2,7-萘啶酮类天然产物NPD01及其结构衍生物的全合成和生物活性研究

Diabetes mellitus (DM) has become the third chronic non-communicable disease threatening human health. Studies have shown that insufficient insulin secretion, insulin resistance and dyslipidemia caused by excessive glucocorticoid (GC) are the main causes of type 2 diabetes mellitus (T2DM). The 11β-HSD protein family is the key enzyme in the process of GC transformation and accumulation. 11β-HSD1 inhibitors with high selectivity can block the excessive accumulation of GC and interfere with the development of diabetes mellitus, which has become a research and development hotspot in the field of diabetes prevention and treatment. NPD01, as a leading anti-diabetic compound, has considerable research value. However, the defects of the natural leading compounds, such as their low content and the scarcity of sources, limit the further mechanism study. Therefore, this project intends to carry out the total synthesis of the leading compound NPD01, which can provide fundamental research for the synthesis of 2,7-naphthyl drugs. The structure of NPD01 was simplified and modified, and a series of derivatives were obtained and active molecules were screened out subsequently. Based on the above work, the main pharmacodynamic functional groups and the optimum active configuration of NPD01 analogues and the preliminary pharmacological mechanism of anti-diabetes in vivo and in vitro were explored. This project will lay a foundation for elucidating the structure-activity relationship of the 11β-HSD1 inhibitory activity of naphthodinone alkaloids and the development of new anti-diabetic drugs in the future.

糖尿病（DM）已成为对人类健康威胁性居于第三位的慢性非传染性疾病。研究表明，过量的糖皮质激素（GC）引发的胰岛素分泌不足、胰岛素抵抗及脂代谢紊乱是2型糖尿病（T2DM）的主要诱因。11β-HSD蛋白被证实是机体GC转化和累积过程的关键酶。高选择性的11β-HSD1抑制剂可阻断GC的过量富积，干预糖尿病发生发展，已成为糖尿病预防治疗领域研发热点。项目前期分离出具备显著11β-HSD1抑制活性的天然产物NPD01，与靶蛋白11β-HSD1的结合表现出独特的立体特异性，具有相当的研究价值。但天然产物含量低，来源匮乏的现状限制了生物活性及作用机制研究工作。.本研究拟在前期研究基础上采用化学方法完成先导物NPD01的全合成，突破来源及物料限制；通过结构修饰筛选活性分子，探究主要药效官能团及最优活性构型，开展初步抗糖尿病药理作用机制研究，为新型抗糖尿病药物的研发提供新思路。

.项目前期分离出具备显著11β-HSD1抑制活性的天然产物NPD01，其与靶蛋白11β-HSD1的结合表现出独特的立体特异性，可作为抗糖尿病的先导化合物。但天然产物含量低，来源匮乏的现状限制了生物活性及作用机制研究工作。本研究原计划采用化学全合成的手段对具有突出11β-HSD1抑制活性的天然产物NPD01进行人工合成，在此过程中，同步开展针对先导化合物NPD01的结构修饰及活性筛查，以期确证其药效官能团及最优活性构型，在此基础上进一步探究该类分子的糖尿病治疗效果及其药理作用机制，为抗糖尿病药物的研发提供参考。.在课题推进过程中，先导化合物NPD01全合成工作的核心难题在于构建含有多个四元立体中心（ACQS）的萘啶酮杂环骨架。受刚性三维结构的影响，ACQS分子往往具有独特的生理药理活性，因而被广泛应用于医药领域。有鉴于此，在过去几十年中，ACQS分子骨架的构建一直是有机合成领域备受关注的挑战性课题之一。目前，研究团队成功合成了合成砌块BD1，但在核心难题——萘啶酮骨架构建上面临巨大的挑战。我们尝试了多种手段均未能搭建出与先导化合物NPD01手性表征一致的ACQS萘啶酮骨架，研究者后续将继续探究NPD01的全合成及药理研究工作。尽管未能成功构建目标ACQS萘啶酮杂环，但在骨架搭建方法研究过程中，研究者利用烯烃双官能团化反应成功开发出两个分别针对ACQS琥珀酰二胺及喹啉酮骨架的高效合成策略。其中ACQS琥珀酰二胺合成策略利用廉价易得的草酰氨酸为酰基自由基前体，在Ag+/S2O82-催化氧化体系作用下，经由一个串联的脱羧/氨基甲酰基化/脱磺酰化/芳基迁移程序，便捷高效的实现了目标分子的构建。此外，反应对水和氧的出色耐受性，操作的简捷性，广泛的底物适用范围进一步提高了该方法学的实用价值，为ACQS琥珀酰二胺类化合物的合成提供新思路。本项目已发表SCI论文1篇（通讯作者，第一标注），培养研究生1名，本科毕业生8名。