3-取代吲哚酮类抗癌药物对抗神经退行性疾病之进展

Research progress of anti-cancer 3-substituted indolines against neurodegenerative disorders

3-取代吲哚酮类化合物设计通过竞争性抑制多种受体酪氨酸激酶对抗肿瘤,其中舒尼替尼、靛玉红等多个化合物已在临床用于肾细胞癌、胃肠间质瘤等治疗。最近研究发现3-取代吲哚酮类化合物在多种细胞、动物模型发挥神经保护活性,可能治疗帕金森病、阿尔兹海默症等神经退行性疾病。本文系统综述3-取代吲哚酮类化合物通过作用于c-Jun氨基末端激酶、糖原合成酶激酶-3β、细胞周期素依赖性激酶-5、肌细胞增强因子-2、神经元性一氧化氮合酶、乙酰胆碱酯酶、单胺氧化酶-B等多个靶点,产生神经保护的作用机制,并展望这类化合物“老药新用”对抗神经退行性疾病的可能性。

3-substituted indolines could competitively inhibit multiple receptor tyrosine kinases,and therefore reduce the growth of cancer cells.Sunitinib and indirubin-3-oxime,two 3-substituted indolines,are clinically used in the treatment of renal cell carcinoma and gastrointestinal stromal tumor.Recently,it has been discovered that these 3-substituted indolines could produce neuroprotective effects in various cellular and animal models,indicating that they may also be used in the treatment of neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s disease in particular.In this review,we focus on the molecular mechanisms underlying the neuroprotective effects produced by 3-substituted indolines via multiple targets,such as JNK,glycogen synthase kinase-3β,cyclin-dependent kinase-5,myocyte,enhancer factor-2,neuronal nitric oxide synthase,acetylcholinesterase and monoamine oxidase-B.We have also discussed the perspective of the development of 3-substituted indolines as novel treatments for neurodegenerative disorders.