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。

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.