Asymmetric Synthesis of Marcolide Antibiotics

描述（由申请人提供）：海洋来源的非芳香聚酮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中获得有意义的数量，因此全化学合成是唯一可以获得足够数量的材料以对这些化合物进行完整的生物学/临床前评估的方法。没有比海绵抑素更能说明这类化合物的天然产物了。这种极其复杂和珍贵的海洋天然产品对60种人类癌细胞系的NCI面板的平均IC50值为0.12 pM。本提案的最终目标是通过设计、合成和评估一系列海绵抑素1类似物，使海绵抑素1用于抗体-药物偶联（ADC）结构，以确定适当的生物偶联连接位点，并确定结构简化的类似物，保留天然产物的亚纳摩尔效力。我们关注ADC方法主要来自两个因素:1)这种方法需要药物材料远远少于传统方法,呈现的合成所需的大量完整的临床评价一个更现实的命题,和2)th低spongistatin 1点力量使它理想的候选人用于ADC,作为药物太少材料使它非凡的力量的目标所需的任何有意义的临床疗效。为了实现这些目标，我们将继续开发合成聚酮类天然产物的合成方法，这些合成方法具有前所未有的台阶经济，效率和可扩展性，以继续推动效率的前沿

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.