CN102844323A - Cdk5抑制剂及其治疗用途 - Google Patents
Cdk5抑制剂及其治疗用途 Download PDFInfo
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- CN102844323A CN102844323A CN2010800552844A CN201080055284A CN102844323A CN 102844323 A CN102844323 A CN 102844323A CN 2010800552844 A CN2010800552844 A CN 2010800552844A CN 201080055284 A CN201080055284 A CN 201080055284A CN 102844323 A CN102844323 A CN 102844323A
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Abstract
本发明涉及细胞周期蛋白依赖性激酶5(Cdk5)的天然来源的抑制剂,其分离自玫瑰红景天根,并且其结构与已知的Cdk抑制剂不同。它们对不同的Cdks显示出选择性,并且通过混合类型的抑制模式而表现出抑制Cdk的效力,这使得其毒性和副作用较小。它们可用于预防和治疗与异常Cdk5活性相关的疾病或病症,例如,急性和/或慢性疼痛、神经性疼痛、糖尿病、癌症、神经退行性疾病和神经病理紊乱等。
Description
对相关申请的交叉引用
本申请要求2009年12月7日提交的美国临时申请No.61/282,039的优先权。
技术领域
本发明涉及分离自天然来源的新的Cdk抑制剂,这种Cdk抑制剂被用于治疗用途。更具体地,本发明涉及分离自植物玫瑰红景天(Rhodiola rosea)的天然来源的Cdk5抑制剂以及它们作为Cdk5抑制剂的生物学活性。
背景技术
利用当今的高通量化学合成技术和高效筛选方法学,在实验室发现细胞水平显示有前景的生物学作用的化合物可能不再困难。但是,由于很多因素的影响,这些化合物转化为临床上有用的化合物比率非常低。其中一个关键的因素是毒性和副作用,在药物开发的后期阶段其通常严重且不被人体所忍受。基于此,由数千年来临床使用的天然来源发现的新化合物重新受到了关注,这是因为它们已经被人类使用了很长时间,且因此它们的毒性和副作用相对于纯粹合成的化合物而言似乎更易接受。
细胞周期蛋白依赖性激酶(Cdk)属于脯氨酸定向的丝氨酸/苏氨酸激酶家族,其在调控细胞周期进展和转录控制中起着重要的作用。Cdk的活化需要与特异性调节亚单位细胞周期蛋白的结合,以及需要在Cdk的特异性苏氨酸残基上的磷酸化。Cdkl、2、3、4和6在调节不同细胞周期的转换中起着重要作用。Cdkl为有丝分裂Cdk,而Cdk2、4和6为分裂期间Cdk,其在休眠Gl至S期的进程中起到调节作用。因此,Cdks的异常活化导致细胞周期失调,例如持续的细胞增殖或不受限制的细胞周期重返,以及随后的疾病(例如癌症)的发生(Shapiro,2006;Malumbres & Barbacid,2009)。由于细胞周期蛋白依赖性激酶5(Cdk5)(一种脯氨酸定向的丝氨酸/苏氨酸激酶)在神经元发育和功能中的必不可少的作用,因此Cdk5是独特的。尽管与其他的Cdks在结构上具有同源性,但Cdk5可能不参与细胞周期的调节。Cdk5的活化依赖于其与两个特异性活化子p35和p39(其在神经元细胞中表达)的结合。因此,尽管Cdk5在细胞中的表达无处不在,但是由于其局限于p35和p39的表达,因此其主要活跃在有丝分裂后的神经元中(Tsai等,1993;Zheng等,1998)。
