Enatioselective Synthesis of Gardneria Oxindole Natural Products

描述（由申请人提供）：吡咯烷基-螺旋吲哚亚结构存在于多种天然和非天然的生物活性化合物中，作为潜在的抗癌剂受到了极大的关注。栀子花的天然产物，包括壳聚糖、栀子花胺和异二聚物栀子花，都含有这种杂环基序，并已被证明具有一系列的生物活性。特别令人感兴趣的是它们对p糖蛋白过表达细胞系的细胞毒性活性，以及在体外有效逆转对抗癌药物长春新碱和阿霉素的多药耐药。此外，体内抑制神经节传导已被证明是由于与烟碱受体的结合。尽管这些药物具有显著的生物活性，但目前还没有合成这些药物的方法；这种缺陷阻碍了对这些生物学特性的进一步研究。本提案将通过检查两种不同的方法来产生附着在氧吲哚核上的环系统，从而开发这些天然产物的对映选择性合成方法。第一种方法将结合一个串联Heck/p-烯丙基捕获反应，在一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，即赫克环化，然后是一种高度新颖的分子内Petasis硼曼尼希环合成。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异二聚体gardmultine的生成。将完成这些天然产物及其关键衍生物的生物学评价。这项工作预计将直接导致产生可能具有额外有用的生物活性的相关类似物。此外，在这项工作过程中开发的合成方法将在合成中找到进一步的用途，因为在这些化合物中发现的基序存在于许多生物学相关分子中。公共卫生相关性：本提案旨在开发化学合成一类有前途的抗癌天然产物所需的方法。对这些化合物的合成方法将使其生物学特性的进一步研究成为可能，并允许产生具有结构修饰的类似物，从而提高其实用性。这类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生成，以及用于开发适用于合成其他新型药物的化学方法。

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.