Preparation of a Solid-Phase Polyketide Synthase Mimic

固相聚酮合酶模拟物的制备

• 批准号: 8201662
• 负责人: Ian Bass Seiple
• 金额: $ 4.63万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201662
• 关键词: Antibiotics; Biological; Biological Factors; Cholesterol; Enzymes; Epothilones; Erythromycin; Fermentation; Human; Individual; Investigation; Laboratories; Malignant Neoplasms; Methods; Modification; Nature; Peptide Synthesis; Phase; Preparation; Procedures; Property; Reaction; Research; Solid; Tetracyclines; analog; design; polyketide synthase; small molecule; theories; thioester

DESCRIPTION (provided by applicant): Polyketides represent a class of small molecules that has had an enormous impact on the human condition. Several natural products and derivatives of this class possess a wealth of pharmacological properties from anti-cancer to antibiotic and even anti-cholesterol activity. Standard methods to prepare these molecules include fermentation and total synthesis. This proposal outlines a new method for the general synthesis of polyketides that is inspired by polyketide synthase, the enzymatic machinery that is utilized in Nature to prepare molecules of this class. This method would capitalize on the use of a solid-supported template to elongate a growing polyketide chain via decarboxylative Claisen reactions between thioesters. If successful, this method could lay the groundwork for an iterative, standardized method for the synthesis polyketides, opening avenues for automated synthesis of natural products and derivatives thereof. PUBLIC HEALTH RELEVANCE: Polyketides such as the tetracyclines, the erythromycins, and the epothilones possess a wealth of pharmacological properties including anti-cancer, antibiotic and anti-cholesterol activity. This proposal outlines a new method for the general synthesis of polyketides that is designed to lay the groundwork for a standardized way to access these molecules to further advance their medicinal potential.

描述（申请人提供）：聚酮化合物代表一类对人类状况产生巨大影响的小分子。该类别的几种天然产物和衍生品具有从抗癌到抗生素甚至抗胆固醇活性的大量药理特性。制备这些分子的标准方法包括发酵和总合成。该建议概述了一种新方法，用于一般合成聚酮化合物，该方法是受到聚酮化合酶合酶的启发，这是一种在自然界中用于制备该类别分子的酶促机械。该方法将利用使用固体支撑模板通过硫代植物之间的脱羧基claisen反应来延伸生长的聚酮链。如果成功，此方法可以为合成聚酮化合物的迭代，标准化方法奠定基础，开辟了自动合成天然产物及其衍生物的途径。 公共卫生相关性：聚酮化合物，例如四环素，红霉素和雌激素，具有丰富的药理特性，包括抗癌，抗生素和抗胆固醇活性。该提案概述了一种一般合成聚酮化合物的新方法，该方法旨在为访问这些分子进一步提高其药用潜力的标准化方法奠定基础。