Synthesis and Study of Natural and Non-natural Antiproliferative Agents

天然和非天然抗增殖剂的合成与研究

• 批准号: 7811820
• 负责人: ANDREW G MYERS
• 金额: $ 34.43万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811820
• 关键词: Acylation; Alkaloids; Amination; Angiogenesis Inhibitors; Atherosclerosis; Award; Binding; Biochemical; Biological; Biological Factors; Blood Vessels; Budgets; Complex; Development; Disease; Evaluation; Family; Funding; Goals; Government; Grant; Growth; Label; Laboratories; Lead; Learning; Macular degeneration; Malignant Neoplasms; Metabolic; Molecular Probes; Molecular Target; Patients; Persons; Pharmacologic Substance; Preparation; Process; Production; Property; Proteins; Reaction; Recovery; Research; Route; Skeleton; Structure; Structure-Activity Relationship; United States National Institutes of Health; Variant; analog; angiogenesis; antiproliferative agents; avrainvillamide; base; cortistatin; design; fluorescence imaging; functional group; improved; in vivo; member; parent grant; public health relevance; research study; response; small molecule; tool

DESCRIPTION (provided by applicant): In this competitive revision proposal we seek to pursue as a new and additional specific aim the development of practical synthetic routes to the cortistatin family of alkaloids, broadly defined. Our approach is based on a versatile advanced synthetic template from which a diverse array of natural and unnatural cortistatins can be rapidly prepared. Analogs widely variant in the A and D rings, as well as along the skeleton connecting these rings will be prepared. We plan to evaluate the effects of the compounds we prepare upon the growth of HUVECs and thereby to develop a comprehensive profile of structure-activity relationships within the class. We also plan to synthesize molecular probes as tools for the identification of protein target(s) of the cortistatins. We propose to synthesize key intermediates for the production of cortistatins in multi-gram amounts from which we will pursue the preparation of large numbers of cortistatin analogs that otherwise would be inaccessible. This proposal is a competitive revision application. Notice Number: NOT-OD-09-058 n Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revisions Applications PUBLIC HEALTH RELEVANCE: Angiogenesis is the process of new blood vessel growth from existing vasculature, and unregulated angiogenesis has been implicated in a variety of diseases including atherosclerosis, macular degeneration, and many forms of cancer. The development of small-molecule inhibitors of angiogenesis provides one of the most promising avenues of therapy for patients with these illnesses. The overall goal of this project is to develop a means to synthesize in the laboratory analogs of the extremely potent natural angiogenesis inhibitors known as the cortistatins, which may serve as lead structures in pharmaceutical design, as well as biological probes to elucidate the protein target(s) of these compounds in vivo.

描述（由申请人提供）：在本竞争性修订提案中，我们寻求将开发广泛定义的皮质抑素家族生物碱的实用合成路线作为新的和额外的具体目标。我们的方法基于多功能的先进合成模板，可以快速制备多种天然和非天然皮质抑素。将制备A环和D环以及沿着连接这些环的骨架的广泛变异的类似物。我们计划评估我们制备的化合物对 HUVEC 生长的影响，从而开发该类别内结构-活性关系的全面概况。我们还计划合成分子探针作为鉴定皮质抑素蛋白靶点的工具。我们建议合成用于生产数克量的皮质抑素的关键中间体，我们将从中制备大量否则无法获得的皮质抑素类似物。该提案是一项竞争性修订申请。通知编号：NOT-OD-09-058 n 通知标题：NIH 宣布恢复法案基金可用于竞争性修订申请 公共健康相关性：血管生成是现有脉管系统生长新血管的过程，不受调节的血管生成与多种疾病有关，包括动脉粥样硬化、黄斑变性和多种癌症。血管生成小分子抑制剂的开发为患有这些疾病的患者提供了最有希望的治疗途径之一。该项目的总体目标是开发一种方法，在实验室中合成极其有效的天然血管生成抑制剂（称为皮质抑素）的类似物，其可以作为药物设计中的先导结构，以及阐明这些化合物在体内的蛋白质靶标的生物探针。