药学学报

喹啉和异喹啉衍生物抗阿尔茨海默症的研究进展

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刘圆秀 , 符志杨 , 关丽萍 ^*

药学学报 | 综述 2026,61(1): 94-108

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药学学报 |综述 2026 , 61 (1) : 94 -108

喹啉和异喹啉衍生物抗阿尔茨海默症的研究进展

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刘圆秀, 符志杨, 关丽萍^*

作者信息

浙江海洋大学食品与药学学院, 浙江舟山 316000

通讯作者:

关丽萍, Tel: 13675809982, E-mail: glp730@zjou.edu.cn

作者简介:

作者贡献:

刘圆秀负责综述框架设计、资料收集和撰写; 符志杨负责对文章进行指导与修改; 关丽萍负责综述选题指导与资源支持。

Research progress of quinoline and isoquinoline derivatives against Alzheimer's disease

Yuan-xiu LIU, Zhi-yang FU, Li-ping GUAN^*

Affiliations

College of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316000, China

出版时间: 2026-01-12 doi: 10.16438/j.0513-4870.2025-0264

文章导航

摘要

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阿尔茨海默症(Alzheimer's disease, AD)作为一种常见的神经退行性疾病, 严重影响患者的认知功能和生活质量, 且目前尚无根治性疗法。因此, 迫切需要探索并开发具有潜力的新型药物分子。喹啉和异喹啉类衍生物因其多样的药理活性, 特别是在抑制β-淀粉样蛋白(amyloid β-protein, Aβ)聚集、减少微管相关单元(tubulin-associated unit, Tau)蛋白磷酸化、调节胆碱能系统以及抗炎和抗氧化应激等方面, 已成为抗AD研究中的重要候选分子。本文综述了喹啉和异喹啉衍生物在抗AD研究中的最新进展, 重点探讨其在体内外生物学评价中的表现, 并阐明其在抗Aβ积聚、调节Tau蛋白去磷酸化、改善胆碱能系统失衡以及抑制神经炎症反应等方面的作用机制, 为喹啉和异喹啉衍生物在AD治疗中的进一步研究提供参考。

关键词

喹啉 / 异喹啉 / 阿尔茨海默症 / 生物学评价 / 作用机制

Abstract

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Alzheimer's disease (AD), a prevalent neurodegenerative disorder, significantly impairs patients' cognitive functions and quality of life, with no definitive cure currently available. Consequently, there is an urgent necessity to explore and develop promising novel drug molecules. Quinoline and isoquinoline derivatives have emerged as key candidates in AD research owing to their diverse pharmacological activities, particularly in inhibiting the aggregation of amyloid β-protein (Aβ), reducing the phosphorylation of tubulin-associated unit (Tau) proteins, modulating the cholinergic system, and exhibiting anti-inflammatory and antioxidant properties. This article provides an overview of the latest advancements in the study of quinoline and isoquinoline derivatives for AD, emphasizing their performance in both in vitro and in vivo biological evaluations. It further elucidates their mechanisms of action in combating Aβ accumulation, regulating Tau dephosphorylation, ameliorating cholinergic system imbalances, and suppressing neuroinflammatory responses, serving as a reference for further research into the application of quinoline and isoquinoline derivatives in AD treatment.

Key words

quinoline / isoquinoline / Alzheimer's disease / biological evaluation / mechanism of action

引用本文

刘圆秀, 符志杨, 关丽萍. 喹啉和异喹啉衍生物抗阿尔茨海默症的研究进展. 药学学报, 2026 , 61 (1) : 94 -108 . DOI: 10.16438/j.0513-4870.2025-0264

Yuan-xiu LIU, Zhi-yang FU, Li-ping GUAN. Research progress of quinoline and isoquinoline derivatives against Alzheimer's disease[J]. Acta Pharmaceutica Sinica, 2026 , 61 (1) : 94 -108 . DOI: 10.16438/j.0513-4870.2025-0264

正文

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据统计, 全球目前约有5 500万人罹患痴呆, 其中阿尔茨海默症(Alzheimer′s disease, AD)约占病例总数的60%~70%^{[1, 2]}。目前, 我国AD疾病负担呈现快速增长趋势: 至2050年我国AD患者总数将突破3 000万例, 较2020年增长逾一倍^{[3, 4]}。同期全球AD患者规模预计攀升至1.52亿例, 提示该疾病正成为21世纪严峻的公共卫生挑战之一^[5]。AD的主要临床特征包括进行性记忆丧失、认知功能下降以及行为和心理症状, 这些症状不仅显著降低了患者的生活质量, 也为家人和社会经济体系带来了沉重负担^{[6, 7]}。

AD的病理机制较为复杂, 由多个因素共同作用(图1)。AD的核心病理学特征包括大脑中β淀粉样蛋白(amyloid β-protein, Aβ)的异常积聚、微管相关单元(tubulin-associated unit, Tau)蛋白的过度磷酸化, 导致神经元内神经纤维缠结(neurofibrillary tangles, NFTs), 进而引发神经元的功能受损和死亡^[8-10]。胆碱能系统的失衡导致大脑皮层和海马等关键区域的乙酰胆碱(acetylcholine, ACh)水平显著下降, 加剧神经元信号传导效率的恶化^{[11, 12]}。小胶质细胞的过度激活和促炎因子的释放, 会导致慢性神经炎症的发生, 加剧神经元的损伤^{[13, 14]}。氧化应激引起的线粒体功能障碍和自由基的积累, 进一步推动了疾病的恶化^[15]。这些病理机制相互作用, 最终共同驱动神经元凋亡与认知功能衰退。

尽管现有治疗AD的方法有所进展, 主要药物如胆碱酯酶抑制剂(如多奈哌齐、利凡斯的明)和N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体拮抗剂(如美金刚)能够改善神经递质功能^[16-18], 但只能短期内缓解症状, 无法阻止疾病持续发展, 且常伴随胃肠道不适和神经系统不良反应等^[19]。因此, 开发更高效且不良反应更少的治疗方法, 成为应对AD这一全球性挑战的关键方向。