Cdk5在神经细胞中起多种生理作用,包括在早期神经发育期间的神经元的迁移(Xie等,2003)和轴突导向(Connell-Crowley等,2000)以及突触形成和突触可塑性(Cheung等,2006;Lai和Ip,2009)。然而,最近已经发现Cdk5在中枢神经系统外发挥重要作用,例如涉及感觉传导通路的疼痛信号传导(Pareek等,2006),以及调节胰腺β细胞中的葡萄糖刺激的胰岛素水平(Wei等,2005)。由于Cdk5起到关键的生理学作用,其不受控的活性已经与多种疾病/病症相关联,从而使得Cdk5可作为治疗药物的潜在分子靶标。在神经元中,Cdk5失调引起神经元细胞凋亡(Cheung和Ip,2004),这表明Cdk5活性的异常调节与神经退行性疾病的发展有显著关系,例如阿尔茨海默氏病(AD)和帕金森病(PD)。异常的Cdk5活性还与癌症发生、进展和转移(例如前列腺和甲状腺瘤)相关联(Strock等,2006;Lin等,2007)。
AD的两个主要病理学标志为老年斑的累积和在发病的脑部中的神经原纤维缠结。Cdk5的失调是由于p25的存在所造成的,p25是在病理条件下p35产生的裂解产物(Patrick等,1999)。在AD患者的脑部中发现了p25蛋白的累积(Patrick等,1999)。最近的发现也表明Cdk5为调节老年斑的形成(Monaco,2004)和神经原纤维缠结(Cruz等,2003)的形成的关键酶之一。
另一种与Cdk5关联的主要神经退行性疾病为PD。病理学上,PD的特征在于由于所选神经元,尤其是在黑质致密部的多巴胺能神经元的渐进性死亡而导致的运动原障碍(Muntane等,2008)。在l-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的PD小鼠模型中,过度的Cdk5的表达和活性与多巴胺能神经元细胞死亡相关(Smith等,2003;Qu等,2007)。此外,有意义的是,Cdk5的抑制能导致多巴胺释放的增加,这可有助于改善PD进展(Chergui等,2004)。Cdk5也发现涉及许多其他的神经退行性疾病和神经性病症,例如亨廷顿病(Anne等,2007)、肌萎缩侧索硬化(ALS;Bajaj等,1998)和局部缺血损伤(Wang等,2003)。
最近的研究表明,异常的Cdk5活性还与糖尿病(2型糖尿病)的发病机制有关。在胰腺β细胞中存在Cdk5的活化剂p35,其活性在葡萄糖刺激下负调控胰岛素释放(Wei和Tomizawa,2007)。并且在高葡萄糖暴露时,小鼠胰腺β细胞中的p35蛋白和Cdk5活性会持续增加(Ubeda等,2006)。此外,在培养的β细胞和糖尿病小鼠模型中,化学抑制剂对Cdk5活性的抑制以葡萄糖依赖方式增加了胰岛素的分泌(Ubeda等,2006)。这些发现与观察到的p35-/-小鼠对于葡萄糖负荷显示的胰岛素分泌增加相一致(Wei等,2005)。认为Cdk5通过葡萄糖毒性期间的Ca2+通道活性的调节或胰岛素基因表达的调节起作用(Wei等,2005;Ubeda等,2006)。因此,Cdk5抑制剂能够作为治疗2型糖尿病的潜在治疗药物(Kitani等,2007)。
Cdk5也已成为止痛药的主要潜在靶标。Cdk5/p35与感觉通路间接相关。例如,在潜在的伤害性神经元调节痛觉过敏中,Cdk5调节细胞分裂素活化蛋白激酶(MAPK)的活化,导致MAPK活性增加。研究还表明Cdk5亦涉及其他的疼痛通路,例如钙-钙调素激酶II、δFosB、NMDA受体和P/Q型电压依赖性钙通道等。此外,研究表明Cdk5抑制剂可能有助于控制急性疼痛。已表明Cdk5/p35涉及疼痛处理,其受到抑制能降低正常疼痛通路的响应性(Pareek等,2006;Pareek和Kulkarni,2006)。更具体地,大鼠中外周炎症诱导Cdk5活性增加。