Preparation of a Solid-Phase Polyketide Synthase Mimic

描述(申请人提供)：聚酮代表一类对人类健康有巨大影响的小分子。这类天然产物和衍生物具有丰富的药理作用，从抗癌到抗生素，甚至抗胆固醇活性。制备这些分子的标准方法包括发酵法和全合成法。这项建议概述了一种受聚酮合成酶启发的一般合成聚酮的新方法，聚酮合成酶是自然界中用来制备这类分子的酶机制。这种方法将利用固体支撑模板的使用，通过硫代酯之间的脱羧基克莱森反应来延长不断增长的聚酮链。如果成功，这种方法可以为合成聚酮的迭代、标准化方法奠定基础，为天然产物及其衍生物的自动合成开辟道路。 与公众健康相关：聚酮类化合物，如四环素类、红霉素类和埃博西酮类具有丰富的药理特性，包括抗癌、抗生素和抗胆固醇活性。这项提案概述了一种新的一般合成聚酮的方法，旨在为进一步提高这些分子的药用潜力的标准化方法奠定基础。

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.