以NF-κB/IKK为靶点的大环蒽醌类似物的合成与抗炎活性构效关系研究

Alzheimer's disease is a devastating neurodegenerative disorder of unknown pathogenesis. Inflammatory responses characterized by NF kappa B activation contribute to the formation and development of the pathogenesis. It is very important for us to look for safe small molecule inhibitors to regulate IKK/NF-kappa B signaling pathway in Alzheimer's disease. Rhein can regulate inflammatory response by inhibiting the activity of protein kinase IKK. We synthesized some macrocyclic anthraquinone derivatives and evaluated the anti-inflammatory activity in vitro. According to the previous study, macrocyclic anthraquinone derivatives can inhibit the release of nitric oxide and downregulate the protein expression such as interleukin (beta 1, 6), tumor necrosis factor (TNF alpha) in microglia cells. Before our research work, there was little report about the modification and structure-activity relationship of macrocyclic anthraquinone derivatives. On this basis, this project intends to rationally design the macrocyclic anthraquinone derivatives targeted IKK protein kinase by bioisosterism and soft drug design principle. These new compounds would be screened on their anti-inflammatory activity in vivo and in vitro which induced the NF kappa B/IKK signaling pathway. The establishment of the structure-activity relationship could help directly for the continued development of macrocyclic anthraquinone derivatives applied in clinical treatment of Alzheimer's disease in future.

阿尔茨海默症是一种进行性神经系统退行性疾病，其中NF-кB信号引起的炎症反应是其发生和发展的重要因素。因此通过小分子抑制剂调控IKK/NF-кB信号对于阿尔茨海默症的控制和治疗具有重要意义。大黄酸能通过抑制IKK蛋白激酶的活性而抑制炎症。申请人前期合成了系列大环蒽醌类大黄酸衍生物，拥有比大黄酸更好的体外抗炎活性，能够通过抑制小胶质细胞中一氧化氮的释放，影响白介素1β和6，肿瘤坏死因子等蛋白表达。目前，针对大环蒽醌类衍生物在抗炎活性方面的结构修饰及机制研究不够深入系统。在此基础上，本课题拟以IKK蛋白激酶为靶标，利用生物电子等排和软药设计原理，合理设计大环蒽醌类衍生物，通过测定IKKβ激酶的活性，细胞NO的释放及相关信号通路调控，考察对AD大鼠的干预。期望在阐明其抗炎作用机制的同时建立构效关系模型，最终为大环蒽醌类衍生物在阿尔兹海默症上的应用提供理论依据。

慢性炎症反应是阿尔茨海默病(AD) 发生发展的重要病理过程，IKK/NF-κB信号途径与炎症的发生、发展具有密切关系。随着IKKβ晶体结构的解析，针对该信号途径的靶向性小分子抑制剂的研发逐渐成为近年来研究的热点。本项目以大环蒽醌的基本骨架为先导化合物，利用生物电子等排和前药设计的理论对大环蒽醌骨架进行优化，引入新的杂环和不同系列亲水疏水取代基，设计并合成45个新型蒽醌衍生物，体外考察新类似物的抗炎活性，总结了化合物的结构和抗炎活性的构效关系，发现在蒽醌的母核上引入含氮杂环能够提高抗炎活性。其体外抗炎能力也与中间连接的碳链的个数有关，当碳链的长度为4时，抗炎活性最强，并获得了一个高效低毒的小分子抑制剂。该类化合物的作用机制为：通过抑制IKBα的磷酸化使得IKK/NF-κB蛋白复合物的稳定，阻止NF-κB进入细胞核，最终控制下游蛋白iNOS和COX2的表达，从而降低炎性因子TNF-α，IL-1β，IL-6，IL-10的释放，发挥抗炎活性。IKK/NF-κB抑制剂的研发，不仅有助于新一代抗炎免疫药物的发现，也可为这类药物进一步用于炎症引起的其他众多疾病提供理论依据。