CN110772503A - 2-甲氧基-6-乙酰基-7-甲基胡桃酮的应用 - Google Patents
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Abstract
本发明涉及药物应用领域,具体而言,涉及一种2‑甲氧基‑6‑乙酰基‑7‑甲基胡桃酮的应用。本发明提供一种2‑甲氧基‑6‑乙酰基‑7‑甲基胡桃酮作为醌氧化还原酶(NQO1)氧化还原循环底物的用途。旨其可以靶向结合NQO1,增加其活性,提升其蛋白表达,对于NQO1相关的疾病有良好的治疗效果。
Description
技术领域
本发明涉及药物应用领域,具体而言,涉及一种2-甲氧基-6-乙酰基-7-甲基胡桃酮的应用。
背景技术
NAD(P)H:醌氧化还原酶(NAD(P)H:quinoneoxidoreductase1,NQO1)是普遍存在于真核细胞内的一类黄素蛋白酶,为体内一种重要的II相反应酶。NQO1通过去电子还原反应参与机体外源物质代谢过程,具有化学保护作用和生物激活作用。同时,NQO1又可催化激活一些化合物,尤其是醌类化合物。NQO1催化过程中,诱导产生大量活性氧(Reactive oxygenspecies,ROS),产生DNA损伤、诱导细胞凋亡。近年来研究发现,与正常组织相比,NQO1在多种恶性肿瘤组织中高表达,而在一些神经退行性疾病中表达降低。因此,NQO1被认为是治疗多种恶性肿瘤和一些神经退行性疾病的潜在分子靶标。因此,高效、特异的NQO1催化的氧化还原循环底物被认为是选择性靶向高表达NQO1的肿瘤的先导化合物和/或药物,具有较为广阔的开发前景和应用潜力。
发明内容
本发明提供了一种2-甲氧基-6-乙酰基-7-甲基胡桃酮的应用,旨其可以靶向结合NQO1,激活其活性,诱导其蛋白表达水平增加,对于NQO1介导的相关疾病有良好的治疗效果。
本发明是这样实现的:
本发明实施例提供一种2-甲氧基-6-乙酰基-7-甲基胡桃酮作为NQO1氧化还原循环底物的用途。
进一步地,在本发明中2-甲氧基-6-乙酰基-7-甲基胡桃酮也可以作为NQO1激活剂的用途。其主要是通过2-甲氧基-6-乙酰基-7-甲基胡桃酮与所述NQO1的活性位点(活性口袋由FAD与NQO1单体中部分氨基酸位点组成,为反应发生的区域,而活性位点为该口袋中具体的氨基酸位点,活性口袋中包含活性位点)结合使得NQO1被激活,且活性位点结合2-甲氧基-6-乙酰基-7-甲基胡桃酮与NQO1的黄素腺嘌呤二核苷酸的异恶嗪环通过疏水和氢键进行结合以及2-甲氧基-6-乙酰基-7-甲基胡桃酮与NQO1的126位和128位的络氨酸残基形成氢键,实现了2-甲氧基-6-乙酰基-7-甲基胡桃酮与NQO1特异性的结合,提升NQO1的活性。同时,2-甲氧基-6-乙酰基-7-甲基胡桃酮可增加NQO1蛋白表达水平。因此,2-甲氧基-6-乙酰基-7-甲基胡桃酮可应用于制备提高NQO1蛋白表达和/或活性增加的药物。
同时,本发明实施例中2-甲氧基-6-乙酰基-7-甲基胡桃酮也可应用在制备NQO1过表达介导的疾病药物,且NQO1过表达介导的疾病包括恶性肿瘤;优选地,所述肿瘤包括胰腺癌、乳腺癌、肺癌、大肠癌以及恶性胶质瘤中的任意一种,更优选地,恶性肿瘤中NQO1高表达的亚型。且其作为治疗NQO1过表达介导的疾病药物的作用是抑制肿瘤细胞增殖和诱导细胞坏死。
本发明的有益效果是:本发明通过上述研究发现2-甲氧基-6-乙酰基-7-甲基胡桃酮可以作为NQO1氧化还原循环底物,继而能够提升NQO1的活性,提高NQO1的蛋白表达水平,使得在肿瘤细胞中特异高表达的NQO1酶催化下产生极度的氧化应激,诱导肿瘤细胞产生坏死,这使得2-甲氧基-6-乙酰基-7-甲基胡桃酮对于NQO1过表达介导的疾病有良好的治疗效果。
附图说明
为了更清楚地说明本发明实施方式的技术方案,下面将对实施方式中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1是本发明实施1提供的检测结果图。A为分子对接推测2-MS可以与NQO1结合结果图。B为细胞热转移技术检测2-MS与NQO1结合稳定NQO1蛋白结果图。