喹啉和异喹啉是重要的杂环化合物, 近年来, 研究人员发现其衍生物具有广泛的生物活性, 例如抗菌^[20]、抗病毒^[21]、抗疟疾^{[22, 23]}、抗氧化^{[24, 25]}、抗炎^[26]、抗惊厥^[27]、镇痛^[27]、抗癌^[27]等, 在神经系统疾病的研究中也展现出优异潜力^[28], 成为AD治疗潜在药物分子的理想候选。AD作为多因子交织的神经退行性疾病, 单一靶点干预往往难以逆转其病理级联反应^[29], 而喹啉和异喹啉衍生物因其内在多靶点属性成为构建联合治疗方案的理想基石^{[30, 31]}。近年来, 研究人员已成功开发出多种喹啉和异喹啉衍生物, 可通过多种独立通路实现对AD的有效干预(图2), 同时也展现出独特的联合增效潜力, 例如喹啉衍生物环丙沙星与亚精胺联用通过协同调节铁死亡关键靶点并增强抗氧化防御, 能够显著改善AD模型大鼠认知功能与神经元损伤^[32]。异喹啉衍生物加兰他敏与喹啉衍生物西洛他唑联用通过增强胆碱能传递、改善脑血流及抑制神经炎症的协同作用, 能够显著提升AD患者的认知、情感及日常功能^[33]。喹啉衍生物氯碘羟喹(chloroquine, CQ)与二氢嘧啶硫酮通过金属依赖机制协同降低Aβ水平并恢复囊泡运输功能, 在酵母和线虫模型中显著减轻神经毒性且减少CQ单药引发的线粒体不良反应^[34]。

尽管喹啉和异喹啉衍生物在抗AD的潜在应用中展现出一定的研究价值, 但在药代动力学特性、安全性和临床转化方面仍面临诸多挑战, 其系统研究仍存在明显滞后性, 仍需开展广泛而深入的研究, 推动其从实验室走向临床的进程^{[35, 36]}。

因此, 通过对现有文献的分析, 本文系统综述了喹啉和异喹啉衍生物抗AD时在体内外生物学评价中的表现, 揭示了这些化合物在多个关键病理环节中的潜在作用, 并分析了这些化合物在AD治疗中的相关分子机制。希望能够为喹啉和异喹啉类化合物向AD临床治疗的转化提供参考。

1　喹啉衍生物抗AD的生物学评价及作用机制

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喹啉具有较强的芳香性和分子刚性, 结构稳定, 在药物设计中被广泛应用^{[37, 38]}。其结构中的氮原子位于1号位置, 其给电子效应使得喹啉及其衍生物与金属离子的配位更加牢固, 能够有效调节细胞内金属离子浓度, 发挥清除自由基、减轻氧化应激反应等潜在的生物活性^[39]。其取代基的电子效应和空间效应对化合物的生物活性也有显著的影响(图3)。2位取代基的电子性质显著影响靶标选择性: 吸电子基通过降低环电子密度增强与酶的相互作用, 并诱导电荷极化以稳定酶-底物过渡态^[40], 而供电子基可通过氢键作用干扰生物大分子构象, 实现选择性抑制^[41]; 4位若引入极性基团能改善水溶性但会限制跨膜渗透^[42]; 6位引入小体积电负性取代基可通过屏蔽氧化敏感位点延长半衰期, 同时平衡分子的亲疏水性以优化细胞内浓度^[43]; 8位氧化还原活性基团则通过生物转化生成活性代谢物, 其还原产物在降低毒性的同时需结合靶向递送策略以提升选择性^[44]; 喹啉3位的烷基或烯基取代可通过无金属催化反应实现绿色合成, 其空间位阻对分子构象和靶标适配性具有调控作用^[45]; 7位取代基体积的精细调节则直接影响与靶标结合腔的空间匹配度, 成为活性优化的重要维度^[46]。此外, 喹啉的芳香环结构通过π-π堆积效应增强了与受体分子的结合能力, 提高了药物的靶向性^[47]。

1.1　Aβ聚集抑制与清除

Aβ是一种由40~42个氨基酸组成的短肽, 主要来源于淀粉样前体蛋白(amyloid precursor protein, APP)的异常切割^[48]。在健康个体中, APP主要通过非淀粉样途径被α-分泌酶切割, 生成无毒片段。但在AD患者中, APP主要通过β-分泌酶(β-secretase)和γ-分泌酶(γ-secretase)的切割, 生成具有神经毒性的Aβ肽^{[49, 50]}。Aβ肽在细胞外液中具有自我聚集的倾向, 形成从单体到寡聚体、纤维和最终的淀粉样斑块的多种结构^[51]。喹啉衍生物可以通过多种机制干预Aβ肽的自聚集和清除, 展现出减缓Aβ沉积的能力。

2020年, Rana等^[52]以喹啉为母核, 引入重氮芳基团, 通过分子对接指导设计抑制剂: 通过π-π堆积干扰Aβ纤维化, 并与胆碱酯酶(acetylcholinesterase, AChE)催化位点(catalytic site, CAS)和外周阴离子位点(peripheral anionic site, PAS)结合, 抑制ACh水解。在体外硫黄素T (thioflavin T, ThT)荧光实验中发现, 喹啉类化合物对Aβ的纤维化聚集抑制率在49.6%~77.2%之间。化合物1 (IC₅₀ = 6.2 µmol·L^-1)和2 (IC₅₀ = 7.0 µmol·L^-1, 图4)还表现出显著抗AChE活性, 展现了双重药理活性。Neuro-2a细胞毒性测试显示, 这些化合物均具有较高的安全性。但这些化合物其对丁酰胆碱酯酶(butyrocholinesterase, BuChE)的抑制活性较弱, 结构仍有优化空间。2022年, Albuquerque等^[53]结合类固醇的膜渗透性与喹啉的抗聚集能力, 通过框架组合策略设计杂化分子。ThT荧光实验结果表明, 喹啉类化合物3 (图4)能够显著延缓Aβ聚集过程的指数增长阶段, 减少聚集体的形成量。细胞实验验证, 这些类固醇-喹啉杂合物能够显著减少预聚集Aβ的数量和平均面积。