尽管具有更高Cdk5活性的p35转基因小鼠对于疼痛刺激更加敏感,但是p35-/-以及Cdk5条件基因敲除小鼠(具有显著减低的Cdk5活性)对于疼痛刺激均显示延迟的响应(Pareek等,2006;Pareek等,2007)。在外周炎症反应中,Cdk5通过负反馈回路还调节促细胞分裂剂激活性蛋白激酶l/2(MEK1/2)/1M的活性(Pareek和Kulkarni,2006)。此外,最近亦确定瞬时受体电位香草酸亚型1(TRPV1)(一种通过热、质子和辣椒辣素活化的配体-门控的阳离子通道)为Cdk5的底物(Pareek等,2007)。基于经Cdk5的TRPV1磷酸化调节疼痛信号传导期间的TRPV1的功能,Cdk5被认为能够作为用于开发止痛药的新的分子靶标。
由于Cdk5与多种疾病相关,因此靶向Cdk5抑制剂的筛选可有助于鉴定潜在的药物先导物。然而,至今仅鉴定了很少的Cdk5抑制剂,而且它们也不是用于神经适应症的临床评估。Roscovitine(2,6,9-取代的嘌呤类似物)为开发的Cdk5抑制剂之一,但其也是靶向Cdkl、Cdk2、Cdk7和Cdk9抑制剂(Meijer等,1997)。当今,roscovitine处于II期临床试验阶段(用于非小细胞肺癌、乳腺癌和B-细胞恶性肿瘤)。Indirubin类为另一类来源于中药的Cdk抑制剂。双吲哚indirubin为当归龙荟丸(一种传统的中药处方)的活性成分,由于其抗有丝分裂和抗肿瘤的活性使其可用于治疗白血病和其他慢性疾病(Leclerc等,2001)。Indirubin抑制多种激酶,包括Cdkl、Cdk5以及糖原合成酶激酶-3β(GSK3β)。认为GSK3β和Cdk5与AD中观察到的TAU的高度磷酸化有关。
概括而言,科学文献清楚地、强烈地表明Cdk5抑制剂对于疼痛的治疗和2型糖尿病的控制是有前景的治疗药物,以及也可以用于治疗神经退行性疾病和神经学病症。但是,缺乏可有效抑制Cdk5(相对于其他的Cdk)的有前景的候选化合物。
发明内容
本发明的目的之一在于提供具有出色Cdk5抑制活性的玫瑰红景天根的正丁醇组分,以及含有其的组合物。
相应地,本发明的另一目的在于提供很多对Cdk5具有高特异性抑制作用的天然存在的化合物。所有的这些化合物分离并纯化自天然植物玫瑰红景天。这些化合物中的一些是新的化合物且具有通式(I)的结构:
式I
其中,R1-R11各自独立地未被取代(即为氢)或被本领域的普通技术人员所认为的合适的相同或彼此不同的取代基所取代。实例如下:F199-C22。″取代基″为有机化学中常用的术语,且本领域的普通技术人员理解为原子或基团,其在烃母链上的氢原子的位置上取代以替换氢原子。本领域的普通技术人员能够判断在烃的母链或骨架的给定位置上存在何种具体取代基,而无需多余的实验。因此,对于本发明和其权利要求而言,术语″取代基″是指在烃的母链上的氢原子的适宜取代,这对于有机化学领域的普通技术人员而言是显而易见的或是容易确定的,而不需要多余的实验。R1-R5的可能的取代基的实例为羟基、烷氧基、酰基、卤素、烷基、杂烷基、芳基烷基、环烷基、环烷基-烷基、卤代烷基、杂环烷基或芳基。对于R6,取代基可为酰基、烷基、杂烷基、芳基烷基、环烷基、环烷基-烷基、卤代烷基、杂环烷基或芳基,不包括Ph-CO。对于R7-R11,取代基可为羟基、烷氧基、酰基、卤素、烷基、杂烷基、芳基烷基、环烷基、环烷基-烷基、卤代烷基、杂环烷基或芳基。由表示的波浪线是指该波浪线所连接的碳原子具有顺式、反式构型或其混合构型。
诚然,正如本领域的普通技术人员所理解,那些天然存在的化合物可以实验室或工业规模通过合成工艺而制备。还可理解,只要那些经鉴定的化合物在其具体情况下可能被使用者认为合适,便可以将其制成药学上可接受的盐、前体药物、水合物及其异构体的形式。
