先导化合物Fla-CN的结构优化、抗糖尿病作用分子机制及其靶点研究

本课题前期发现黄酮衍生物1（Fla-CN）对糖代谢、脂代谢和炎症相关转录因子和关键信号分子具有广泛的基因调控作用，进一步发现Fla-CN对靶向多个转录因子的microRNA (miR-33a/b, miR-29b/c)具有显著调控作用，从而通过作用于microRNA而实现其多靶点的抗糖尿病作用。本课题以具有新颖作用机制的、新黄酮骨架结构Fla-CN为先导化合物，以前期合成探索及活性代谢产物研究结果为设计依据进行结构优化；运用分子细胞药理学手段研究阐明Fla-CN抗糖尿病作用分子机制；并以Fla-CN为活性基团合成功能各异的两类探针分子，用于定位活性化合物在细胞及体内的靶向分布和垂钓靶点，并以高分辨质谱鉴定与探针结合的靶点分子，最后通过优选活性衍生物的体内药效评价发现成药性更高的新药候选化合物。

Flavone derivative 1 (Fla-CN) regulated many genes of transcription factors and signaling molecules related to glycometabolism, lipid metabolism, and inflammation. In addition, Fla-CN significantly regulated microRNAs (miR-33a/b, miR-29b/c) that target several transcription factors, and resulted in multi-target of antidiabetic effects. On the basis of above finding, we study on the structural optimization of lead compound Fla-CN according to pre-synthesized active derivatives and active metabolites of fla-CN. The molecular mechanism of fla-CN is demonstrated by using molecular pharmacological method. Furthermore, the different functions of the two types of probe molecules are designed and synthesized by using the active group of fla-CN, used to locate the active compound in vitro/in vivo distribution and fishing combined with the probe target molecules, and then identified the target molecules by ultra-high resolution mass, in orther to discover a potential new target for anti-diabetic drugs; Finally, the new drug candidates are found by in vivo evaluation on active derivatives of fla-CN.