuraly simplified compound equipped with a linker that retains the low pM potency of spongistatin 1.

说明(申请人提供)：海洋来源的非芳香族聚酮天然产物通常具有显著的结构复杂性和特殊的生物活性。由于这些激动人心的化合物通常不能从自然来源获得任何有意义的数量，全化学合成是唯一可以获得足够数量的材料来对这些化合物进行全面的生物/临床前评估的方法。没有天然产品比海绵抑素1更能体现这类化合物。这种极其复杂和珍贵的海洋天然产品对60个人类癌细胞株的NCI小组的平均IC50值为0.12 PM这项建议的最终目的是通过设计、合成和评价一系列海绵抑素1的类似物，使海绵抑素1用于抗体-药物结合物(ADC)构建，以确定适合生物偶联的连接物部位，并鉴定结构显著简化的类似物，保持天然产品的亚纳摩尔效力。我们对ADC方法的关注主要源于两个考虑：1)这种方法需要的药物材料比传统方法少得多，使得合成全面临床评估所需的各种量成为一个明显更现实的命题，以及2)海绵抑素1的低PM效力使其成为用于ADC的理想候选药物，因为很少的药物材料使其达到任何有意义的临床疗效所需的非凡效力的目标。为了实现这些目标，我们将继续开发合成聚酮天然产物的合成方法，这些方法具有前所未有的阶梯经济、效率和可扩展性的特点，以继续推动效率的前沿。 化学合成。然后，我们将应用这些方法来开发一种海绵抑素1的合成方法，该方法可以很容易地用于所设计的类似物的制备。最后，我们将鉴定和合成大量结构上最显著的简化化合物，该化合物配备了保持海绵抑素1低PM效力的连接子。