图2为本发明实施2提供的检测结果图。A和D为2-MS可以增强重组NQO1蛋白活性结果图。B、C、E和F为2-MS与细胞提取蛋白中NQO1蛋白活性结果图。
图3为本发明实施3提供的检测结果图。2-MS剂量(A)与时间(B)依赖性的抑制细胞活性结果图。C为2-MS剂量依赖性的降低细胞ATP水平结果图。D为Annexin V/7AAD双染检测2-MS诱导细胞死亡结果图。E为细胞克隆试验检测2-MS细胞毒性作用结果图。F为斑马鱼肿瘤异种移植模型检测2-MS抗肿瘤作用结果图。G为2-MS降低肿瘤面积的统计结果图。
图4为本发明实施4提供的检测结果图;2-MS通过激活NQO1产生抗肿瘤作用。A为siRNA技术沉默掉NQO1基因对2-MS杀死肿瘤细胞的活性的影响结果图。B为DIC抑制NQO1对2-MS杀死肿瘤细胞的活性的影响结果图。
图5为本发明实施5提供的检测结果图。2-MS主要通过诱导调节性坏死杀伤肿瘤细胞。A为2-MS对凋亡相关蛋白的影响结果图。B为2-MS与TMZ对caspase的影响结果图。C为zvad-fmk对2-MS杀死肿瘤细胞的影响结果图。D为Hoechst33342/PI双染检测2-MS杀死肿瘤细胞的作用结果图。E为Nec-1s对2-MS杀死肿瘤细胞的影响结果图。F为Nec-1s对2-MS消耗肿瘤细胞ATP的影响结果图。G为siRNA技术沉默掉RIP1,RIP3基因对2-MS杀死肿瘤细胞的活性的影响结果图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
本发明实施例提供2-甲氧基-6-乙酰基-7-甲基胡桃酮一种新的用途,其可以有效与NQO1进行靶向结合,可以作为高效的NQO1氧化还原循环底物,继而提升NQO1的活性,诱导NQO1过表达的细胞坏死,继而对于NQO1过表达相关的疾病有良好的治疗效果,特别是恶性肿瘤中的NQO1高表达的恶性胶质肿瘤以及胰腺癌、乳腺癌等。氧化还原循环底物该化合物为NQO1的有效底物,在NQO1介导下,通过氧化还原反应循环,产生大量的活性氧。
实施例1
2-甲氧基-6-乙酰基-7-甲基胡桃酮(缩写为2-MS)靶向结合醌氧化还原酶(缩写为NQO1)
(1)将2-MS和NQO1进行分子对接模拟
模拟结果参见图1中的A。根据图1中的A可知,2-MS平面结构与NQO1活性口袋(活性口袋由FAD与NQO1单体中部分氨基酸位点组成,为反应发生的区域)一侧的FAD(黄素腺嘌呤二核苷酸)的异恶嗪环平行,在活性口袋中通过一系列疏水键和氢键与NQO1单体结合。进一步分析发现,2-MS通过与NQO1的TYR126、TYR128残基形成氢键,也就是与NQO1的126位和128位的酪氨酸残基形成氢键,增加与NQO1的结合稳定性。
(2)利用细胞热转移技术(CETSA)判断2-MS是否与NQO1结合
具体操作如下:
收集U251/U87细胞蛋白样品,离心取上清液;将蛋白样品均分2份,按照体积比100:1分别加入DMSO(对照组)和2-MS(实验组),室温静置30min;分别将对照组和实验组样品均分为7份,各在45℃,50℃,55℃,60℃,65℃,70℃和75℃条件下加热5min,离心取上清液;加入loading buffer进行蛋白变性;western blot检测比较DMSO处理组和2-MS处理组中NQO1蛋白随温度变化的稳定性,并利用软件Image J量化,绘制热溶解曲线。
检测结果参见图1中的B,根据图1中的B可知,在U251/U87两个细胞系中,2-MS处理后的蛋白样品,NQO1蛋白的热溶解曲线出现显著位移,说明2-MS能够直接结合NQO1,上述实验结果显示2-MS可与NQO1靶向结合。
实施例2
判断2-MS能否激活NQO1活性
(1)利用外源性重组人NQO1蛋白检测2-MS对NQO1活性的影响,通过酶反应体系中消耗的NAD(P)H的量来表示NQO1的活性。
具体操作如下:
