Asymmetric Synthesis of Macrolide Antibiotics

大环内酯类抗生素的不对称合成

基本信息

批准号：
9277048
负责人：
JAMES L LEIGHTON
金额：
$ 8万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
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

项目摘要

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.

描述（由申请人提供）：海洋来源的非芳香聚酮化合物天然产物通常以显着的结构复杂性和非凡的生物学活性为特征。由于这些令人兴奋的化合物通常在自然来源的任何有意义的数量中都无法获得，因此总化学合成是唯一可以访问足够量的材料来访问这些化合物的完整生物学/临床前评估的方法。没有天然产物比海绵蛋白1更好地体现了这类化合物。这种非常复杂和珍贵的海洋天然产品的平均IC50值对NCI面板的平均IC50值为60人类癌细胞系的平均值为0.12 pm。该提案的最终目标是通过设计，合成和评估海绵状蛋白1的设计，合成和评估来适应用于抗体 - 毒物结合物（ADC）结构1的构造，以确定生物结合的适当接头站点，以确定生物结合的适当链接器位点，以识别自然而然的类似物，以确定一个自然化的生产力。我们对ADC方法的关注主要源于两个考虑因素：1）与常规方法相比，这种方法需要少得多的药物材料，从而使完整临床评估所需的数量综合综合了一个更现实的命题，而2）spongistatin 1的较低PM PM的效力使得在ADC中使用额外的效果，使得既有剂量的均可成为一种刻薄的药物，从而使其成为较小的效果，因此，这是我们的含义。功效。为了实现这些目标，我们将继续开发合成方法来合成聚酮化合物天然产品，这些产品的特征是前所未有的阶梯经济，效率和可扩展性，以继续推动效率的边界化学合成。然后，我们将将这些方法应用于海绵蛋白1的合成的开发中，这些方法很容易适应设计的类似物的制备。最后，我们将识别并合成大量最显着的结构性简化化合物，配备了连接器，该化合物保留了Spongistatin 1的低PM效力。