长春胺抗胰岛beta细胞凋亡作用机制及其构效关系研究

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.

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。

本项目前期研究发现长春胺盐酸盐在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。胰腺切片分析发现在两种动物模型上长春胺均显著改善了胰岛β细胞的受损状况，进一步实验研究发现长春胺对STZ刺激导致的胰岛β细胞凋亡具有保护作用。在此基础上，本项目重点开展了长春胺抗胰岛β细胞凋亡作用的分子机制研究；探索它的化学反应性，在其易进行官能团化的C14位和C10位进行了系统的结构改造，设计合成了A~J共十大类化合物库，约100个化合物。通过体外测试这些化合物对STZ诱导损伤的胰岛β细胞的保护活性，初步总结了其结构与胰岛β细胞凋亡保护作用的构效关系，并得到11个细胞活性显著提高的衍生物，其活性较先导化合物长春胺提高了11~55倍。体内药效评价显示化合物Vin-B04能够降低db/db糖尿病小鼠的空腹血糖水平，改善口服糖耐量，降低血清中糖化血红蛋白水平。相关作用机制研究表明该类衍生物是通过IRS2/PI3K/Akt信号通路发挥保护β细胞的作用，逆转STZ诱导的细胞凋亡，促进β细胞生存。本项目通过系统的药效学评价最终发现了2个具有新颖作用机制的抗2型糖尿病药物候选物。

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