近年来的研究表明, 金属离子(尤其是Zn²⁺和Cu²⁺)能够显著促进Aβ的聚集^{[54, 55]}。2012年, 在一项小型Ⅱ期临床试验(NCT00112785)中, 喹啉衍生物CQ (4, 图4)通过重新分配金属离子来靶向Aβ和金属离子之间的相互作用, 减小了AD受试者的认知能力下降率^[56]。2018年, Yang等^[57]将8-羟基喹啉与肉桂酸通过哌嗪环连接, 设计多靶点抑制剂。合成的喹啉衍生物5 (图4)通过螯合Aβ-Cu²⁺/Zn²⁺复合物, 阻断金属诱导的Aβ聚集及反应性氧物种(reactive oxygen species, ROS)生成, 使Aβ负荷降低约30%, 展现出潜在的神经保护作用。2020年, Bowroju等^[58]融合8-羟基喹啉与吲哚结构, 引入哌嗪桥增强空间灵活性, 合成的喹啉衍生物能同时抑制Aβ自聚集和金属诱导聚集。通过体外实验发现, 化合物6 (EC₅₀ = 1.72 µmol·L^-1)、7 (EC₅₀ = 1.48 µmol·L^-1)和8 (EC₅₀ = 1.08 µmol·L^-1, 图4)显著降低了Aβ的聚集速率, 与已知药物CQ (EC₅₀ = 9.95 µmol·L^-1)相比具有显著优势。在Aβ异常聚集过程中, 糖原合成酶激酶-3β (glycogen synthasc kinase-3β, GSK-3β)通过促进APP向淀粉样蛋白水解途径的转化, 促进了Aβ的生成过程^{[59, 60]}。金属螯合剂PBT2 (9, 图4)能够形成二元和三元Cu²⁺复合物。它曾作为AD的治疗方法进行临床试验, 但未能超过第2阶段。2011年, Crouch等^[61]以8-羟基喹啉为基础, 引入N,N-二甲基氨基甲酰基侧链, 增强亲脂性的同时维持适度金属亲和力。所得喹啉类化合物PBT2 (MIC₅₀ = 2.5 µmol·L^-1)通过介导Zn²⁺和Cu²⁺从细胞外转运到细胞内, 促进GSK3β在丝氨酸位点(Ser9)磷酸化, 有效抑制其活性, 随后通过钙调神经磷酸酶-GSK3/CREB/CaMKII轴多信号通路调控, 减少Aβ的生成和聚集^{[58, 62]}。但长期使用可能影响生理金属平衡, 需警惕潜在毒性(肝肾损伤等)。2010年IIa期临床试验(NCT00471211)显示该化合物显著改善早期患者执行功能并降低脑脊液Aβ水平^[63]。然而, 2023年对该化合物的结构生物学研究揭示了潜在限制因素: 其与Aβ形成三元Cu²⁺复合物的低特异性可能限制疗效^[64]。这一结构特性可能与此前为期12个月的Ⅱ期分子影像学试验(ACTRN 12611001008910和ACTRN 12613000777796)的局限性有关: PBT2能适度降低高基线Aβ负荷(颞顶叶标准化摄取值比SUVR > 2.5)患者的匹兹堡化合物B正电子发射断层扫描(pittsburgh compound-B positron emission tomography, PiB-PET)信号, 但未能显著区分药物与安慰剂组的疗效^[65]。未来需优化选择性并针对线性Aβ累积阶段开展更大规模试验, 以验证其通过金属离子稳态调节延缓AD进展的假说。

1.2　Tau蛋白磷酸化调控

Tau蛋白在稳定微管结构和维持神经元细胞的形态和功能中起重要作用, 正常情况下, Tau蛋白通过磷酸化和去磷酸化的动态平衡调节其功能^{[66, 67]}。在AD患者大脑中, 过度磷酸化的Tau蛋白会聚集成NFTs, 损害神经细胞的结构和功能, 导致认知功能障碍^{[68, 69]}。GSK-3β不仅影响Aβ的聚集, 同时也是与Tau蛋白异常磷酸化密切相关的激酶, 它能够促进Tau蛋白的错误折叠和聚集, 形成神经纤维缠结^{[70, 71]}。

2023年, Emmerich等^[72]基于虚拟筛选和分子对接, 结合药代动力学预测, 引入烷基及芳氨基取代基以增强极性与空间适配性。发现所得到的喹啉类化合物能够特异性地结合到GSK-3β的ATP结合位点, 阻止ATP与酶的结合, 进而抑制其激酶活性。体外GSK-3β结合实验结果表明, 化合物10 (IC₅₀ = 9.4 µmol·L^-1)、11 (IC₅₀ = 9.1 µmol·L^-1)、12 (IC₅₀ = 4.9 µmol·L^-1)和13 (IC₅₀ = 9.1 µmol·L^-1, 图4)能够有效抑制GSK-3β活性。尽管这些化合物对GSK-3β表现出较高的抑制活性, 但对GSK-3α的抑制活性更强(例如化合物12的IC₅₀ ≈ 2 µmol·L^-1), 导致降低其选择性, 且这些化合物对其他激酶如PKBβ和PKCγ也表现出一定的抑制作用, 这可能带来脱靶效应。该研究表明, 喹啉类化合物能够竞争性结合GSK-3β的ATP结合位点, 抑制其活性, 从而减少Tau的磷酸化聚集和神经毒性^[73]。同年, Noori等^[74]基于多靶点策略, 融合喹啉骨架与苯甲基哌啶单元, 通过取代基优化亲脂性与氢键作用。合成的化合物14 (图4)暴露于SH-SY5Y神经母细胞瘤细胞72 h成功降低了40%的GSK-3β mRNA水平, 而对GSK-3α没有显著影响。由此提出, 该化合物可选择性轻微降低GSK-3β水平并间接降低Tau磷酸化而不影响GSK-3α的理想候选物, 这种选择性和温和地降低效果使其在治疗AD方面具有潜在的临床应用价值。2024年, Abdo Moustafa等^[73]采用杂环融合策略, 设计并合成了一系列新型喹啉-2-酮衍生物, 其中化合物15 (IC₅₀ = 4.68 nmol·L^-1)、16 (IC₅₀ = 7.38 nmol·L^-1)和17 (IC₅₀ = 8.27 nmol·L^-1, 图4)通过与GSK-3β的ATP结合位点竞争性结合, 表现出优异的抑制活性, 优于对照药物星形孢菌素(IC₅₀ = 6.12 nmol·L^-1)。体内模型实验结果表明, 化合物15显著改善了东莨菪碱诱导的小鼠认知功能障碍, 其转移潜伏时间从251.53 s增加到327.27 s (P < 0.01)。这些喹啉类化合物不仅在体外表现出显著的活性, 还在体内模型中显示出改善认知功能的潜力, 为开发新型抗AD药物提供了重要参考。

