Synthesis and Study of Medicinally Important Molecules

项目摘要/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， 并将其应用于解决具有生物和医学重要性的问题，并最终影响人类健康。 我们的项目专注于自然(项目1A-C)和非自然(项目2)的合成和研究 具有治疗癌症、神经疾病和抗药性的特殊潜力的分子 传染病。在项目1中，我们的目标是合成Lyconadin生物碱(1A)、桥联大环内酯(1B)和 多环二萜(1C)天然产物及其类似物，并根据这些特权鉴定化合物 用于新的治疗开发的支架。在项目2中，我们的目标是开发出新颖实用的两性产品 二胺化方法，包括对映体选择性版本，以提供新的途径，以N- 杂环化合物，包括哌嗪、1，4-二氮杂环、1，4-重氮杂环和相关的大环化合物 显著增加了碳原子上的取代多样性。选定的天然分子代表 复杂分子合成的最新挑战以及潜在的新疗法 各种人类疾病。然而，这些天然产物及其类似物的获取极其困难， 这严重阻碍了他们的生物医学发展。N-杂环是不可缺少的结构 基序存在于药物化学中，存在于许多救命药物分子中。然而，取代基是 一般仅限于氮原子，而碳原子上的取代多样性严重不足 原子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。这项研究的预期结果将提供(I)工具箱中的新反应和策略 药物化学家和合成化学家都要准备功能分子，(Ii)收集药用 具有结构新颖性、复杂性和多样性的相关分子，可用于更远更大的生物 学术机构和制药行业的评估，以及(Iii)新的抗癌、抗癌和 具有潜在体内和体内作用新模式的神经退行性和抗微生物先导化合物 临床评估。

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.