SBIR Phase I: Ring Contraction Metathesis Reaction for the Generation of Novel Polyene Macrolides

SBIR 第一阶段：用于生成新型多烯大环内酯的缩环复分解反应

• 批准号: 0943648
• 负责人: steven riesinger
• 金额: $ 14.46万
• 依托单位: MedChem Partners LLC
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0943648&HistoricalAwards=false
• 关键词: SBIR; Phase; Ring; Contraction; Metathesis

This Small Business Innovation Research (SBIR) Phase I project will develop a process for modifying macrolide natural products in general and Rapamycin in particular using a relatively new chemical transformation called the ring contraction metathesis reaction. The modified compounds will contain a novel contracted core that is inaccessible by conventional methods in a cost effective way. Rapamycin is an immunosuppressant used widely in transplantation, autoimmune and oncological diseases and drug coated stents. The major draw back of rapamycin is its extremely long half-life (63h) which leads to tolerability issues. The novel synthetic transformation outlined in this Phase I Research will allow for the synthesis of a novel new rapamycin analogs with improved pharmacological properties, such as shorter half-life. The broader impacts of this research are the following: First, development of this reaction into a general synthetic process will allow for the generation of a variety of new and novel compounds which cannot be prepared in any other way. The ring contraction process will generate novel natural product structures that could function as new chemical probes to better understand biological processes. Furthermore, novel macrolide compounds could advance national health concerns by providing new drugs with an improved therapeutic profile. Secondly, the generation of novel Rapamycin analogs will improve the health and quality of life of organ transplant patients as well as form the basis for ongoing research in oncology and auto immune diseases.

这个小型企业创新研究(SBIR)第一阶段项目将开发一种方法，用于修饰大环内酯类天然产物，特别是雷帕霉素，使用一种称为环收缩歧化反应的相对较新的化学转化。经修饰的化合物将包含一种新的收缩核心，这是传统方法无法以经济高效的方式获得的。雷帕霉素是一种免疫抑制剂，广泛应用于移植、自身免疫和肿瘤疾病以及药物涂层支架。雷帕霉素的主要缺点是其超长的半衰期(63h)，这会导致耐受性问题。在这项第一阶段研究中概述的新的合成转化将允许合成一种新的雷帕霉素类似物，具有更好的药理特性，如更短的半衰期。这项研究的更广泛的影响如下：第一，将该反应发展成一般的合成过程将允许产生各种新的和新的化合物，这些化合物是任何其他方法都无法制备的。环收缩过程将产生新的天然产品结构，这些结构可以作为新的化学探针来更好地了解生物过程。此外，新的大环内酯类化合物可以通过提供治疗效果更好的新药来促进国家健康问题。其次，新雷帕霉素类似物的产生将改善器官移植患者的健康和生活质量，并为正在进行的肿瘤学和自身免疫性疾病研究奠定基础。