CN115120597A - 一种新型Nrf2激活剂及用途 - Google Patents
一种新型Nrf2激活剂及用途 Download PDFInfo
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- CN115120597A CN115120597A CN202210805342.5A CN202210805342A CN115120597A CN 115120597 A CN115120597 A CN 115120597A CN 202210805342 A CN202210805342 A CN 202210805342A CN 115120597 A CN115120597 A CN 115120597A
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Abstract
本发明提供一种式I的化合物或其药学上可接受的盐作为Nrf2激活剂的应用，其中，m独立地选自0～4中的整数，R1和R2独立地选自氢、羟基、卤素、C1‑3烷基、被卤素取代的C1‑3烷基或C1‑3烷氧基。所述Nrf2激活剂用于制备治疗和/或预防由Keap1‑Nrf2/ARE信号通路介导和/或氧化应激介导的疾病的药物。
Description
技术领域
本发明属于化学医药技术领域，特别是涉及一类新型核因子E2相关因子2(nuclear factor erythroid-2related factor 2，Nrf2)激活剂的制药用途，有望用于制备预防或治疗由Keap1-Nrf2/ARE信号通路或氧化应激(oxidative stress,OS)介导的疾病的药物。
背景技术
核因子E2相关因子2(nuclear factor erythroid-2related factor 2，Nrf2)，是一个参与抗氧化防御的关键转录因子，它调节涉及细胞稳态的约250个基因，包括抗氧化蛋白，解毒酶，药物转运蛋白和许多细胞保护蛋白。
在正常生理条件下，负调控蛋白Kelch样ECH相关蛋白1(Kelch-like ECH-associated protein 1,Keap1)将Nrf2锁定在胞质内，阻止其进入细胞核，并与泛素连接酶3(Cullin3)相互作用介导Nrf2泛素化降解以维持细胞内Nrf2的稳态。各种刺激因素可导致Keap1及其二聚体空间构象发生改变，Nrf2即可与Keap1解离入核，发挥生物学功能(Keum,Y.S.；Choi,B.Y.Molecular and chemical regulation of the Keap1-Nrf2 signalingpathway.Molecules,2014,19(7):10074-10089.)。
抗氧化反应元件(antioxidant response element,ARE)位于II相解毒酶和抗氧化应激酶基因上游调节区，是一个特异的DNA启动子结合序列。Nrf2是这个序列的激活因子，当活化的Nrf2与Keap1解离后进入细胞核，与Maf蛋白(包括Maf G、Maf K、Maf F)结合成异二聚体，再与ARE结合，使受ARE调控的基因开始转录,从而启动II相解毒酶和抗氧化应激蛋白等保护性基因的表达(Hayes,J.D.；Dinkova-Kostova,A.T.The Nrf2 regulatorynetwork provides an interface between redox and intermediarymetabolism.Trends in Biochemical Sciences,2014,39(4):199–218.)。Nrf2在机体抗氧化、抗炎防御机制中至关重要，它可作为由氧化应激(oxidative stress,OS)、炎症导致的相关疾病的潜在治疗靶点。