将50ng的外源性重组人NQO1蛋白,分别在96孔板中与DMSO,DIC,2-MS,2-MS+DIC反应,反应体系为25mM Tris·HCl(pH7.5),0.01%Tween20,0.7mg/ml BSA(pH 7.4),5μMFAD,200μM NADH,反应体积为200μL,用酶标仪检测NADH 340nm处的吸收。
结果参见图2中的A和D,根据图2中的A和D可知,2-MS显著增加NQO1的活性,其激活NQO1的活性几乎完全可以被NQO1的选择性抑制剂双香豆素(DIC)逆转。
(2)在高表达NQO1的U251/U87两株胶质瘤细胞系上检测2-MS对内源性NQO1活性的影响
具体操作如下:
将50μg的细胞提取蛋白,分别在96孔板中与DMSO,DIC,2-MS,2-MS+DIC反应,反应体系为25mM Tris·HCl(pH7.5),0.01%Tween20,0.7mg/ml BSA(pH 7.4),5μM FAD,200μMNADH,反应体积为200μL,用酶标仪检测NADH 340nm处的吸收。
结果参见图2中的B、C和E。根据图2中的B、C和E可知,2-MS显著增加内源性NQO1的酶活性,其激活的活性也几乎完全可以被DIC逆转。
(3)检测在两株胶质瘤细胞系上不同时间点2-MS对于NQO1蛋白水平的影响
具体操作如下:
将U251/U87细胞种于6孔板中,贴壁后用2-MS分别处理0min,30min,1h,2h,4h;收集蛋白样品,Western blotting检测2-MS处理后不同时间点NQO1蛋白表达情况。
检测结果参见图2中的F。根据图2中的F可知,2-MS以时间依赖性方式增加NQO1蛋白水平。上述实验结果显示2-MS可以提高NQO1表达水平。强烈激活NQO1活性。
实施例3
(1)MTT和ATP检测2-MS对于人胶质瘤细胞系U87和U251细胞活力的影响
(a)MTT的检测方法如下:
将U251/U87种于96孔板(10000个/孔);贴壁后分别用DMSO和2-MS处理24h;24h加入每孔加MTT溶液(5mg/ml,PBS配制)20uL,孵育4h;终止培养,小心吸弃孔中上清液,每孔加入100uL DMSO,震荡15min,待蓝紫色结晶甲臜充分溶解后利用酶标仪在570nm处测定吸光度OD值。
(b)ATP的检测方法如下:
将U251/U87种于96孔板(10000个/孔);贴壁后分别用DMSO和2-MS处理8h;利用ATP检测试剂盒测定ATP水平。
检测结果参见图3中的A-C,根据图3中的A、B和C可知,与对照组比较,2-MS处理组ATP水平显著下降,说明2-MS在两株细胞中均能显著降低细胞活力。
(2)利用AnnexinV/7AAD双染检测细胞调亡
操作方法如下:
将U251/U87种于12孔板;贴壁后分别用DMSO和2-MS处理24h,利用AnnexinV/7AAD双染检测试剂盒检测细胞死亡。细胞凋亡早期磷脂酰丝氨酸由细胞膜内侧转到细胞膜表面,AnnexinV可与之结合;7AAD是一种核酸染料,不能透过完整细胞膜,但可透过凋亡中晚期和坏死细胞的细胞膜而使细胞核染红,AnnexinV/7AAD双染可将凋亡早晚期和坏死细胞区分开。
检测结果参见图3中的D,根据图3中D可知,2-MS处理组能够显著增加AnnexinV和7AAD阳性细胞,提示2-MS诱导的细胞死亡不是凋亡,而是坏死。
(3)平板克隆形成实验
具体操作如下:
将U251/U87种于6孔板(500个/孔),使细胞在孔中均匀单个分布;贴壁后分别用DMSO和2-MS处理8h;8h后更换1%血清培养基,继续培养7天进行单细胞克隆;7天后,吸弃培养基,PBS洗2-3次,加入1%多聚甲醛固定30min;吸弃多聚甲醛,加入结晶紫染色10min;吸弃结晶紫,PBS洗2-3次;拍照。
检测结果参见图3中的E。克隆形成实验的目的是通过细胞在细胞培养板上的克隆形成能力来提示细胞的增殖能力。根据图3中的E可知,与对照组相比,2-MS处理组能够显著减少细胞克隆形成数量,2-MS显著抑制了克隆形成,提示其可显著抑制细胞的增殖。
(3)体内抗肿瘤效果测试