1.3　胆碱能系统调节

AD患者胆碱能系统退化表现为水平下降以及AChE活性降低, BuChE活性在疾病后期显著升高, 导致突触间隙ACh浓度不足^[75-77]。喹啉衍生物他克林(18, 图4)能够可逆性抑制AChE, 增加突触间隙ACh浓度, 改善认知功能^[78]。然而, 由于其具有肝毒性和低选择性, 目前已退出市场^[79]。研发人员在此基础上进行多靶点设计, 开发出多种可同时抑制AChE和BuChE的新型喹啉类化合物, 在AD后期BuChE活性升高时更具优势, 具有临床应用潜力^[80-82]。

2018年, Pinz等^[83]通过向喹啉环引入苯硒基团优化其抗氧化和抗胆碱酯酶活性。行为学实验结果表明, 喹啉衍生物19 (图4)处理组的小鼠在多种认知测试中表现出显著改善。例如在巴恩斯迷宫实验中, 该化合物处理后的小鼠能够显著减少潜伏期, 表明其空间学习和记忆能力明显恢复。与AD模型组相比, 处理组小鼠的AChE活性降低约30%~40%。2023年, Chen等^[80]构建了喹啉-O-氨基甲酸酯骨架, 优化得到的高活性衍生物通过疏水作用占据胆碱酯酶的CAS和PAS, 抑制ACh水解; 同时通过自由基清除和金属螯合作用减少Aβ聚集。其合成的喹啉衍生物20 (图4)显示出显著的AChE (IC₅₀ = 1.3 μmol·L^-1)和BuChE (IC₅₀ = 0.81 μmol·L^-1)抑制活性, 优于现有药物多奈哌齐对BuChE的抑制活性(IC₅₀ = 5.6 μmol·L^-1)。2024年, Saffour等^[84]通过将喹啉与1, 3, 4-噁二唑环结合设计, 实验结果表明所有合成的化合物对AChE的抑制活性均高于BuChE。在1 000和100 µmol·L^-1浓度下, 大多数化合物对AChE的抑制率超过50%, 但需较高浓度。相比之下, 化合物21 (IC₅₀ = 0.033 µmol·L^-1，图4)的效力显著优于其他化合物, 其活性与参考药物多奈哌齐(IC₅₀ = 0.020 1 µmol·L^-1)相当, 化合物22 (IC₅₀ = 0.096 µmol·L^-1)和23 (IC₅₀ = 0.177 µmol·L^-1, 图4)也表现出显著的抑制活性。

1.4　神经炎症抑制与胶质细胞调控

神经炎症反应在AD患者大脑中的表现通常为小胶质细胞和星形胶质细胞的过度激活, 导致炎症因子的释放及神经损伤^[85-87]。这不仅会加剧Aβ的积聚, 还促使Tau蛋白的病理改变, 这些都与认知功能衰退密切相关^{[88, 89]}。2015年, Wen等^[90]在喹啉母核上引入氧杂蒽环和三唑环两种杂环结构。得到的喹啉类化合物24和25 (图4)在二甲苯致小鼠耳水肿实验中能够显著减少耳水肿, 其在腹腔注射100 mg·kg^-1剂量下的抑制率分别为63.19%和68.28%, 显著高于对照药布洛芬(63.11%)。进一步实验发现化合物25在脂多糖(lipopolysaccharide, LPS)诱导的RAW 264.7巨噬细胞模型中, 显著抑制了TNF-α和IL-6的产生, 并且呈剂量依赖性, 有潜力发展为治疗AD的候选药物。2022年, Ji等^[91]的研究也表明喹啉类化合物具有良好的降低炎症因子分泌的活性。检测发现, 与LPS刺激组相比, 从花椒果实中分离的喹啉类化合物26 (图4)处理组IL-1β表达降低了约50%, 且有效抑制IL-6的释放, 显示出良好的抗炎特性。