本发明的另一目的在于提供一种具有高特异性的抑制Cdk5活性,尤其是抑制Cdk5/p25和Cdk5/p35活性的方法。该目标通过将酶与分离自天然植物玫瑰红景天的化合物接触而实现。该化合物中的一些为式II或III化合物:
式II
其中,R1-R7各自独立地未被取代(即为氢)或被本领域的普通技术人员所认为的合适的相同或彼此不同的取代基所取代。该化合物的实例如下:F199-C6、F199-C16、F199-C23、F199-C35、F199-C42和F199-C57。
式Ⅲ
其中,R1-R11各自独立地未被取代(即为氢)或被本领域的普通技术人员所认为的合适的相同或彼此不同的取代基所取代。该化合物的实例如下:F199-C34。还存在其他的本发明的Cdk5抑制剂,它们的结构不同于式II或III。实例如下:F199-C4和F199-C22。关于此处所指的化合物的结构的详细信息在本说明书的后面提供。
本发明的另一目的在于提供一种治疗或预防由Cdk5活性的异常变化引起的疾病的方法。此类疾病的实例为急性和慢性疼痛、糖尿病、癌症、神经退行性疾病和神经病理学紊乱(例如,AD、PD、ALS和亨廷顿病)。该目标通过如前所述向患者给药治疗有效量的化合物而实现。
除了对Cdk5的作用外,本发明的治疗方法还保护神经元细胞免受淀粉样β肽(Aβ)诱导的神经毒性和细胞凋亡的影响。Aβ是一种源自淀粉样前蛋白(APP)的裂解产物,其累积于胞外或老年斑(AD的标志)上。尽管AD的实际原因仍然不清楚,但很多报道已经引证了Aβ在疾病的起始和进展中起着重要作用。此外,研究显示Aβ具有神经毒性,能导致神经元损失以及随后的记忆损失和认知障碍。
赋予本发明特征的新颖性的多个特征在随附的权利要求中详细指出且构成了该公开的一部分。为了更好的理解本发明、其实施优势及其用途所获得的具体目标,参考附图以及下列附图说明,其示例性地描述了本发明的优选实施方案。
附图说明
图1显示Cdk5/p25和Cdk5/p35的剂量响应曲线。将不同浓度的Cdk5/p25或Cdk5/p35与底物和ATP一起培养1小时。该测试一式四份进行。
图2显示roscovitine以剂量-依赖性方式对Cdk5激酶活性的抑制作用。将多种浓度的Roscovitine与30ng/ml的Cdk5/p25或Cdk5/p35一起培养。该测试一式四份进行。
图3显示本发明化合物的抑制作用。将各化合物(30μΜ)与30ng/ml的Cdk5/p25或Cdk5/p35一起培养。30μΜ的Roscovitine对Cdk5/p25和Cdk5/p35均具有100%的抑制。该测试一式四份进行,数据为4个独立试验的平均值。
图4显示本发明化合物对Cdk5/p25活性的剂量依赖性抑制作用。该测试一式四份进行,数据为4个独立试验的平均值。
图5显示化合物F199-C6对大鼠皮质神经元抗Αβ兴奋性毒性的保护作用。将胚胎大鼠皮质神经元(7DIV)使用多种浓度的化合物(3-50μΜ)预处理,然后与Αβ25-35(10μΜ)共同培养。培养过夜后,进行MTT测试。细胞存活以相对于溶剂对照(DMSO)的百分比计算。该测试一式四份进行,数据使用student-t检验比较,*=P<0.05。
图6显示化合物F199-C34在图5描述的条件下对大鼠皮质神经元抗Αβ兴奋性毒性的保护作用。
图7显示化合物F199-C22在图5描述的条件下对大鼠皮质神经元抗Αβ兴奋性毒性的保护作用。
图8显示F199-C16对不同的Cdk复合体的不同抑制作用。
图9显示F199-C23对不同的Cdk复合体的不同抑制作用。
图10显示F199-C34对不同的Cdk复合体的不同抑制作用。
图11显示F199-C16和F199-C23对Cdk5/p25复合体的抑制模式。
图12显示在疼痛的动物模型中F199-C16对舔足响应的作用。
图13显示本发明的总提取物和玫瑰红景天的多种组份对Cdk5/p25的作用。
具体实施方式
总提取物的制备
