胰岛beta细胞的功能受损或数量减少是2型糖尿病发生及恶化的决定性因素，因此避免其凋亡，恢复其数量和功能是2型糖尿病药物未来发展的方向。前期研究发现老药长春胺盐酸盐在db/db和STZ/HFD诱导的糖尿病小鼠模型上具有显著的抗2型糖尿病活性。分析数据发现其在 HF/STZ 模型上的药效比在 db/db 上的要好；进一步分析它们的胰腺切片，在两种动物模型上发现均显著改善了胰岛细胞的受损状况，因此，我们提出假说：长春胺可能是通过改善胰岛细胞的受损状况，从而改善2型糖尿病症状。进一步实验研究发现长春胺对受到STZ刺激导致胰岛beta细胞凋亡具有保护作用。本项目将重点开展长春胺抗胰岛细胞凋亡作用的分子机制研究；探索它的化学反应性，并进行系统的结构修饰，总结长春胺的结构与抗胰岛beta细胞凋亡的构效关系，为胰岛beta细胞凋亡保护剂及其新药发现提供可靠的科学依据。

The reduced pancreatic beta-cell mass and impaired function are fundamental to the pathogenesis and development of type 2 diabetes mellitus (T2DM), thus prevent beta-cell apoptosis, restore its mass and function is the direction for the future development of anti-T2DM drugs. In our previous study, we found vincamine treatment significantly improved glucose homeostasis in db/db and HF/STZ mice, as reflected by its functions in increasing plasma insulin concentration, protecting the pancreatic beta-cells from damage, decreasing fasting blood glucose and glycated hemoglobin (HbA1c), improving OGTT. It protected beta-cells from the STZ-induced apoptosis in MIN6 cells. Vincamine showed potent in vitro and in vivo activities, cheap supply, good drugabilities and IP available, therefore, it is a good anti-T2DM drug lead for further structural optimization. In this project, we will focus on clarifying its mechanism of beta-cell protection, exploring its chemical properties, preparing its derivative libraries with structure-diversity, synthesizing enough analogues in each type library, testing their in vitro protecting beta-cells against STZ-induced cell death, summing up the structure-activity relationship; evaluating drug-like properties and in vivo anti-T2DM activities of several selected derivatives with high in vitro activities. Our research will provide reliable scientific data for studies on anti-T2DM drug candidates with protecting beta-cell apoptosis.