OS是由于机体活性氧(reactive oxygen species,ROS)生成增加，抗氧化能力减弱，引起脂质、蛋白和DNA等发生损伤。肌萎缩性侧索硬化症(amyotrophic lateralsclerosis,ALS)、多发性硬化症(multiple sclerosis,MS)、弗里德里希共济失调(Friedrich’s ataxia)、中风等疾病的发病机制与OS密切相关。针对这些疾病，目前很有前景的策略可通过调控Keap1-Nrf2/ARE信号通路来维持机体内的氧化还原平衡(Brandes,M.S.；Gray,N.E.NRF2 as a therapeutic target in neurodegenerative diseases.ASNNeuro,2020,12:1-23.)。研究表明，随着年龄的增长，脑内OS加剧，同时伴随Nrf2的表达减少；而大量临床研究证实了Nrf2激活剂能有效治疗这些疾病，如富马酸二甲酯(dimethylfumarate,DMF)是一种已知的Nrf2激活剂，于2013年获FDA批准作为治疗MS的一线用药；姜黄素作为一种Nrf2激活剂,在治疗ALS中发挥作用等(Cuadrado,A.；Rojo,A.I.；Wells,G,etal.Therapeutic targeting of the NRF2 and KEAP1 partnership in chronicdiseases.Nat Rev Drug Discov,2019,18(4):295-317.)。
OS也是多种生殖系统疾病的发病机制，卵泡异常发育、卵巢早衰及不孕症等均与ROS的过量产生有关(Lu,J；Wang,Z；Cao,J；Chen,Y；Dong,Y.A novel and compact reviewon the role of oxidative stress in female reproduction.Reproductive Biologyand Endocrinology.2018,16:80)。Keap1-Nrf2/ARE信号通路参与调控生殖系统的氧化还原平衡，可以作为防治生殖系统疾病的一个潜在靶点来发挥积极作用(马玉聪，杨爱敏，张拴成，杜惠兰.核因子E2相关因子2/抗氧化反应元件信号通路在生殖系统中的研究进展.中华生殖与避孕杂志.2021,41(12):1154-1159.)。
卵巢早衰(premature ovarian failure，POF)是指月经初潮年龄正常或延迟、第二性征发育正常的女性，在40岁之前出现围绝经期综合征等症状，持续6个月以上闭经，生殖器官萎缩，性功能降低甚至不孕的一种妇科内分泌性疾病。卵巢早衰发病率日益增高，已经成为严重危害女性身心健康的疾病。近年来研究显示，无论从组织水平、分子水平，还是基因水平引起卵巢早衰，都伴有卵巢颗粒细胞的凋亡，这也说明了颗粒细胞的凋亡与卵巢早衰有着直接的关系(Massin,N.；Meduri,G.；Bachelot,A.，et al.Evaluation ofdifferent markers of the ovarian reserve in patients presenting withpremature ovarian failure.Mol Cell Endocrinol.2008,282(1-2):95-100.；叶娜，董晓英，李冬华.卵巢早衰的颗粒细胞凋亡机制研究进展.首都医科大学学报,2014,35(3):379-383.)。
卵巢颗粒细胞包绕在卵母细胞周围，为卵母细胞的生长发育提供营养和成熟因子，并通过自身的抗氧化体系保护卵母细胞免受氧化应激的损伤。Nrf2蛋白作为抗氧化的关键因子，主要在次级卵泡和窦卵泡的卵巢颗粒细胞和卵母细胞中表达，而在初级卵泡和始基卵泡中表达较少。Nrf2在生育期小鼠卵巢组织中的表达量最高，而在幼龄期和绝育期的卵巢组织中表达量偏低，推测Nrf2与卵巢储备具有相关性，有保护卵巢储备功能的作用(陈菁,卢晓声,吕杰强.不同周龄小鼠卵巢中Nrf2蛋白的表达和定位.中国妇幼保健,2017,32(22):5722-5724.)。