干燥的玫瑰红景天根2005年10月采集于中国新疆伊犁地区,且于2005年10月购买自四川成都医药公司。首先,将该干燥的红景天根(300g)干燥并浸泡在1.5L 70%乙醇(EtOH,料液比为1:5)中30分钟。然后将该药草-溶剂混合物回流3次,每次2小时。将提取液过滤,并将滤液蒸发至干,得到44.0g总提取物(TE)。
精制组份(F199-BU)的制备
将TE(44.0g)溶于/悬浮于300mL水中,并依次使用氯仿(CF,300mL)和水饱和的丁醇(BU,300mL)以1∶1体积比萃取。每种不同的溶剂萃取重复5次,并将该溶剂提取物过滤,干燥,得到组份CF(14.5g)、BU(17.6g)和WA(10.2g)。F199-BU组份的HPLC检测参数:HPLC条件:建立高效液相色谱-二极管阵列检测器(HPLC-DAD)方法,用于F199-BU批次090725T和F199-BU批次080602T的分析和质量控制。Waters HPLC系统(由600泵、717自动进样器和UV/VIS2996二极管阵列检测器组成)用于所有的分析。色谱分离在SunFireC18柱(粒径:5μm,4.6mmx150.0mm)上进行,利用乙腈(作为溶剂A)和水(作为溶剂B)作为流动相,以1.0ml/分钟的流速在室温下进行。梯度洗脱从0至45分钟使用10%至60%的溶剂A(0-35分钟,10%至50%ACN;35-40分钟,50%至60%ACN;40-45分钟,60%至10%ACN)。将各样品通过0.45μm Millipore注射头过滤器过滤,进样20微升的样品用于HPLC分析。
F199化合物的分离
本发明使用鉴定代码″F199″开头的化合物是按照如下所述方式,利用本领域普通技术人员已知的多种反应分离自玫瑰红景天的。应当理解,本领域的普通技术人员还会理解替代性方法也可以用于分离本发明的目标化合物。
将经干燥的玫瑰红景天根使用95%的乙醇水溶液(35L,35L,35L,2h/次)回流提取三次。将该95%EtOH提取液真空下浓缩,得到浸膏(900g)。将该浸膏悬浮于水中,然后依次分配于石油醚、乙酸乙酯和正丁醇中。将这些萃取液蒸发,分别得到总共90g石油醚提取物、250g乙酸乙酯提取物,和360g正丁醇提取物。
然后,将乙酸乙酯提取物(250g)先用硅胶柱层析,其利用氯仿-甲醇极性递增的混合物洗脱,最终使用甲醇洗脱,获得108个洗脱流份(Fr.l-Fr.108)。根据TLC(薄层层析)板显色结果,合并类似的流份。反复进行柱色谱(硅胶或Sephadex LH-20)和重结晶方法分离得到化合物没食子酸(F199-C4,18mg)(自流份Fr.21-22)、rhodalin(F199-C6,22mg)、litvinolin(F199-C16,36mg)(自流份Fr.62-69)、6-O-没食子酰基松香(F199-C22,10mg)、4′-甲氧基草质素(F199-C23,22mg)(自流份Fr.72-75)、6-O-没食子酰基熊果酚甙(F199-C34,17mg),和表没食子儿茶素-3-没食子酸酯(F199-C35)(自流份Fr.89-90)。
将部分正丁醇提取物(200g)进行硅胶柱层析,使用乙酸乙酯/乙醇/水(比例为20∶2∶1、16∶2∶1、10∶2∶1、6∶2∶1、4∶2∶1)洗脱,得到66个洗脱流份。利用反复柱色谱(硅胶或Sephadex LH-20,最终使用制备型HPLC纯化)分离,得到化合物山奈酚-3-O-β-D-吡喃木糖基(l→3)β-D-吡喃葡萄糖苷(F199-C42,9mg)(自Fr.12-14)和isomericitrin(F 199-C57,6mg)(自Fr.41-54)。
Cdk5激酶测试和动力学研究
