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

基本信息

批准号：
8749350
负责人：
Pavel Nagorny
金额：
$ 28.19万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8749350
关键词：
3-hydroxybutanal Academia Allergic Reaction Animal Sources Animals Area Biological Biological Factors Biological Process Bufadienolides 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 Nature Pain Pattern Pharmaceutical Preparations Phosphoric Acids Plant Sources Plants Play Preparation Process Property Reaction Reliance Research Role Steroids Strophanthidin Techniques Therapeutic Agents Work analog base bufadienolide catalyst chemical synthesis drug discovery fitness glycosylation hellebrin hormone regulation improved novel therapeutics oxidation polyol programs public health relevance scaffold small molecule

项目摘要

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新的对映选择性手性催化剂控制的生物活性类固醇和二萜方法。由于类固醇激素对于调节人体内重要生物过程的重要性，很大一部分基于天然产物的药物源自各种天然或非天然类固醇。类固醇药物用于治疗炎症、过敏反应、心脏病、癌症、代谢疾病，以及避孕和健身等重要的健康相关领域。大多数类固醇药物是使用从植物或动物来源分离的原料通过半合成获得的。虽然如今此类过程可以在工业规模上进行，但对半合成方法的依赖极大地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着提高难以制备具有不寻常取代或氧化模式的立体异构甾体支架的可用性。本研究的目的是开发立体选择性迈克尔/双羟醛级联反应，并将其应用于异海香烷家族强心类固醇和二萜的快速组装。为了实现这一目标，我们提出以下具体目标：（1）开发新型立体选择性催化迈克尔/双羟醛级联反应，用于立体选择性合成强心烯内酯和蟾蜍二烯内酯； (2) 开发手性磷酸（CPA）控制的基于卡烯内酯的多元醇的区域选择性和立体选择性糖基化； (3) 开发具有生物活性的异海哌烷的不对称方法。