目前，有不少关于Nrf2激活剂改善卵巢储备能力的研究。番茄红素和糖原合成酶激酶-3可通过上调Nrf2来促进其下游抗氧化酶SOD、GSH的表达来发挥抗氧化作用，改善老龄和化疗造成的卵巢功能低下(Liu,X.T.；Lin,X.；Zhang,S.Y.,et al.Lycopeneameliorates oxidative stress in the aging chicken ovary via activation ofNrf2/HO-1pathway.Aging,2018,10(8):2016-2036；Niringiyumukiza,J.D.；Cai,H.C.；Chen,L.,et al.Protective properties of glycogen synthase kinase-3inhibitionagainst doxorubicin-induced oxidative damage to mouse ovarian reserve.BiomedPharmacother,2019,116:108963.)。另外，用于治疗MS的Nrf2激活剂DMF也被证实对小鼠卵巢具保护作用(Akino,N.；Wada-Hiraike,O.；Isono,W.,et al.Activation of Nrf2/Keap1pathway by oral Dimethylfumarate administration alleviates oxidative stressand age-associated infertility might be delayed in the mouse ovary.ReprodBiol Endocrinol,2019,17(1):23.)。人胎盘间充质干细胞分泌的表皮生长因子(epidermal growth factor，EGF)可提高卵巢早衰小鼠的原始卵泡、次级卵泡及窦卵泡数目，其机制与EGF上调Nrf2/HO-1的表达相关。这些药物及干细胞研究有望在提高卵巢储备能力、改善妊娠结局方面发挥重要作用。
发明内容
本发明提供如下式I的化合物或其药学上可接受的盐作为Nrf2激活剂的应用，
其中：
m独立地选自0～4中的整数，优选2或3；
R1和R2独立地选自氢、羟基、卤素、C1-3烷基、C1-3烷氧基、被卤素取代的C1-3烷基或被卤素取代的C1-3烷氧基；优选地，R1选自羟基、卤素、或C1-3烷氧基。
在本发明中，所述Nrf2激活剂用于制备治疗和/或预防由Keap1-Nrf2/ARE信号通路介导和/或氧化应激介导的疾病的药物。优选地，所述疾病选自缩性侧索硬化症、弗里德里希共济失调、多发性硬化症、中风、卵泡异常发育、卵巢早衰和不孕症。
本发明的Nrf2激活剂对氧化应激(OS)介导的神经元损伤具有良好保护作用，能有效抑制过氧化氢诱导的神经细胞凋亡；恢复线粒体膜电位；抑制caspase-3活化；降低ROS水平；提高谷胱甘肽含量和超氧化物歧化酶(SOD)活性。另外，本发明的Nrf2激活剂对卵巢颗粒细胞也有显著保护效应。
附图说明
图1示出在H2O2诱导的人SH-SY5Y神经细胞损伤模型中，化合物Mep-S调控Keap1-Nrf2/ARE信号通路机制，其中a表示SH-SY5Y细胞中HO-1、NQO-1、Akt、phosphorylated Akt蛋白水平(条带图)，b表示SH-SY5Y细胞中Keap1、细胞核和细胞浆内Nrf2蛋白水平(条带图)，c表示HO-1蛋白水平(半定量图)，d表示NQO-1蛋白水平(半定量图)，e表示phosphorylated Akt蛋白水平(半定量图)，f表示Keap1蛋白水平(半定量图)，g表示细胞核内Nrf2蛋白水平(半定量图)，h表示细胞浆内Nrf2蛋白水平(半定量图)，*P<0.05,**P<0.01。
图2示出化合物Mep-S的神经保护作用，其中a表示Mep-S抑制H2O2导致的神经元凋亡(流式图)，b表示细胞凋亡的半定量图，c表示Mep-S抑制H2O2导致的caspase-3激活(条带图)，d表示caspase-3激活蛋白水平(半定量图)，*P<0.05,**P<0.01。
具体实施方式
如下式I的化合物或其药学上可接受的盐作为Nrf2激活剂的应用，
其中：
m独立地选自0～4中的整数；