Cdk5激酶测试按照指示手册中所述进行(Invitrogen,cat.no.PV3673)。该测试采用FRET的偶联酶模式,并且基于磷酸化的和未磷酸化的肽对蛋白酶裂解的差别选择性为基本原理。该测试使用标记的供体荧光团(香豆素)和受体荧光团(荧光素)合成的肽底物(Z′-LYTETM肽底物)组成一FRET对。在初始反应中,Cdk5将ATP的γ-磷酸转移至底物上的丝氨酸/苏氨酸残基上,在初始反应中存在的激酶抑制剂抑制了磷酸化。在继发反应中,加入位点-特异性蛋白酶,并以本质上高于磷酸化底物的速率裂解未磷酸化的Z′-LYTETM肽底物。裂解破坏了未磷酸化底物上的供体和受体荧光团之间的FRET,而未裂解的磷酸化底物维持FRET。化合物抑制Cdk5活性的效力通过计算发射比例进行测量。
Cdk5激酶测试通过添加Z′-LYTETM肽底物和ATP以及Cdk5/p25或Cdk5/p35激酶溶液在384-孔黑色聚苯乙烯板(Corning 3676)中进行。将该板在室温培养1小时。然后在黑暗中加入显色液1小时。最后,加入终止液,香豆素和荧光素发射信号在荧光酶标仪上测量(Tecan,infinite F500)(激发波长:400nM,发射波长分别为445nM和520nM)。为了计算Cdk5/p25和Cdk5/p35的活性,Z′-LYTE磷酸肽用作100%磷酸化对照,而没有磷酸化的Z′-LYTE肽用作0%磷酸化对照,以建立最大和最小发射比例值,从而能够计算激酶磷酸化的百分比。为了测定对Cdk5活性的抑制作用,将要进行测试的组份和化合物在激酶反应中培养。在反应中,零抑制测试用DMSO(溶剂)而非化合物进行测定。Roscovitine(一种公知的Cdk5抑制剂)用作抑制激酶活性的阳性对照。测试一式四份进行,数据来自至少4个独立试验的平均值。组分和化合物对于Cdk1/细胞周期蛋白B和Cdk2/细胞周期蛋白A激酶活性研究采用类似的实验方案。各个激酶复合体的活性通过滴定评估,在抑制研究中使用得到的EC30值。由于激酶复合体的活性随着制备的不同批次而变化,EC30将在每一新批次的激酶中进行测试。在剂量-依赖性研究中,化合物对激酶复合体的IC50值根据3-5个独立试验的平均值而测定。化合物的动力学研究通过Cdk5/p25激酶测试利用多种浓度的ATP和测试化合物进行。动力学参数通过非线性最小二乘法利用GraphPad Prism 5软件进行测定。
Aβ测试
脑皮质神经元取自18天老鼠胚胎,进行7天的细胞培养后进行细胞模型测试。在这些细胞中,Aβ25-35肽引起的毒性通过培养2天后经MTT检测进行评估。进行该Aβ测试以研究本发明保护皮质神经元免受由外源Aβ25-35肽添加诱导的细胞死亡。该测试一式两份进行,数据来自至少3个独立试验的平均值。
疼痛动物模型
成年ICR小鼠(6-8周龄)在测试前圈在实验室3天。测试从上午9点至下午3点进行。将小鼠随机分组并称重。小鼠使用单剂量的F199-C16(10-100mg/kg,腹膜内注射)预处理,然后注射10μl的2.5%甲醛至右后爪的足底。在甲醛注射后0-10分钟(早期)和11-40分钟(后期)记录舔足时间(单位为秒)。整个过程通过数字单色影像照相机监测并记录。数据表示为平均值±SEM。(*p<0.05;ANOVA,利用Student-Newman Keuls检验)。
Cdk5/p25和Cdk5/p35的激酶活性
Cdk5/p25和Cdk5/p35的激酶活性利用如上所述的Z′-LYTETM激酶测试试剂盒(Invitrogen)进行。测试数据显示于图1中,其为剂量响应曲线的形式。不同浓度的Cdk5/p25或Cdk5/p35与底物和ATP培育1小时。如图1所示,激酶活性(表示为磷酸化的百分比)随着增加酶Cdk5/p25和Cdk5/p35的浓度而递增。如曲线所示,对于Cdk5/p25的EC50为约35.8ng/ml,Cdk5/p25为约34.4ng/ml。
