Synthesis and Study of Medicinally Important Molecules

药用重要分子的合成与研究

• 批准号: 10459633
• 负责人: Mingji Dai
• 金额: --
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-04 至 2022-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459633
• 关键词: Address; Alkaloids; Biological; Carbon; Collection; Communicable Diseases; Complex; Development; Diterpenes; Drug Industry; Drug resistance; Elements; Evaluation; Goals; Health; Human; Institution; Lead; Macrocyclic Compounds; Macrolides; Methodology; Natural Products; Nerve Degeneration; Nitrogen; Organic Synthesis; Outcomes Research; Pharmaceutical Chemistry; Pharmaceutical Preparations; Piperazines; Problem Solving; Reaction; Research; analog; anti-cancer; antimicrobial; base; bioactive natural products; cancer therapy; cost; drug discovery; flexibility; human disease; in vivo; innovation; nervous system disorder; novel; novel therapeutics; programs; research clinical testing; scaffold; small molecule; therapeutic development

Project Summary/Abstract The goal of our research program is to innovate in both the strategy and methodology of organic synthesis, and apply them to solve problems of biological and medicinal importance and ultimately impact human health. Our program focuses on synthesis and study of both natural (Project 1A-C) and unnatural (Project 2) molecules with particular potential for the treatment of cancer, neurological disorders, and drug resistant infectious diseases. In project 1, we aim to synthesize lyconadin alkaloids (1A), bridged macrolides (1B), and polycyclic diterpene (1C) natural products and their analogs and identify compounds based on these privileged scaffolds for novel therapeutic development. In project 2, we aim to develop novel and practical amphoteric diamination methodologies including the enantioselective versions to provide new avenues toward N- heterocycles including piperazine, 1,4-diazepane, 1,4-diazocane, and related macrocyclic compounds with significantly increased substitution diversity on the carbon atoms. The selected natural molecules represent both the state of the art challenges for complex molecule synthesis as well as potential novel therapeutics for various human diseases. However, access of these natural products and their analogs are extremely difficult, which significantly hampered their biomedical development. The N-heterocycles are indispensable structural motifs in medicinal chemistry and exist in many lifesaving drug molecules. However, the substituents are generally limited on the nitrogen atoms and there is a significant lack of substitution diversity on the carbon atoms due to the limitations of the current synthetic methodologies. Our research program will address these gaps. The expected outcomes of this research will provide (i) new reactions and strategies in the toolbox of both medicinal chemists and synthetic chemists to prepare functional molecules, (ii) a collection of medicinally relevant molecules featuring structural novelty, complexity, and diversity for further and larger biological evaluations in academic institutions and pharmaceutical industries, and (iii) novel anticancer, anti- neurodegenerative and antimicrobial lead compounds with potentially novel mode of actions for in vivo and clinical evaluations.

项目总结/摘要 我们研究计划的目标是在有机合成的策略和方法上进行创新， 并将其应用于解决生物学和医学重要性问题，最终影响人类健康。 我们的计划侧重于自然（项目1A-C）和非自然（项目2）的合成和研究 具有治疗癌症、神经障碍和耐药性的特别潜力的分子 传染病在项目1中，我们的目标是合成石蒜素生物碱（1A），桥连大环内酯（1B）， 多环二萜（1C）天然产物及其类似物，并基于这些特权鉴定化合物 新的治疗发展的支架。在项目2中，我们的目标是开发新颖实用的两性 二胺化方法，包括对映选择性的版本，以提供新的途径，N- 杂环化合物，包括哌嗪、1，4-二氮杂环庚烷、1，4-二氮杂环辛烷和相关的大环化合物， 显著增加了碳原子上的取代多样性。所选的天然分子代表了 复杂分子合成的现有技术的挑战以及潜在的新的治疗方法 各种人类疾病。然而，获得这些天然产品及其类似物是极其困难的， 这严重阻碍了他们的生物医学发展。N-杂环是结构上不可缺少的 基序在药物化学中存在，并存在于许多救生药物分子中。然而，取代基是 通常限制在氮原子上，并且在碳原子上显著缺乏取代多样性 由于目前合成方法的限制，我们的研究计划将解决这些问题 差距。本研究的预期成果将提供（i）工具箱中的新反应和战略， 药物化学家和合成化学家来制备功能分子，（ii）药物化学家的集合 具有结构新奇、复杂性和多样性的相关分子，用于进一步和更大的生物学研究。 在学术机构和制药行业的评价，和（iii）新的抗癌，抗肿瘤， 具有潜在的新作用模式的神经变性和抗微生物先导化合物， 临床评价。