Synthesis of Biologically Important Furanosteroids

具有生物学意义的呋喃类固醇的合成

• 批准号: 0646876
• 负责人: Peter Jacobi
• 金额: $ 47.4万
• 依托单位: Dartmouth College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0646876&HistoricalAwards=false
• 关键词: Synthesis; Biologically; Important; Furanosteroids

The furanosteroids are a class of novel fungal metabolites, several of which are potent inhibitors of phosphatidylinositol 3-kinase (PI-3 kinase), an enzyme that plays a key role in the life cycle of cells. However, the known members of this class are far too toxic and non-selective for development as anti-tumor agents. Because of this, there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs. This project addresses the development of a concise synthetic approach to the furanosteroids that should be equally applicable to the biologically important natural products as well as structural analogs. The methodology proposed takes advantage of a sequence of reactions, leading from readily available starting materials to the final target compounds without isolation of intermediate structures. More specifically, synthetic approaches will be explored for the preparation of viridian, demethoxyviridin, viridiol, demethoxyviridiol, wortmannin and desacetoxywortmannin. The key step in the synthesis of all of these compounds is an intramolecular Diels-Alder/retro-Diels-Alder reaction of an alkyne with an oxazole to give a bridged intermediate that, without isolation, immediately undergoes a retro-Diels-Alder reaction to produce a furan ring. This strategy allows for remarkably short synthetic schemes given the complexity of the final compounds. With the support of this award from the Organic and Macromolecular Chemistry Program, Professor Peter A. Jacobi, of the Department of Chemistry at Dartmouth College, is developing new methods for the efficient synthesis of representatives of a unique class of molecules, produced naturally by fungi, known as the furanosteroids. Some of these compounds are potent inhibitors of an enzyme that plays a key role in the life cycle of cells. As such, they hold promise as a new class of therapeutic agents for diseases characterized by rapid cell proliferation, as is the case in cancer. However, the known members of this class are far too toxic and non-selective for development as anti-tumor agents. Thus, there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs, but progress in this area has been slow because of the great difficulties associated with synthesizing these compounds. Professor Jacobi and his students are developing a concise synthetic approach to the furanosteroids, that should be equally applicable to the biologically important natural products as well as structural analogs. Ultimately, these studies could lead to the discovery of simpler analogs of the natural products that have enhanced biological activity but are significantly less toxic and more site specific.

呋喃甾类化合物是一类新型真菌代谢产物，其中几种是磷脂酰肌醇3-激酶（PI-3激酶）的有效抑制剂，PI-3激酶是一种在细胞生命周期中起关键作用的酶。然而，这类已知的成员对于开发为抗肿瘤剂来说毒性太大且无选择性。正因为如此，人们对开发天然存在的化合物和更简单的类似物的新合成途径非常感兴趣。该项目致力于开发一种简洁的呋喃甾类化合物的合成方法，该方法应同样适用于生物学上重要的天然产物以及结构类似物。所提出的方法利用了一系列的反应，导致从容易获得的起始材料的最终目标化合物，而无需分离的中间体结构。更具体地说，将探索用于制备绿色、脱甲氧基绿色、绿色二醇、脱甲氧基绿色二醇、渥曼青霉素和脱乙酰氧基渥曼青霉素的合成方法。合成所有这些化合物的关键步骤是炔与恶唑的分子内Diels-桤木/逆Diels-桤木反应，得到桥连中间体，其无需分离，立即经历逆Diels-桤木反应，产生呋喃环。考虑到最终化合物的复杂性，这种策略允许非常短的合成方案。在有机和高分子化学项目的支持下，彼得·A·达特茅斯学院化学系的Jacobi正在开发一种新的方法，用于有效合成一类独特分子的代表，这种分子由真菌天然产生，称为呋喃甾类。这些化合物中的一些是在细胞生命周期中起关键作用的酶的有效抑制剂。因此，它们有望成为一类新的治疗剂，用于以快速细胞增殖为特征的疾病，如癌症。然而，这类已知的成员对于开发为抗肿瘤剂来说毒性太大且无选择性。因此，人们对开发天然存在的化合物和更简单的类似物的新合成途径有着浓厚的兴趣，但由于合成这些化合物的巨大困难，该领域的进展一直很缓慢。Jacobi教授和他的学生正在开发一种简洁的呋喃甾类化合物合成方法，该方法同样适用于生物学上重要的天然产物以及结构类似物。最终，这些研究可能会导致发现更简单的天然产物类似物，这些天然产物具有增强的生物活性，但毒性明显降低，更具位点特异性。