多靶点抗糖尿病并发症药物先导物-基于喹喔啉酮的设计与构效关系研究

Diabetic complications, such as neuropathy, nephropathy, cataracts, retinopathy, together with cardio-cerebral vascular disease and cancer are top causes of morbidity and mortality in the world, but no specific drug is available. A growing body of research suggests that the complications are related to the polyol pathway catalyzed by aldose reductase and activated under hyperglycaemic conditions, and that the accumulation of sobitol produced in the pathway and the induced oxidative stress in the downstream are key causal mechanisms of diabetic complications. Moreover, oxidative stress also makes the enzyme desensitized to its inhibitors. Therefore, multitargeted strategy of simultaneous suppression of aldose reductase and oxidative stress will be key to the development of drugs for the treatment of diabetic complications. Most of the known aldose reductase inhibitors (ARIs) have shortages such as side effects or the insufficiency of efficiency in vivo and are lack of antioxidative function, and thus development of new ARIs is needed. We have recently developed several groups of ARIs, of which quinoxalinones showed distinguished activity and some antioxident activity. The present study will focus on effects of phenolic hydroxyl groups systematically substituted in the aromatic ring of the C-3 side chain or the framework and of other substituents, and then on the further optimization by structure-relationship studies in order to obtain multitargeted ARIs as more effective drug candidates of antidiabetic complications.

糖尿病并发症如肾、视网膜和神经系统疾病，与心血管疾病和癌症同为发病率和死亡率最高的疾病，目前全球缺乏针对性药物。越来越多的研究表明，高血糖条件下，醛糖还原酶为限速酶的多元醇途径激活与糖尿病并发症高度相关，其中，糖代谢产物山梨醇积累及伴生的氧化应激是主要疾病成因。氧化应激还反馈性钝化醛糖还原酶对抑制剂的敏感性。因此,同时遏制醛糖还原酶及氧化应激的多靶点策略是新药创制的关键。目前的经典抑制剂或具毒副作用或体内有效性低，也不具备抗氧化作用。我们近年设计合成了多种新型抑制剂，其中，喹喔啉酮类表现突出，其抗氧化设计也初见成果，这为进一步多靶点抗糖尿病并发症的新型高效抑制剂开发提供了基础。本项目将以喹喔啉酮为结构平台，对该侧链的芳环或喹喔啉酮母核的芳环配置以酚羟基，同时考察其它取代基的效应，通过构效关系研究、系统优化分子的结构配置，由此将抗氧化特性导入目标分子、构建多靶点的高效醛糖还原酶抑制剂。

糖尿病并发症如肾、视网膜和神经系统疾病，与心血管疾病和癌症同为发病率和死亡率最高的疾病。越来越多的研究表明，高血糖条件下，醛糖还原酶为限速酶的多元醇途径激活与糖尿病并发症高度相关，其中，糖代谢产物山梨醇积累及伴生的氧化应激是主要疾病成因。氧化应激还反馈性钝化醛糖还原酶对抑制剂的敏感性。因此,同时遏制醛糖还原酶及氧化应激的多靶点策略是新药创制的关键。.在本项目中，我们设计并获得了多个系列的喹喔啉酮类目标化合物，并通过体外生物活性实验及构效关系分析表明了此类衍生物为具有抗氧化活性的高效多功能醛糖还原酶抑制剂，同时筛选出了体外活性最优的目标化合物。之后利用链脲佐菌素糖尿病小鼠模型和db/db糖尿病小鼠模型对其进行体内生物活性评价。在构效关系研究中发现，化合物C3位苯乙烯侧链和酚羟基的引入能够明显提高酶抑制活性以及抗氧化活性。另外，将羧基侧链替换为三氟甲磺酰胺基侧链可以大幅度的提高了化合物的体外抗氧化活性，同时有效地提高化合物的亲脂性，改善化合物的脂水分配。在体内活性研究中发现，目标化合物可以有效地改善模型动物中的脂质过氧化物、氧化氢酶和甘油三酯的水平，表现了较强的抗氧化活性。. 通过本项目的研究，尤其是根据体外构效关系的结论和体内抗氧化活性的验证，为后续的研究即开发多功能和多靶点醛糖还原酶抑制剂研究提供了研究基础和依据。