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(申请人提供)：本提案的重点是开发新的手性催化剂控制的生物活性类固醇和二萜类化合物的对映选择性方法。由于类固醇激素在调节人体重要生物过程中的重要性，以天然产物为基础的药物有很大一部分来自各种天然或非天然类固醇。类固醇类药物被用于治疗炎症、过敏反应、心脏病、癌症、代谢性疾病，以及与健康有关的重要领域，如避孕和健身。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的原料进行半合成而获得的。虽然如今这类过程可以在工业规模上进行，但对半合成方法的依赖大大限制了可用于生物评估的类固醇小分子的结构多样性。相比之下，完全合成的方法可以显著提高原本难以制备的具有不寻常取代或氧化模式的立体异构体类固醇支架的可用性。这项研究的目的是发展立体选择性的Michael/Double Aldol级联反应，并将其应用于心脏类固醇和异海松烷家族的二萜类化合物的快速组装。为了实现这一目标，我们提出了以下具体目标：(1)开发新的立体选择性催化Michael/Double Aldol级联反应，用于合成Cardenolide和Bufadienolide；(2)开发手性磷酸(CPA)控制的Cardenolide多元醇的区域选择性和立体选择性糖基化反应；(3)开发一种不对称方法合成具有生物活性的异海松烷。