以咖啡酸苯乙酯为先导物的新型Nrf2激动剂的设计合成、筛选及构效关系研究

Based on Keap1-Nrf2 signaling pathways for sugar metabolic regulation of drug in the body, different from the direct role of sugar metabolism classic drugs, have become a hotspot of the new generation of anti-diabetics drug research. Caffeic acid phenethyl ester, is a promising lead compounds targeted at Keap1-Nrf2 protein. On the basis of the docking results of the CAPE and Keap1-Nrf2 protein, this proposal plans to design and synthesize a series of CAPE, employing the characteristics of Michael addition reaction and building principles and methods of “natural product-like library”, evaluate combined activity with Keap1 enzyme and activation function in the cell and structure-activity relationships, and keep on optimizing the structure of moleculars till finding anti-diabetics drug candidate compounds, meanwhile continue to conform the in vivo effects and pharmacokinetic properties of the candidate compounds by STZ rats experiments and the SAR. This proposal will provide the scientific basis for research of anti-diabetics drugs with unique target, efficiency, low toxicity and druggability, and will produce a great significance and potential application value.

针对Keap1-Nrf2靶蛋白的降糖药物，不同于直接作用糖代谢过程的传统药物，已成为新一代抗糖尿病药物研发的热点。来源于蜂胶的咖啡酸苯乙酯（CAPE）通过体内的tio-Michael加成反应能有效激活Nrf2转录因子，是颇具前景的抗糖尿病先导化合物。但是CAPE分子中各官能团的药效作用仍不明确，且生物代谢的不稳定制约了其应用。本项目以CAPE为先导物，基于CAPE与Keap1蛋白的对接结果、Michael加成反应的特点及“类天然产物库”构建原理和方法，设计合成系列CAPE衍生物；研究其与Keap1蛋白的结合及细胞内活性，不断优化分子结构，寻找降糖药物候选化合物。采用STZ大鼠模型，确认候选化合物的体内药效，用Wistar大鼠模型研究药代动力学性质；总结构效和构动关系，明确CAPE衍生物各官能团的药效作用，提高代谢稳定性，为研发高效、成药性好，且作用靶点独特的新型抗糖尿病药物提供科学依据。

Keap1-Nrf2靶点是新一代的降糖药物研究的热点。本项目基于已有的咖啡酸苯乙酯（CAPE）的构效关系，以CAPE为先导物，基于CAPE与Keap1蛋白的对接结果、Michael加成反应的特点及“类天然产物库”构建原理和方法，设计合成了4类CAPE衍生物共200多个；体内外实验表明，部分化合物有较好的成药性。不断优化分子结构，寻找到了降糖药物候选化合物。最后，采用STZ大鼠模型，确认候选化合物的体内药效，用Wistar大鼠模型研究药代动力学性质；总结构效和构动关系，明确了CAPE衍生物各官能团的药效作用，提高代谢稳定性，为研发高效、成药性好，且作用靶点独特的新型抗糖尿病药物提供了科学依据和进一步研发的目标。