星形胶质细胞在维持神经稳态和支持神经元功能方面发挥重要作用, 但在AD患者脑中, 星形胶质细胞过度活化, 导致促炎因子分泌增加, 进一步恶化神经炎症^[92-94]。研究表明, 喹啉衍生物能够减少星形胶质细胞介导的炎症反应, 促进抗炎因子的释放, 平衡促炎和抗炎反应^[95]。核转录因子-κB (nuclear factor-kappa B, NF-κB)是炎症反应的核心调节因子, 在AD相关神经炎症中高度活跃^[96]。通过抑制蛋白κB-α (inhibitor of κB-α, IκBα)的磷酸化和降解, 阻止NF-κB从胞质转移到细胞核, 减少促炎因子的释放^{[97, 98]}。2020年, Xie等^[99]研究发现, 通过在喹啉环上修饰羧酰胺结构所得到的喹啉类化合物拉奎莫德(27, 图4)显著降低了IκBα的磷酸化水平, 抑制NF-κB p65的核转位, 减少促炎因子的释放, 可能对AD相关的神经炎症具有潜在的治疗作用。未来可进一步探讨其透过血脑屏障的能力, 促进其中枢神经系统的应用。2022年, Hu等^[100]研究了经典喹啉类化合物羟氯喹(28, 图4)通过调节TLR4/NF-κB信号通路减轻炎症反应的机制。结果显示, 该化合物显著降低了TLR4、p-IκBα、p-NF-κB p65的蛋白表达(P < 0.01), 抑制了NF-κB p65的核转位。同时显著减轻了小胶质细胞激活, 减少了Iba-1阳性细胞密度(P < 0.01), 对促炎因子表达的抑制作用也十分显著(P < 0.01)。2024年, Xu等^[101]将白藜芦醇与喹啉环结合, 发现喹啉衍生物29 (图4)能够抑制小胶质细胞介导的神经炎症。免疫荧光结果显示, 该化合物显著减少了小胶质细胞激活, 并显著降低了IL-6、TNF-α和IL-1β的mRNA表达, 表明其具有良好的抗炎作用。在MCAO/R大鼠中, 化合物29显著降低了p-IκBα蛋白的表达, 减轻了IκBα蛋白的降解, 表明该化合物能够抑制NF-κB信号通路的激活。Toll样受体(toll like receptor, TLR)是小胶质细胞表面的重要模式识别受体, 在Aβ诱导的神经炎症中起关键作用^[102]。流式细胞术和共免疫沉淀实验表明, 该化合物能够抑制TLR4与髓样分化蛋白-2 (myeloid differentiation protein 2, MD-2)的结合。该研究首次揭示了喹啉衍生物通过靶向TLR4抑制NF-κB信号通路, 并抑制小胶质细胞激活, 有望减轻神经炎症和神经元损伤。

1.5　抗氧化应激与细胞凋亡调控

氧化应激是AD的重要病理特征之一。过量的自由基和ROS会促进Aβ的聚集和沉积、加速Tau蛋白的异常磷酸化, 触发神经炎症反应, 进而加速AD的病理进程^{[103, 104]}。超氧化物歧化酶(superoxide dismutase, SOD)、过氧化氢酶(catalase, CAT)和谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)是细胞内重要的抗氧化酶, 它们通过清除ROS来保护细胞免受氧化损伤^[105]。喹啉衍生物能够清除自由基以及增强抗氧化酶的活性等, 进而减轻氧化应激, 还能通过调节细胞内金属离子稳态和增强线粒体功能等机制抑制神经元的凋亡, 并保护神经元免受损伤^[106]。

2023年, Knez等^[107]以8-羟基喹啉为核心, 通过引入硝酮基团设计合成系列化合物, 自由基清除实验结果显示化合物30 (EC₅₀ ≈ 119.2 μmol·L^-1)和31 (EC₅₀ ≈ 126.0 μmol·L^-1, 图4)具有与白藜芦醇相当的抗氧化活性(EC₅₀ ≈ 100 μmol·L^-1)。且化合物31不仅具有抗氧化应激的活性, 还表现出抑制胆碱酯酶(cholines, ChEs)和单胺氧化酶(monoamine oxidase, MAOs)、金属离子螯合、神经保护等多种功能。2024年, Jena等^[108]基于喹啉-咪唑杂化骨架, 通过微波辅助一锅法合成5,6-二氢吡啶并咪唑喹啉衍生物。在SH-SY5Y神经细胞模型实验中, 发现1 μmol·L^-1喹啉类化合物32 (图4)对神经毒性剂导致的细胞死亡的抑制效果与10 μmol·L^-1阳性对照依布硒啉相当, 表现出更强的神经保护活性。研究还发现, 该喹啉类化合物能减少MPP⁺诱导的ROS生成, 显著维持线粒体膜电位, 保护神经细胞免受线粒体功能障碍的影响。2025年, Meng等^[109]以白藜芦醇为先导, 通过取代基修饰设计得到喹啉衍生物33 (图4)。免疫印迹实验结果显示, 该化合物显著提高了Bcl-2/Bax比值, 减少了细胞凋亡(P < 0.01)。此外, 化合物33显著降低了MCAO/R大鼠脑组织和OGD/R处理细胞中的ROS水平(P < 0.01), 并显著提高了SOD活性, 降低了丙二醛(malondialdehyde, MDA)和H₂O₂水平(P < 0.01)。该研究揭示了喹啉衍生物33通过调节线粒体自噬和抗氧化作用, 显著改善神经元损伤, 未来可进一步研究其长期给药的安全性, 探索其临床应用潜力。

2　异喹啉衍生物抗AD的生物学评价及作用机制

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与喹啉相比, 异喹啉的分子刚性稍弱, 结构更具灵活性, 这种灵活性使其在与特定生物靶标结合时更适配^[110]。异喹啉类化合物的功能特性还体现在不同位点的协同作用机制中(图5), 1位疏水取代基通过填充酶活性口袋的疏水腔提升抑制效率, 并通过阻断关键代谢位点延长作用时间^[111]; 氮原子在2号位置的变化直接影响了异喹啉的电子效应, 与喹啉相比, 异喹啉的氮原子对分子的电子影响较小, 因此其极性和亲和力有所不同^[112]; 3位卤素原子通过特殊分子间作用增强抗菌选择性, 维持对耐药靶标的结合能力^[113]; 5位苯并稠合结构通过增强π-π堆叠效应可调控受体亚基的激活状态^[114]; 8位杂环并合可利用静电互补与多靶点协同提升治疗效能^[115]。截至目前, 异喹啉类化合物尚未有明确针对AD适应症的药物进入临床试验阶段, 但部分天然异喹啉生物碱或合成衍生物已处于临床前研究阶段。