基于FRET的测试中测量的Roscovitine对Cdk5的抑制作用
Roscovitine(Ros)是一种公知的Cdk5激酶抑制剂。其对Cdk5/p35和Cdk5/p25的抑制作用利用Z′-LYTETM激酶测试试剂盒(Invitrogen)作为阳性对照进行检测。图2显示出roscovitine以剂量-依赖性方式造成Cdk5/p25和Cdk5/p35激酶活性的降低,IC50值为0.16μΜ,与文献报导的相当(Meijer等,1997)。
本发明化合物对Cdk5的抑制作用
利用如上所述的基于FRET的Cdk5激酶测试方法,对本发明化合物的Cdk5激酶活性的抑制作用进行了检测。用于筛选Cdk5抑制剂的Cdk5/25和Cdk5/p35的量为该激酶复合体的EC30,该EC30使用激酶复合体的滴定研究进行确定。随后通过比较在加入测试化合物情况下的Cdk5激酶的肽底物磷酸化百分比和没有测试化合物的情况下的Cdk5的肽底物磷酸化百分比,从而计算化合物抑制Cdk5活性的效力。
如图3所示,分离自玫瑰红景天的11个化合物(F199)对Cdk5/p25和Cdk5/p35的激酶活性均显示不同程度的抑制作用。F199-C1(胡萝卜甙)、F199-C22(6-O-没食子酰基松香,新结构)和F199-C42(山奈酚-3-O-β-D-吡喃木糖基(l→3)β-D-吡喃葡萄糖苷)对Cdk5活性显示弱抑制(<25%)。F199-C4(没食子酸)、F199-C6(rodalin)和F199-C57(isomericitrin)显示中等抑制(25-50%),而F199-C16(litvinolin)、F199-C23(4′-甲氧基草质素)、F199-C34(6-O-没食子酰基熊果酚甙)和F199-C35(表没食子儿茶素-3-没食子酸酯)显示强烈抑制(50-75%)。文献报道F199-C1(胡萝卜甙)和F199-C2(山奈酚)具有中等抑制Cdk5活性,因此作为对照。
IC50和最大抑制率
选取分离自玫瑰红景天的七个天然化合物(F199),并测定其IC50和最大抑制率。将多种浓度的F199化合物与Cdk5/p25一起培养。通过比较在加入测试化合物情况下的Cdk5/p25的肽底物磷酸化百分比和没有加入测试化合物情况下的Cdk5/p25的肽底物磷酸化百分比,从而计算各个化合物抑制Cdk5活性的效力。结果显示于表1和图4中,在七个测试的化合物中,F199-C16(litvinolin)和F199-C34(6-O-没食子酰基熊果酚甙)对Cdk5/p25具有最小的IC50和最高的最大抑制率。
表1
化合物 | IC50(μM) | 最大抑制率 |
F199-C4(没食子酸) | 40.6 | 64.19%,200μM |
F199-C6(rhodalin) | 34.4 | 56.61%,200μM |
F199-C16(litvinolin) | 3.24 | 87.5%,200μM |
F199-C22(6-O-没食子酰基松香) | 20.1 | 46.5%,200μM |
F199-C23(4′-甲氧基草质素) | 1.21 | 45%,200μM |
F199-C34(6-O-没食子酰基熊果酚甙) | 5.63 | 70%,200μM |
F199-C35(表没食子儿茶素-3-没食子酸酯) | 14.72 | 68.4%,200μM |
由Aβ诱导的抗兴奋性毒性的作用
Aβ的外源性加入通过细胞凋亡引起皮层神经元的细胞死亡。进行MTT测试(一种公知的细胞死亡测试)以研究本发明化合物在原代皮质神经元细胞中防止Aβ-诱导的兴奋性毒性的能力。将胚胎大鼠皮质神经元(7DIV)用多种浓度的各化合物(3-50μM)预处理,然后与Aβ25-35(10μM)共同培养。培养过夜后,进行MTT测试。计算相对于溶剂对照(DMSO)的细胞存活百分比。该测试一式两份进行,数据使用student-t检验进行分析,*=P<0.05。示例性化合物F199-C6、F199-C34和F199-C22的结果分别示于图5、图6和图7中。其表明,与DMSO对照组相比,这些化合物在约30μM和50μM下显著地促进了神经元细胞的存活(抗Aβ毒性),这些结果证明了本发明化合物在降低Aβ诱导的兴奋性毒性中具有显著的效果。