R1和R2独立地选自氢、羟基、卤素、C1-3烷基、被卤素取代的C1-3烷基或C1-3烷氧基。
本发明中涉及的式I的化合物或其药学上可接受的盐的制备过程以及各基团的定义参见CN102816151A，其公开了系列左旋美普他酚衍生物(Mep-S)具有治疗阿尔茨海默病的用途。
以下药理测试实施例进一步说明本发明，但不限制本发明。
实施例1：化合物Mep-S调控Keap1-Nrf2/ARE信号通路机制及神经保护作用。采用H2O2诱导的人SH-SY5Y神经细胞损伤模型，探讨化合物Mep-S对神经损伤的保护作用及机制。
实验方法细胞培养：将人神经母细胞瘤细胞SH-SY5Y(American Type CultureCollection,Manassas,VA,USA)放置于37℃，5％CO 2培养箱中进行培养。培养液为DMEM/F-12，2mM谷氨酰胺，100U/ml青霉素，100μg/ml链霉素和10％FBS。细胞以2×104个/孔的密度接种到96孔板，并使其增殖至90％。
细胞随机分为四组：空白对照组、过氧化氢组(Veh)、Mep-S组及NAC组(一神经保护药，作为阳性对照)。Mep-S组(1μM)及NAC组(1mM)细胞预先给予相应浓度药物预处理1h。然后除空白对照组给予生理盐水外，其余各组细胞与H2O2(400μM)孵育24小时。
Western blot法检测各组神经细胞凋亡蛋白(Caspase3)及Keap1-Nrf2/ARE通路相关蛋白(Keap1、Nrf2、HO-1、NQO-1等)的表达水平，使用增强化学发光法(Pierce,Rockford,IL,USA)对条带进行可视化，并通过Image Studio Lite 5.2进行量化分析。
Annexin V/PI双染法检测Mep-S对细胞氧化损伤的保护作用：采用流式细胞术测定细胞凋亡，使用FITC Annexin V凋亡检测试剂盒(BD Pharmingen，Franklin Lakes，NJ，USA)，按说明书操作。
实验结果
结果如图1所示：H2O2氧化损伤SH-SY5Y细胞中HO-1和NQO-1的蛋白水平显著低于空白对照组(P<0.01)；同时Keap 1(Nrf2的负调节因子)和细胞质Nrf2的蛋白水平升高，而核Nrf2的蛋白水平降低(与对照组相比，P<0.01)。Mep-S或NAC预处理组显著抑制H2O2损伤导致的HO-1、NQO-1和核Nrf2蛋白水平的降低，以及Keap 1和细胞质Nrf2的增加(与H2O2损伤组比，P<0.05)。磷脂酰肌醇-3-激酶(PI3K)/Akt途径是通过促进Nrf2磷酸化和核转位的Nrf2信号的重要上游调节器(Li ST.Acta Pharmacol Sin.2018；39:1294-1304.)。我们发现，H2O2损伤组SH-SY5Y细胞中Akt的磷酸化水平显著低于空白对照组(P<0.01)，而Mep-S或NAC干预后可显著恢复其表达水平(P<0.05)。
Annexin V/PI双染法结果如图2所示:H2O2损伤组细胞的凋亡率是对照组的2.2倍(P<0.01)。Mep-S或NAC预处理可显著降低SH-SY5Y细胞的凋亡率(P<0.05)。细胞凋亡蛋白表达如图2所示，Mep-S显著抑制H2O2诱导损伤下的活化caspase-3水平的上调(P<0.05)。
上述实验中，Mep-S测试浓度仅为阳性对照药NAC的千分之一，但两者效果相当，表明Mep-S是一强效Nrf2激活剂，并对OS介导的神经元损伤具有良好保护作用，减少神经细胞凋亡。
实施例2：化合物(C1，即Mep-S(式I化合物，m＝3；R1＝OH；R2＝H)，C2(式I化合物，m＝3；R1＝Cl；R2＝H)，C3(式I化合物，m＝3；R1＝OCH3；R2＝H)，C4(式I化合物，m＝3；R1＝H；R2＝H))在1μM浓度下对卵巢颗粒细胞的保护作用。本实施例采集小鼠卵巢原代颗粒细胞，用具有颗粒细胞毒性作用的化疗药物多柔比星(doxorubicin，DOX)诱发细胞毒性，检测系列受试物对卵巢颗粒细胞的保护作用。
