Enatioselective Synthesis of Gardneria Oxindole Natural Products

说明书(申请人提供)：吡咯烷基-螺吲哚亚基存在于多种生物活性化合物中，天然和非天然的，作为潜在的抗癌药物受到了极大的关注。Gardneria oxindole天然产物，包括甲壳胺和Gardneramine以及杂二聚体gardmutin，都含有这种杂环基序，并已被证明具有一系列生物活性。特别令人感兴趣的是，它们对P-糖蛋白过度表达的细胞系具有细胞毒活性，并在体外有效地逆转了抗癌药物长春新碱和阿霉素的多药耐药性。此外，体内神经节传递的抑制已被证明是由于拟议的与尼古丁受体的结合。尽管具有这种显著的生物活性，但目前还没有导致这些制剂的合成方法；这一缺陷阻碍了对这些生物学特性的进一步研究。这项提议将通过审查两种不同的方法来开发这些天然产物的对映选择性合成方法，以生成连接到氧化吲哚核上的环系。第一种方法将结合串联Heck/p-烯丙基捕获反应，在单个步骤中设置关键的相邻立体中心。还将探索一种互补的方法，即先进行Heck环化，然后进行高度新颖的分子内Petsis硼酸Mannich环合成。通过使用这些方法获得两种单体天然产物，然后将研究高度复杂的杂二聚体gardmutin的生成。将完成对这些天然产品以及关键衍生品的生物学评估。这项工作有望直接导致相关类似物的产生，这些类似物可能具有额外的有用生物活性。此外，在这项工作中开发的合成方法将在合成中进一步使用，因为在这些化合物中发现的基序存在于许多生物相关的分子中。与公共健康相关：这项提案寻求开发进行一类有前景的抗癌天然产品的化学合成所需的方法。对这些化合物的合成方法将使进一步研究它们的生物学特性成为可能，并允许产生结构修改的类似物，从而提高它们的有用性。这种类型的研究在药物开发过程中起着至关重要的作用；作为临床候选药物的来源，用于研究生物功能的化学工具的产生，以及适用于其他新型药物合成的化学方法的开发。

DESCRIPTION (provided by applicant): The pyrrolidinyl-spiroxindole substructure is found in a variety of bioactive compounds, natural and unnatural in origin, that have received significant attention as potential anti-cancer agents. The Gardneria oxindole natural products, which include the monomers chitosenine and gardneramine and the heterodimer gardmultine, contain this heterocyclic motif and have been shown to possess a range of biological activities. Of particular interest is their cytotoxic activity against a p-glycoprotein overexpressing cell-line and potent in vitro reversal of multidrug resistance to the anti-cancer agents vincristine and doxorubicin. Additionally, in vivo inhibition of ganglionic transmission has been demonstrated resulting from proposed binding to the nicotinic receptor. Despite this remarkable bioactivity, there are no synthetic methods leading to these agents; a deficiency which inhibits further study of these biological properties. This proposal will develop enantioselective synthetic approaches to these natural products through the examination of two distinct methodologies to generate the ring systems attached to the oxindole nucleus. The first approach will incorporate a tandem Heck/p-allyl capture reaction to set the key adjacent stereocenters in a single step. A complementary approach, featuring a Heck cyclization followed by a highly novel intramolecular Petasis boronic Mannich ring synthesis, will also be explored. With access to the two monomeric natural products using these methods, the generation of the highly complex heterodimer gardmultine will then be examined. Biological evaluation of these natural products, as well as key derivatives, will be completed. This work is anticipated to directly lead to the generation of related analogs that may possess additional useful bioactivity. Furthermore, synthetic methodologies developed in the course of this work will find further use in synthesis, as motifs found in these compounds are present in a number of biologically relevant molecules. PUBLIC HEALTH RELEVANCE: This proposal seeks to develop the methods needed to perform the chemical synthesis of a promising class of anti-cancer natural products. Synthetic approaches towards these compounds will enable further studies of their biological properties, as well as permitting the generation of analogs with structural modifications that should improve their usefulness. Studies of this type play a crucial role in the drug development process; as a source of clinical candidates, for the generation of chemical tools for the study of biological function, and for the development of chemical methods applicable to the synthesis of other novel agents.