基于天然骨架和药物片段构建新型ALR2抑制剂及抗炎作用研究

Aldose reductase (ALR2) is one of the key targets for the research and development of the medicine of antidiabetic complications，and recent research demonstrated it played important roles to a number of inflammatory diseases. Because of current ARIs with low selective inhibition and poor pharmacokinetics, the problem of hypersusceptibility and low curative effect in clinic exists, no ARI is approved by FAD till now,therefore the research and development of new ARI is a need with great meaningful.In the previous Research, we found that the compounds, which were designed and synthesized using curcumin as template, exhibited potent ALR2 inhibitory and anti-inflammatory activities. Meanwhile, it was found that the skeleton of natural product ，Agelastatin， was similar to the structure of Ranirestat which is in the III clinic trials, and the molecular modeling and docking demonstrated that target moleculars exhibited high selective and inhibitory activities agaist ALR2. Therefore, this proposal plans to continously design and synthesize noval small moleculars, with computer aid, based on skeleton of Curcumin analogues or Agelastatin by inserting the characteric fragments of ARIs, study their inhibitory activities, selective inhibition and structure-activity relationship, and keep on optimizing the structure of moleculars till finding new lead compound, meanwhile study the anti-inflammatory activity and related mechanisms.This proposal presents the interdisciplinary combination, which will provide the theory instruction and experimental basis for research and development of new ARI drugs.

醛糖还原酶（ALR2）是糖尿病并发症药物研发的重要靶点，研究证明其在炎症相关疾病中也具有极其重要的作用。由于现有ALR2抑制剂（ARI）选择性低和药动性差，导致临床过敏和疗效问题，还未见FDA认可上市的ARI药物，因而研发新型ARI具有重要意义。在前期研究中，我们发现基于Curcumin骨架设计合成的类似物具有良好的ALR2抑制活性和抗炎作用；同时，在骨架类似搜索中，发现天然产物Agelastatin与临床III期Ranirestat母体相似，分子对接证明其对ALR2具有高度选择抑制作用。因此，本项目拟继续基于Curcumin类似物及Agelastatin骨架，引入ARI特征片段，通过分子模拟对接，设计、合成新型ARI小分子，研究其抑制作用、选择性及构效关系，不断优化分子结构，寻找新型ARI先导化合物，研究其抗炎作用及机理。本项目体现多学科交叉，可为研发新型ARI药物提供理论和实验依据。

在本项目的资助下，开展了姜黄素类化合物的设计、合成及抗炎活性研究和天然产物Agelastatin A衍生物的合成及活性研究工作。研究过程中发现姜黄素类化合物对醛糖还原酶2有较好的抑制活性及选择性，同时对炎症也有较好的抑制效果，为基于醛糖还原酶抑制发展抗炎药物提供了一些有意义的经验。此外，合成了姜黄素-NASIDs复配物及开展了抗炎活性研究，同时探讨了复配物对NASIDs对肝损伤的改善效果。经过条件摸索和优化，成功完成了Agelastatin A的合成，通过中间体合成类结果类似的天然产物，为Agelastatin A的合成提供了一定的借鉴意义。最后，基于片段组合设计，合成了系列喹啉化合物，并进行了醛糖还原酶及拓扑异构酶I抑制活性研究，发现这类化合物通过抑制拓扑异构酶I的途径达到抗炎的效果，这为基于Topo I抑制发展新颖抗炎药物提供新的思路。在研究过程中，培养了1名青年教师、4名博士后及5位研究生、发表了SCI论文22篇及申请专利3件，已实现项目研究的目的。