实验材料动物：SPF级雌性ICR小鼠，6只，21-23d，体质量(14±2)g。由上海西普尔-必凯实验动物有限公司提供的雄雌鼠在本所动物房繁殖的F1代，实验动物合格证号：SCXK(沪)2015-0016。动物房饲养条件：室温(23±2)℃，湿度45％-55％，光照时间12h，自由摄食水。
试剂：CCK-8试剂，购自上海睿安生物科技有限公司；M2操作液、ɑ-MEM培养液、胎牛血清(FBS)，购自Gibco公司；二甲基亚砜(DMSO)、矿物油，均购自美国Sigma公司；多柔比星(DOX)，购自上海金穗生物科技有限公司；受试物C1～C4溶于甲醇(10μM)，用时取10μL。
实验方法
体外小鼠颗粒细胞的培养：取21-23d雌性ICR小鼠，麻醉后脱臼处死，用75％的酒精消毒腹部皮肤，取出双侧卵巢，在解剖镜下刺破有腔卵泡，使颗粒细胞释放于含20％FBS的M2培养液中，1000r/min离心5min，去上清液，用培养液洗3次，然后放入含5％FBS的α-MEM培养液的96孔板中继续培养(内含100U/mL青霉素，100U/mL链霉素，100mU/mL卵泡刺激素，10mU/mL黄体生成激素)。
96孔板内颗粒细胞增殖到70％-80％，取出培养液，依次加入10μL受试药(C1(式I化合物，m＝3；R1＝OH；R2＝H)，C2(式I化合物，m＝3；R1＝Cl；R2＝H)，C3(式I化合物，m＝3；R1＝OCH3；R2＝H)，C4(式I化合物，m＝3；R1＝H；R2＝H))、10μL终浓度为25μg/mL DOX和80μL新鲜培养液。同时设立只加受试药的对照孔(10μL受试药+90μL新鲜培液)，以便观察受试药本身对颗粒细胞的作用。实验还设立只含颗粒细胞阴性对照孔(100μL新鲜培液)和颗粒细胞+DOX的阳性对照孔(10μL DOX+90μL新鲜培液)。每个受试药浓度设置4个复孔，阴性和阳性对照组16个复孔。培养24h后，加入10μL CCK-8，静置作用2-3小时，用酶标仪测定每孔的吸光度(OD)值(450nm)计算小鼠颗粒细胞生存率。采用SPSS 16.0统计软件进行统计学分析。组内比较采用t检验，组间比较采用多因素方差分析，以p<0.05为差异有统计学意义。
实验结果
阴性对照组显示小鼠卵巢颗粒细胞生长状况良好；阳性对照组显示加入终浓度为25μg/mL的DOX后，颗粒细胞的生长明显受到抑制(p<0.01)，加入测试药后，C1～C3均能提高颗粒细胞存活率，表明其在1μM浓度下对DOX引起的卵巢颗粒细胞的毒性有保护效应(结果见表1)，其中优选化合物为C3。
表1
| 分组 | 细胞存活率(％) |
| 阳性对照组(DOX) | 61.8 |
| DOX+C1(m＝3；R<sub>1</sub>＝OH；R<sub>2</sub>＝H) | 72.1 |
| DOX+C2(m＝3；R<sub>1</sub>＝Cl；R<sub>2</sub>＝H) | 69.4 |
| DOX+C3(m＝3；R<sub>1</sub>＝OCH<sub>3</sub>；R<sub>2</sub>＝H) | 78.7 |
| DOX+C4(m＝3；R<sub>1</sub>＝H；R<sub>2</sub>＝H) | 63.9 |
Claims (4)
1.如下式I的化合物或其药学上可接受的盐作为Nrf2激活剂的应用，
其中：
m独立地选自0～4中的整数；
R1和R2独立地选自氢、羟基、卤素、C1-3烷基、C1-3烷氧基、被卤素取代的C1-3烷基或被卤素取代的C1-3烷氧基。
2.根据权利要求1所述的应用，其特征在于，所述Nrf2激活剂用于制备治疗和/或预防由Keap1-Nrf2/ARE信号通路介导和/或氧化应激介导的疾病的药物。
3.根据权利要求2所述的应用，其特征在于，所述Nrf2激活剂用于制备治疗和/或预防肌萎缩性侧索硬化症、弗里德里希共济失调、多发性硬化症、中风、卵泡异常发育、卵巢早衰或不孕症的药物。
4.根据权利要求1至3中任一项所述的应用，其特征在于，m为2或3，R1选自羟基、卤素、或C1-3烷氧基。
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