基于二氢色原酮骨架新类似物的设计合成与其降糖活性构效关系研究

Diabetes mellitus is a common chronic disease characterized by high level of blood glucose, insulin resistance and abnormal insulin secretion，it has a serious threat to our health of human kind. In all, it's very important for us to look for safe and high performance anti-hyperglycemic activity drug from natural products. According to the previous study on the synthesis and anti-hyperglycemic evaluation of dihydro chromone-hesperetin ether and ester compounds, these compounds have good anti-hyperglycemic activities and their binding mechanism with peroxysome proliferator-activated receptor (PPAR-γ) have also been revealed by computer-aided design. Before our research work, there was little report about the modification and structure-activity relationship of dihydro chromone -hesperetin. Therefore, new analogues of dihydro chromone will be designed via PPAR-γ ( as receptor) and dihydro chromone skeleton-based novel compound (as ligand) with computer-aided design (Accelrys Discovery Studio 2.5 software). These new designed compounds would be synthesized and screened on their anti-hyperglycemic activities with the effects of functional factors which induced the impairment of β cell function and insulin resistance. After that, the structure-activity relationship (SAR) between dihydro chromone analogues and anti-hyperglycemic activities should be established. The establishment of SAR could help direct for the continued development of dihydro chromone analogues as anti-hyperglycemic drug in the future.

糖尿病是一种表现为高血糖，胰岛素抵抗和胰岛素分泌紊乱的常见慢性疾病，对人类身心健康具有严重的威胁，因此，从天然产物中寻找安全高效的降糖药物具有重要的意义。本项目前期通过合成二氢色原酮-橙皮素醚、酯类化合物发现其具有降糖活性，并通过计算机辅助药物设计，研究了该类化合物与过氧化物酶体增殖物激活受体(PPAR-γ)的结合机制。此前，针对二氢色原酮-橙皮素在降糖活性方面的结构修饰及构效关系研究，很少有文献报道。因此，本项目基于二氢色原酮的基本骨架，利用PPAR-γ为初选靶点，通过计算机Accelrys Discovery Studio 2.5软件辅助，有针对性的设计合成二氢色原酮新类似物，并通过测定引起β细胞功能受损和胰岛素抵抗功能因子的活性，验证新类似物的降糖作用。在阐明类似物降糖机制的同时，建立构效关系模型，为后续二氢色原酮类似物降糖药物的开发提供一定的借鉴。

项目基于二氢色原酮的基本骨架，利用PPAR-γ为初选靶点，通过计算机Accelrys Discovery Studio 2.5软件辅助，有针对性的设计合成二氢色原酮新类似物约200个，并通过蛋白质印迹法(Western Blot), 测定引起β细胞功能受损和胰岛素抵抗功能因子的活性，验证和阐明了新类似物的降糖信号通路机制，同时建立构效关系模型。另外，基于脂多糖和D-氨基半乳糖诱导的小鼠急性肝损伤为模型还开展类似物的抗炎和抗氧化活性机制研究。这些研究为后续二氢色原酮类似物降糖药物的开发提供一定的借鉴。