New methods and strategies for the synthesis of bioactive steroids and terpinoids

合成生物活性类固醇和萜类化合物的新方法和策略

• 批准号: 9039632
• 负责人: Pavel Nagorny
• 金额: $ 28.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039632
• 关键词: 3-hydroxybutanal; Academia; Allergic Reaction; Animal Sources; Animals; Area; Biological; Biological Process; Carbon; Cardenolides; Cardiac; Contraceptive methods; Development; Digitoxigenin; Disease; Diterpenes; Evaluation; Family; Goals; Health; Healthcare; Heart Diseases; Hormones; Human; Human body; Industry; Inflammation; Lead; Life; Malignant Neoplasms; Metabolic Diseases; Methodology; Methods; Molecular Medicine; Molecular Probes; Natural Products; Nature; Pain; Pattern; Pharmaceutical Preparations; Phosphoric Acids; Plant Sources; Plants; Play; Preparation; Process; Property; Reaction; Research; Role; Steroids; Strophanthidin; Techniques; Therapeutic Agents; Work; analog; base; bioactive natural products; bufadienolide; catalyst; chemical synthesis; drug discovery; fitness; glycosylation; hellebrin; hormone regulation; improved; novel therapeutics; oxidation; polyol; programs; scaffold; small molecule

DESCRIPTION (provided by applicant): This proposal is focused on the development of new enantioselective chiral catalyst-controlled approaches to bioactive steroids and diterpenes. Due to the importance of steroidal hormones for the regulation of vital biological processes in the human body, a significant portion of natural product-based drugs are derived from various natural or unnatural steroids. Steroid-based drugs are utilized for the treatment of inflammation, allergic reactions, heart diseases, cancer, metabolic diseases, and in important health-related areas such as contraception and fitness. The majority of steroid-based drugs are obtained by semi-synthesis using feedstock isolated from plant or animal sources. While nowadays such processes could be conducted on an industrial scale, the reliance on semi-synthetic methods significantly limits the structural diversity of the steroid-based small molecules available for biological evaluation. In contrast, fully synthetic approaches could significantly improve the availability of otherwise difficult-to-prepare stereoisomeric steroidal scaffolds with unusual substitution or oxidation patterns. The objective of the proposed research is to develop stereoselective Michael/double aldol cascade reactions and apply them to the rapid assembly of cardiac steroids and diterpenes of the isopimarane family. To achieve this objective, we propose the following specific aims: (1) to develop new stereoselective catalytic Michael/double aldol cascade reactions for the stereoselective synthesis of cardenolides and bufadienolides; (2) to develop chiral phosphoric acid (CPA)-controlled regioselective and stereoselective glycosylation of cardenolide-based polyols; (3) To develop an asymmetric approach to bioactive isopimaranes.

描述（由申请人提供）：该提案的重点是开发生物活性类固醇和二萜的新对映选择性手性催化剂控制方法。由于类固醇激素对于调节人体重要生物学过程的重要性，因此基于天然产物的大部分药物来自各种天然或不自然的类固醇。基于类固醇的药物用于治疗炎症，过敏反应，心脏病，癌症，代谢疾病，以及在与健康相关的重要区域（例如避孕和适​​应性）中。大多数基于类固醇的药物是通过使用从植物或动物来源分离出的原料来获得半合成的。尽管如今可以以工业规模进行此类过程，但对半合成方法的依赖显着限制了可用于生物学评估的基于类固醇的小分子的结构多样性。相比之下，完全合成的方法可以显着提高具有异常取代或氧化模式的原本难以释放的立体体类固醇支架的可用性。拟议的研究的目的是开发立体选择性迈克尔/双藻级联反应，并将其应用于Isopimarane家族的心脏类固醇和二萜的快速组装中。为了实现这一目标，我们提出了以下特定目的：（1）开发新的立体选择性催化迈克尔/双藻级联反应，以实现Cardenolides和Bufadienolides的立体选择性合成； （2）开发手性磷酸（CPA）基于心脏化合物多元醇的区域选择性和立体选择性糖基化； （3）开发一种非对称方法来生物活性等异径。