Asymmetric Synthesis of Marcolide Antibiotics

描述（由申请人提供）：海洋来源的非芳香族聚酮化合物天然产物通常具有显著的结构复杂性和非凡的生物活性。由于这些令人兴奋的化合物通常无法从天然来源获得任何有意义的数量，因此全化学合成是唯一的方法，通过该方法可以获得足够量的材料用于这些化合物的全面生物学/临床前评价。没有天然产物比海绵抑素1更好地纯化这类化合物。这种极其复杂和珍贵的海洋天然产物对NCI 60种人类癌细胞系的平均IC 50值为0.12 pM。该提议的最终目标是通过设计、合成和评价一系列海绵抑素1类似物以鉴定用于生物缀合的适当接头位点并鉴定保留天然产物的亚纳摩尔效力的显著结构简化的类似物，使海绵抑素1适应用于抗体-药物缀合物（ADC）构建体。我们对ADC方法的关注主要来自两个考虑：1）该方法需要比常规方法少得多的药物材料，使得完全临床评价所需的各种量的合成成为明显更现实的提议，和2）海绵抑素1的低pM效力使得其成为用于ADC的理想候选物，因为只有很少的药物材料到达靶点，所以任何有意义的临床功效都需要非凡的效力。为了实现这些目标，我们将继续开发用于合成聚酮化合物天然产物的合成方法，其特征在于前所未有的步骤经济性、效率和可扩展性水平，以继续推动生物技术领域的效率前沿。 化学合成然后，我们将应用这些方法来开发合成的spongistatin 1，可以很容易地适用于在设计的类似物的制备。最后，我们将鉴定并合成大量的最显著结构简化的化合物，该化合物配备有保留海绵抑素1的低pM效力的接头。

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.