操作步骤如下:将荧光标记的U251细胞(100个/只)接种到斑马鱼幼鱼的卵黄囊中,1天后开始分别使用2-MS(0nM,50nM,200nM)、阳性药物替莫唑胺TMZ(100μM)处理,采用浸泡药浴方式进行渗透给药,定期观察肿瘤面积,用药2天后拍照,收集斑马鱼组织样品。
检测结果参见图3中的F和G,根据图3中的F和G可知,200nM的2-MS与100μM的TMZ均可显著地抑制肿瘤生长。尤其是,与阳性药物TMZ组相比,2-MS在200nM剂量的抑制作用与100μM的TMZ差别无显著性(P>0.05),这提示,2-MS的效价更高,对肿瘤的生长抑制作用更为显著。
实施例4
确定2-MS抑制肿瘤生长的作用是否通过激活NQO1
(1)siRNA技术检测
操作方法如下:
将U251/U87种于6孔板,待细胞融合至70-90%时,按照转染试剂lipofectamine3000说明书分别转染Si-NQO1(实验组)和Si-NC(对照组),培养8h后更换正常培养基;培养48h后分别消化实验组和对照组细胞种于96孔板(10000个/孔),贴壁后实验组和对照组均分别给药DMSO和2-MS处理8h;利用ATP检测法检测细胞活力。
检测结果参见图4中的A。根据图4中的A可知,2-MS杀伤肿瘤细胞的作用被NQO1的SiRNA显著逆转。这提示2-MS对肿瘤细胞的杀伤作用是通过NQO1所介导的。
(2)双香豆素特异性抑制NQO1实验
操作方法如下:
将U251/U87种于96孔板(10000个/孔);贴壁后加入双香豆素(DIC,10μM)预处理1h,1h后分别给药DMSO和2-MS处理24h;利用MTT检测法检测细胞活性。
检测结果参见图4中的B。根据图4中的B可知,NQO1的特异性抑制剂DIC也可以显著逆转2-MS杀伤肿瘤细胞的作用。
综上,上述两个实验结果说明2-MS通过NQO1介导杀伤肿瘤细胞。
实施例5
确认2-MS如何杀死肿瘤细胞
检测2-MS诱导的胶质瘤细胞死亡是否通过激活Caspase(含半胱氨酸的天冬氨酸蛋白水解酶)诱导凋亡
操作方法如下:
(1)Caspase蛋白表达
将U251/U87种于6孔板,贴壁后用2-MS(0,5,7.5,10μM)分别处理,收集蛋白样品,Western blotting检测2-MS处理8h后Caspase蛋白的表达情况。
(2)Caspase3/7活性检测
将U251/U87种于96孔板,贴壁后分别用DMSO,2-MS,TMZ处理8h。利用caspase3/7活性检测试剂盒检测caspase活性。
(3)泛Caspase抑制剂z-vad-fmk对2-MS杀伤肿瘤细胞的作用
将U251/U87种于96孔板,贴壁后用z-vad-fmk进行预处理1h。1h后分别用DMSO,2-MS处理24h。利用MTT检测法检测细胞活性。
检测结果参见图5中的A-C。根据图5中的A可见,2-MS对Caspase蛋白的表达无明显影响,也未检测到Caspase的切割。由B可见,阳性药物TMZ可显著增加Caspase活性,而2-MS对Caspase3/7的活性无明显影响。由C可见,Caspase泛抑制剂z-vad-fmk不能逆转2-MS诱导的细胞死亡。因此,这说明2-MS与阳性药物TMZ不同,它不激活Caspase。
(2)Hoechst33342/PI双染检测
操作方法如下:
将U251/U87种于12孔板,贴壁后分别用DMSO和2-MS处理24h,利用Hoechst33342/PI双染试剂盒检测。Hoechst33342可穿透细胞膜,进入正常细胞和凋亡细胞,与DNA结合在紫外下发出蓝色荧光,且凋亡细胞染色质固缩,荧光强于正常细胞;PI不能透过正常细胞膜,不能进入具有完整细胞膜的正常细胞及凋亡细胞,而对于坏死细胞,其细胞膜完整性被破坏,PI可穿透细胞膜使坏死细胞染色发出红色荧光。故PI阳性细胞提示为坏死细胞,而Hoechst33342阳性细胞为凋亡细胞。
检测结果参见图5中的D。由图5中的D可见,2-MS处理组的细胞并未观察到Hoechst33342的强烈荧光,却以浓度依赖性方式增加PI阳性细胞数。这与图3结果相符合,提示2-MS诱导肿瘤细胞死亡不是凋而是坏死。