2.1　Aβ聚集抑制与清除

异喹啉衍生物的抗Aβ聚集能力同样瞩目。有研究发现, 异喹啉类化合物可通过激活热休克因子1 (heat shock transcription factor 1, HSF-1), 显著上调包括hsp-16.11、hsp-16.2和hsp-16.49在内的sHSP基因的表达, 这些基因编码的小分子热休克蛋白(small heat shock protein, sHSP)具有分子伴侣功能, 能够识别并结合Aβ肽, 防止其不可逆聚集, 并协助其正确折叠^{[28, 116, 117]}。2021年, Jia等^[118]通过转录组测序和实时定量聚合酶链式反应(polymerase chain reaction, PCR)实验发现, 异喹啉衍生物巴马汀(34, 图6)通过激活HSF-1, 显著上调了sHSP基因表达, 并发现Aβ沉积显著减少。这些结果表明, 该化合物通过上调HSF-1及其靶基因的表达, 显著抑制Aβ聚集, 减少细胞毒性。但该研究主要集中在体外和线虫模型, 其在体内的具体作用机制和效果需要进一步验证。2024年, Zhou等^[119]报道了一种四氢异喹啉化合物可以通过增强溶酶体降解功能, 通过清除Aβ聚集体从而抑制AD。在APP/PS1阿尔茨海默症模型中, 化合物35和36 (图6)分别使海马区Aβ斑块减少69.8%和67.5%, 皮质区Aβ水平下降36.3%和47.0%; 药代动力学显示其脑血浆浓度比(B/P)达5.2~7.4倍, 口服生物利用度分别为6.73%和76.4%。展现出优异的抗AD潜力, 成为AD临床前候选药物。

异喹啉类化合物还能够通过与Aβ的肽链及其氨基酸残基发生特异性相互作用, 干扰Aβ的自聚集过程。2021年, Marasco等^[120]探索了植物来源的异喹啉衍生物对Aβ聚集的影响。实验结果表明, 异喹啉类化合物37和38 (图6)使ThT荧光信号降低了约40%, 通过结合Aβ不同构象干扰其自组装。同年, Ingham等^[121]则从抑制聚集和分解已聚集的蛋白双重作用机制角度研究异喹啉类化合物抗Aβ聚集方面潜在的应用价值。研究人员用200 μmol·L^-1异喹啉类化合物ANTC-15 (39, 图6)处理花生四烯酸诱导的预制前体纤维(pre-formed precursor fiber, PPFs)时, 两种单克隆毒性构象敏感捕获抗体(TOC1和TNT1)的水平显著降低。TOC1活性物质水平降低了约50%, TNT1活性物质水平降低了40%。结果表明, 该新型化合物作为潜在的抗Tau聚集剂既可以抑制花生四烯酸(arachidonic acid, ARA)诱导的细丝, 又可以分解预先形成的ARA原纤维, 为AD等神经退行性疾病提供新的治疗思路。但该化合物的高疏水性可能限制其作为治疗剂的潜力, 且该研究仅针对特定Tau构象有效, 对疾病相关构象(如AD脑源性纤维)的抑制效果未验证。2023年, Dong等^[122]研究发现, 异喹啉衍生物小檗碱(40, 图6)通过与Aβ原纤维末端结合, 阻止原纤维向成熟原纤维的转变以及伸长过程。细胞毒性实验结果显示, 该化合物确实可以显著降低Aβ纤维的细胞毒性, 但其在体内的效果和生物利用度需要进一步验证。

2.2　Tau蛋白磷酸化调控

PI3K/Akt/GSK-3β信号通路在调节Tau蛋白磷酸化中起着关键作用^{[123, 124]}, 异喹啉衍生物可通过调节该信号通路在抗Tau蛋白异常磷酸化方面发挥重要作用, 还可通过基于自噬的途径降低Tau蛋白水平, 其机制涉及上调PIK3C3 (编码hVps34蛋白)和BECN1 (编码Beclin-1蛋白)的基因表达水平, 激活Ⅲ类PI3K/Beclin-1通路, 通过生成磷脂酰肌醇3-磷酸(phosphatidylinositol 3-phosphate, PI3P)促进自噬体的形成, 从而加速Tau蛋白的自噬清除^{[125, 126]}。2020年, Chen等^[127]研究发现, 在动物模型实验中, 异喹啉衍生物小檗碱处理显著增加了GSK-3β在Ser9位点的磷酸化水平, 表明其通过抑制GSK-3β活性减少了Tau蛋白在Ser202和Ser404位点的磷酸化。同时, 小檗碱处理显著提高了Akt的磷酸化水平, 进一步增强了GSK-3β的抑制作用, 因为Akt是GSK-3β的上游激酶, 能够通过磷酸化调节其活性。此外, 免疫蛋白和免疫荧光实验结果显示, 小檗碱处理显著增加了LC3-Ⅱ/LC3-Ⅰ比值, 表明自噬活性增强。与此同时, 小檗碱处理的小鼠海马中Beclin-1水平显著上升, 而Bcl-2水平显著下降, 表明其通过Ⅲ型PI3K/Beclin-1/Bcl-2通路调节自噬, 从而促进Tau蛋白的清除。该研究表明小檗碱可通过同时靶向Tau蛋白的磷酸化和自噬清除途径, 发挥对AD的治疗作用。

腺苷酸激活蛋白激酶(adenosine 5′-monophosphate-activated protein kinase, AMPK)是细胞内能量代谢的关键调节酶, 其激活对多种生物过程具有重要影响^[128]。在AD病理进程中, AMPK的激活能够抑制GSK-3β活性, 以及增强PP2A活性进而促进Tau蛋白的去磷酸化^[129-132]。2018年, Zhou等^[133]在AMPK激活实验中发现, 异喹啉衍生物小檗碱可以显著增加AMPK的磷酸化水平, 进而上调转录因子NUR77, 促进FGF21转录, 间接影响Tau蛋白的磷酸化。2022年, Li等^[134]的研究也证实了小檗碱对AMPK的激活作用。其实验结果表明, 小檗碱通过肝激酶B1 (liver kinase B1, LKB1)激活AMPKα (Thr172)的磷酸化, 进而促进下游通路中促进Tau蛋白的去磷酸化。这些研究表明, 异喹啉衍生物可通过激活AMPK通路, 间接促进Tau的去磷酸化。

