Enatioselective Synthesis of Gardneria Oxindole Natural Products

栀子羟吲哚天然产物的对映选择性合成

• 批准号: 7611339
• 负责人: Martin John Schnermann
• 金额: $ 4.52万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-28 至 2012-01-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611339
• 关键词: Amines; Antineoplastic Agents; Attention; Binding; Biological; Biological Factors; Biological Process; Boronic Acids; Cell Line; Cell Nucleus; Chemicals; Clinical; Complex; Cyclization; Development; Dimerization; Doxorubicin; Evaluation; Generations; Glycoproteins; In Vitro; Lead; Malignant Neoplasms; Methodology; Methods; Modification; Multi-Drug Resistance; Nicotinic Receptors; Play; Process; Property; Reaction; Research Design; Role; Source; System; Vincristine; Work; analog; chemical synthesis; cytotoxic; drug development; gardneramine; improved; in vivo; interest; monomer; novel; overexpression; oxindole; public health relevance; tool; transmission process

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.

描述（由申请人提供）：吡咯烷基-螺环吲哚亚结构存在于多种天然和非天然来源的生物活性化合物中，这些化合物作为潜在的抗癌剂受到了极大的关注。Gardneria oxindole天然产物，包括单体chitosenine和gardneramine以及异二聚体gardmultine，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-糖蛋白过表达细胞系的细胞毒活性和对抗癌剂长春新碱和多柔比星的多药耐药性的有效体外逆转。此外，已证明神经节传递的体内抑制是由于与烟碱受体的结合。尽管有这种显著的生物活性，但没有合成方法导致这些试剂;这一缺陷抑制了对这些生物学特性的进一步研究。该提案将通过两种不同的方法来产生连接到羟吲哚核的环系统的检查，开发这些天然产物的对映选择性合成方法。第一种方法将包括串联Heck/p-烯丙基捕获反应，以在单个步骤中设置关键的相邻立构中心。一个互补的方法，具有赫克环化，然后是一个非常新颖的分子内Petasis硼酸曼尼希环合成，也将进行探讨。通过使用这些方法获得两种单体天然产物，然后将检查高度复杂的异源二聚体gardmultine的产生。将完成对这些天然产物以及关键衍生物的生物评价。预计这项工作将直接导致产生可能具有额外有用生物活性的相关类似物。此外，在这项工作的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相关的分子中。公共卫生相关性：该提案旨在开发进行一类有前途的抗癌天然产物的化学合成所需的方法。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，这些结构修饰应提高其有用性。这种类型的研究在药物开发过程中发挥着至关重要的作用;作为临床候选药物的来源，用于生成用于研究生物功能的化学工具，以及用于开发适用于合成其他新型药物的化学方法。