综上,上述实验结果显示2-MS诱导细胞死亡不是凋亡,与Caspase无关,而是坏死。
(3)程序性坏死的激酶RIP1的抑制剂Nec-1s对2-MS的杀伤肿瘤细胞作用的逆转
操作方法如下:
将U251/U87种于96孔板,贴壁后用Nec-1s预处理1h。1h后分别用DMSO,2-MS处理细胞24h或者8h。利用MTT检测法检测处理24h和ATP检测法检测处理8h后的细胞活性。
检测结果参见图5中的E和F。由图5中的E和F可见,程序性坏死的主要调节激酶RIP1的特异性抑制剂Nec-1s可以显著逆转2-MS诱导的细胞死亡。这提示2-MS诱导的细胞死亡是程序性坏死。
(4)siRNA技术检测
操作方法如下:
将U251/U87种于6孔板,待细胞融合至70-90%时,按照转染试剂lipofectamine3000说明书分别转染Si-RIP1(实验组),Si-RIP3(实验组)和Si-NC(对照组),培养8h后更换正常培养基;培养48h后分别消化实验组和对照组细胞种于96孔板(10000个/孔),贴壁后实验组和对照组均分别给药DMSO和2-MS处理12h。利用MTT检测法检测细胞活力。
检测结果参见图5中的G。由图5中的G可见,运用siRNA技术分别沉默RIP1和RIP3,均可以显著逆转2-MS诱导的细胞死亡。这说明RIP1和RIP3参与调节2-MS诱导的细胞死亡。
综上,上述实验结果显示与TMZ不同(主要通过诱导凋亡),2-MS主要通过诱导坏死杀死肿瘤细胞。
以上所述仅为本发明的优选实施方式而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.2-甲氧基-6-乙酰基-7-甲基胡桃酮作为NQO1氧化还原循环底物的用途。
2.2-甲氧基-6-乙酰基-7-甲基胡桃酮作为NQO1激活剂的用途;
优选地,2-甲氧基-6-乙酰基-7-甲基胡桃酮对NQO1的激活作用可被NQO1选择性抑制剂逆转;
优选地,NQO1选择性抑制剂逆转选自双香豆素、苯茚二酮和Diminutol中的至少一种,优选为双香豆素。
3.根据权利要求2所述的用途,其特征在于,NQO1的激活是通过所述2-甲氧基-6-乙酰基-7-甲基胡桃酮与所述NQO1的活性位点结合。
4.根据权利要求3所述的用途,其特征在于,2-甲氧基-6-乙酰基-7-甲基胡桃酮与所述NQO1的活性位点结合包括2-甲氧基-6-乙酰基-7-甲基胡桃酮与NQO1的黄素腺嘌呤二核苷酸的异恶嗪环通过疏水作用和氢键进行结合。
5.根据权利要求4所述的用途,其特征在于,2-甲氧基-6-乙酰基-7-甲基胡桃酮与所述NQO1的活性位点结合还包括2-甲氧基-6-乙酰基-7-甲基胡桃酮与NQO1的126位和128位的酪氨酸残基形成氢键。
6.2-甲氧基-6-乙酰基-7-甲基胡桃酮在制备提高NQO1蛋白表达水平的药物中的应用。
7.2-甲氧基-6-乙酰基-7-甲基胡桃酮在制备治疗NQO1高表达介导的疾病药物中的应用。
8.根据权利要求7所述的应用,其特征在于,NQO1高表达介导的疾病包括恶性肿瘤。
9.根据权利要求8所述的应用,其特征在于,所述恶性肿瘤包括胰腺癌、乳腺癌、肺癌、大肠癌、白血病以及恶性胶质瘤中的任意一种,更优选地,所述恶性肿瘤为NQO1高表达的亚型。
10.根据权利要求8所述的应用,其特征在于,2-甲氧基-6-乙酰基-7-甲基胡桃酮作为NQO1氧化还原循环底物;
优选地,2-甲氧基-6-乙酰基-7-甲基胡桃酮激活NQO1;
优选地,2-甲氧基-6-乙酰基-7-甲基胡桃酮抑制肿瘤细胞生长;
优选地,2-甲氧基-6-乙酰基-7-甲基胡桃酮通过激活NQO1抑制肿瘤细胞生长;
优选地,2-甲氧基-6-乙酰基-7-甲基胡桃酮抑制肿瘤生长通过抑制肿瘤细胞增殖和诱导肿瘤细胞坏死;
优选地,激酶RIP1和/或激酶RIP3调节2-甲氧基-6-乙酰基-7-甲基胡桃酮诱导的肿瘤细胞坏死;
优选地,激酶RIP1抑制剂和/或激酶RIP3抑制剂可逆转2-甲氧基-6-乙酰基-7-甲基胡桃酮诱导的肿瘤细胞坏死。
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