2.3　胆碱能系统调节

胆碱能受体功能下降是导致AD患者记忆和学习能力减退的重要因素^[135], 尤其是烟碱型乙酰胆碱受体(nicotinic acetylcholine receptor, nAChR)在AD中的表达下降, 会严重影响神经递质的释放和突触可塑性^{[136, 137]}。异喹啉类生物碱代表药物加兰他敏(41, 图6)能够结合nAChR的变构调节位点, 可逆性抑制AChE, 同时还能竞争性结合AChE活性位点, 从而抑制ACh水解^[138]。其双重作用机制协同提升ACh信号传递强度, 改善突触可塑性。

2020年, Plazas等^[30]研究了花椒根中的异喹啉生物碱对ChE的抑制作用, 实验结果表明, 化合物42和43 (图6)对电鳗乙酰胆碱酯酶(acetylcholinesterase from electrophorus electricus, EeAChE)的IC₅₀值分别为0.65和0.15 µmol·L^-1; 对人重组乙酰胆碱酯酶(recombinant acetylcholinesterase, HrAChE)的IC₅₀值分别为1.25和0.52 µmol·L^-1; 对马血清丁酰胆碱酯酶(butyrylcholinesterase from equine serum, EqBChE)的IC₅₀值分别为5.73和0.88 µmol·L^-1。此外, 这些异喹啉类化合物还表现出对单胺氧化酶A和Aβ聚集显著的抑制活性, 是开发治疗AD药物的有前景的多靶点抑制剂。2024年, Marchán-García等^[139]通过交叉脱氢偶联合成策略设计, 以二苄基磷酰氯为原料, 经TBHP氧化构建α-氨基膦酸酯-四氢异喹啉杂化物。研究发现异喹啉类化合物44 (图6, IC₅₀ = 9 nmol·L^-1)在BuChE抑制实验中具有显著抑制活性, 与标准药物他克林(IC₅₀ = 4 nmol·L^-1)相当。动力学研究表明, 该化合物通过非竞争性抑制作用, 与BuChE的PAS结合来发挥作用, 为AD治疗提供了新的治疗策略, 尤其是在避免与底物竞争的情况下, 有利于减少胃肠道的不良反应。

2.4　神经炎症抑制与胶质细胞调控

异喹啉类化合物在抑制神经炎症方面也表现出较强的作用, 为治疗AD提供了新的思路。2023年, Akhtar等^[140]研究了新型手性吡唑并异喹啉衍生物的抗炎功效, 发现化合物45 (图6, IC₅₀ = 20.76 μmol·L^-1)对一氧化氮(nitric oxide, NO)抑制活性最强。在免疫印迹实验中, 化合物45能够显著下调LPS诱导的RAW 264.7细胞中iNOS蛋白的表达, 表明其通过抑制iNOS的表达和NO的释放, 减少小胶质细胞的活化, 从而减轻神经炎症。在小鼠模型中, 化合物46 (图6)在10 mg kg^-1的浓度下, 表现出约64.4%的耳水肿抑制率, 与对照药物塞来昔布(70.05%)的效果相当, 证明其具有显著的抗神经炎症的作用。2024年, Abo-Elmagd等^[141]基于四氢异喹啉和1,2,4-三唑结构设计了一系列衍生物, 旨在通过替换传统的羧酸基团为1,2,4-三唑环, 减少临床应用时的胃肠道不良反应, 同时增强抗炎活性。在体外环氧化酶(cyclooxygenase, COX)抑制实验中, 化合物47 (IC₅₀ = 0.87 μmol·L^-1)、48 (IC₅₀ = 1.27 μmol·L^-1)和49 (IC₅₀ = 0.58 μmol·L^-1, 图6)表现出较强的COX-2抑制活性, 与标准药物塞来昔布(IC₅₀ = 0.82 µmol·L^-1)相当。该结果与体内大鼠足跖水肿实验结果一致, 这些化合物在所有时间点(1、2、3、4 h)均显示出显著的抗炎活性, 保护率范围为37.09%~84.17%, 优于塞来昔布(22.09%~43.57%)。炎症介质检测结果表明, 这些化合物显著降低了血清中PGE-2、TNF-α和IL-6的水平, 表明其抗炎作用是通过抑制这些炎症介质的产生实现。此外, 化合物49在胃肠道安全性上的表现同样优异, 其溃疡形成指数(1.33)显著低于塞来昔布(3.0)和吲哚美辛(2.7)。这些结果表明, 这些异喹啉类化合物不仅具有较高的抗炎活性, 还在长期用药中具有良好的安全性, 在药物开发和临床应用中具有较大的潜力, 但仍需进一步的临床试验和研究来验证其疗效和安全性。

异喹啉类衍生物还可通过抑制NLRP3炎症小体组装, 并上调Sirt-1活性, 拮抗炎症小体过度活化, 从而减轻炎症反应^{[142, 143]}。2020年, Wang等^[144]研究了异喹啉衍生物粉防己碱(tetrandrine, Tet, 50, 图6)对脑缺血再灌注(ischemia-reperfusion injury, I/R)损伤的保护作用, 并探讨其通过上调Sirt1蛋白的表达水平从而抑制NLRP3炎症体激活的分子机制。实验结果显示, Tet显著减少了Iba-1阳性细胞的数量和NLRP3的共定位, 并显著抑制了NLRP3、裂解的caspase-1、IL-1β和IL-18的表达。该研究表明异喹啉衍生物可通过上调Sirt-1表达, 抑制NLRP3炎症体激活, 从而减轻I/R损伤。

异喹啉类化合物还可通过调节其他关键信号通路来抑制炎症因子的表达, 进而减轻炎症反应和神经元损伤。2015年, Chung等^[145]通过一锅、多步和连续加成反应合成了一类新的异喹啉类化合物, 并研究其对NF-κB的抑制作用。发现化合物51 (图6)是转录因子NF-κB的有效抑制剂, 它能够阻断TNF-α诱导的NIH 3T3细胞中的IκBα降解、p65核易位, 以及NF-κB和DNA结合活性。2022年, Liu等^[146]研究发现异喹啉衍生物Tet还可通过调节IRE1α/JNK/CHOP信号通路, 抑制内质网应激诱导的神经炎症, 从而减少GADD34、TRAF1和p-PERK的活化。这进一步降低了TNF-α和NF-κB的表达水平, 最终减轻实验性创伤性脑损伤中的炎症反应和神经元凋亡^[28]。

2.5　抗氧化应激与细胞凋亡调控

在抗氧化应激方面, 异喹啉衍生物可通过激活细胞内抗氧化酶系统的SOD、CAT和GSH-Px, 增强细胞的抗氧化能力^[147], 并可通过调节转录因子(nuclear factor erythroid-2-related factor 2, Nrf2)上调抗氧化酶的表达。2016年, Qu等^[148]研究发现异喹啉衍生物四氢巴马汀(tetrahydropalmatine, THP, 52, 图6)在D-半乳糖(D-galactose)诱导的大鼠记忆障碍模型中表现出显著的保护作用。实验结果表明, THP可显著降低MDA和NO水平, 同时显著提高谷胱甘肽(glutathione, GSH)含量及SOD、CAT和GSH-Px等抗氧化酶的活性(P < 0.05), 并显著降低NF-κB和caspase-3表达(P < 0.05)。表明其在减轻神经炎症和细胞凋亡方面具有积极作用。2017年, Mahmoud等^[149]研究发现异喹啉衍生物小檗碱同样可以降低MDA和NO水平, 增加GSH含量和多种抗氧化酶活性, 并显著降低NF-κB和caspase-3表达以发挥抗炎和抗细胞凋亡作用。进一步实验发现, 该异喹啉衍生物可通过上调Nrf2/HO-1通路以及抑制KEAP1对Nrf2的抑制作用, 促进Nrf2核转位, 进而促进抗氧化酶的的基因表达, 减轻氧化损伤。此外, 2019年, Shou等^[150]研究发现小檗碱还可通过上调抗凋亡基因BCL2的表达, 下调促凋亡基因Bax和CASP3的转录水平, 使细胞凋亡率由23.4%降为10.9% (P < 0.001)。还通过激活WNT/β-catenin通路促进神经元分化, 上调促神经标记物ASCL1、神经生成素1 (neurogenin 1, NeuroG1)、神经元分化2 (neuronal differentiation 2, NeuroD2)和双皮质素(doublecortin, DCX)的表达。这些多靶点作用协同减轻氧化应激对神经细胞的损害, 并促进神经再生。

AD的病理进程中通常伴随有异常的钙离子稳态和激活的细胞死亡信号通路^{[151, 152]}。异喹啉衍生物能够通过调节钙离子通道或相关信号通路, 维持细胞内Ca²⁺的正常水平, 从而减少由钙过载引起的细胞死亡。如异喹啉类化合物Tet是一种天然的钙通道阻滞剂, 能够抑制电压门控钙离子通道(voltage-gated calcium channel, VGCC), 减少Ca²⁺的过度内流。同时通过调节Ca²⁺依赖性钾离子通道的活性, 进一步维持细胞内钙稳态^[153]。该异喹啉化合物还可通过靶向micro RNA-202-5p来抑制瞬时受体电位香草酸2型(transient receptor potential vanilloid type 2, TRPV2)的激活, 减少TRPV2介导的钙内流, 从而通过调节细胞凋亡并维持钙稳态^[154]。在创伤性脑损伤(traumatic brain injury, TBI)模型中, Tet通过调节IRE1α/JNK/CHOP信号通路, 不仅可以减轻实验性TBI炎症, 还可有效减轻神经元凋亡^[146]。

线粒体活性氧(mitochondrial reactive oxygen species, mtROS)的过度产生是细胞损伤和凋亡的重要诱因^[155]。2024年, Zhong等^[156]研究了小檗碱通过调节mTOR/mtROS轴抑制NLRP3炎症小体激活, 从而减轻心肌细胞氧化应激损伤的机制。实验结果表明, 小檗碱显著降低了db/db小鼠心肌和H9C2细胞中p-mTOR表达(P < 0.01)。进一步分析表明，其可减少NLRP3炎症小体活化及成熟IL-1β/IL-18分泌(P < 0.05), 从而缓解心肌细胞氧化应激损伤。

3　展望与挑战

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喹啉和异喹啉衍生物凭借其独特的分子结构和多样的生物活性, 在AD治疗研究中崭露头角。这些化合物通过多种途径干预AD复杂的病理过程, 在体内外生物活性评价模型中表现优异, 展现出作为多靶点药物的潜力。Aβ聚集和Tau蛋白过度磷酸化这两种病理特征是导致神经退行性变化的关键所在, 喹啉和异喹啉衍生物能有效抑制上述两种病理特征的进展, 不仅如此, 它们还具备抗氧化和抗炎作用, 能够有效缓解氧化应激和神经炎症对神经元造成的损伤, 进一步为神经细胞构建起坚实的保护屏障。同时, 这些化合物在调节神经递质系统功能方面也发挥着积极作用, 帮助改善认知功能障碍, 为AD治疗提供了更为全面且深入的干预策略。然而, 尽管喹啉和异喹啉衍生物在基础研究阶段展现出诸多优势, 但其临床转化仍面临诸多挑战。例如, 药物的生物利用度有待进一步提高, 药代动力学特性需要持续优化, 潜在的不良反应也需要进行更为深入全面的研究。

随着药物筛选技术的飞速发展以及分子靶向研究的不断深入, 喹啉和异喹啉类化合物有望成为抗AD治疗领域的有力工具。特别是通过结构优化和分子设计, 进一步引入特定的官能团或对骨架进行修饰, 以提高其选择性、稳定性和药代动力学特性, 必能加速推动这些化合物从基础研究的实验室走向临床应用, 最终为广大AD患者带来新的希望。

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2026年第61卷第1期

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doi: 10.16438/j.0513-4870.2025-0264

接收时间：2025-03-11
首发时间：2026-09-21
出版时间：2026-01-12

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收稿日期：2025-03-11
修回日期：2025-05-21

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浙江海洋大学食品与药学学院, 浙江舟山 316000

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关丽萍, Tel: 13675809982, E-mail: glp730@zjou.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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