不同的Cdks的选择性
F199化合物显示出对于不同类型的Cdks的不同选择性或特异性,对于开发与不同Cdks相关的不同适应症的治疗药物而言,这是有用的信息。图8显示出F199-C16强效地抑制Cdk1/细胞周期蛋白B复合体,其对Cdk5/p35和Cdk5/p25均显示出较轻的抑制。F199-C16对Cdk2/细胞周期蛋白A的抑制作用最小。如图9所示,F199-C23对Cdkl/细胞周期蛋白B、Cdk5/p35和Cdk5/p25复合体的抑制类似,但其对Cdk2/细胞周期蛋白A的抑制作用最小。对于F199-C34,尽管对Cdk5/p25复合体显示强效的抑制作用,但是其对Cdkl/细胞周期蛋白B、Cdk2/细胞周期蛋白A和Cdk5/p35复合体的作用较小。
对Cdk5/p25复合体的混合型抑制
化合物F199-C 16和F199-C23的抑制模式,通过在0.5、1、2和4μΜ的浓度下,测量它们对病理学Cdk5/p25复合体的作用来检测(浓度递增的ATP,利用FRET测试)。图11显示F199-C16和F199-C23均对Cdk5/p25复合体显示出典型的混合抑制,而roscovitine显示出典型的竞争性抑制。
减少疼痛模型中的舔足响应
在疼痛的动物模型中检测了F199-C16的作用。通过向小鼠的爪中注射甲醛诱导疼痛。如图12中所示,F199-C16以剂量-依赖性方式减少了右后爪的舔足时间。在100mg/kg下,该化合物在甲醛诱导的疼痛的早期(0-10分钟)和后期(11-40分钟)均显著地减少了舔足时间。
总提取物和多种组份对Cdk5的作用
玫瑰红景天的总提取物(TE)如上所述制备。然后将TE利用溶剂分配进一步精制,得到3个组份:氯仿(CF)、正丁醇(BU)和水部位(WA)。如图13所示,F199-TE、F199-CF和F199-BU抑制病理学Cdk5/p25和Cdkl/细胞周期蛋白B比Cdk5/p35更加有效。F199-BU对Cdk1/细胞周期蛋白B和Cdk5/p25的IC50值分别为0.045和0.035ng/μl,对Cdk5/p35的IC50值为0.11ng/μl。
F199-BU的HPLC色谱
由玫瑰红景天提取物(F199-TE)制备的精制的组份(F199-BU)显示出Cdk5抑制作用,如图13所示。制备精制的组份的方法如上所述。如图14所示,两批F199-BU(090725T和080620T)的HPLC色谱大部分重叠,表明利用我们现有的制备流程,该组份是可高度重现的且是稳定的。
分离自玫瑰红景天的化合物的表征
没食子酸(F199-C4):
该化合物的分子量为170,分子式为C7H6O5(基于下表中的1H和13C NMR数据),确定为没食子酸。
化合物没食子酸的1H和13C NMR数据
位置 | 1HNMR | 13C NMR |
1 | 121.78 | |
2 | 7.05(1H,s) | 110.16 |
3 | 146.16 | |
4 | 13938 | |
5 | 146.16 | |
6 | 7.05(1H,s) | 110.16 |
7 | 170.15 |
Rhodalin(F199-C6):
该化合物的分子量为434,分子式为C20H18O11(基于下表中的1H和13C NMR数据),确定为rhodalin。
化合物rhodalin的1H和13C NMR数据(CD3OD)
Litvinolin(F199-C16):
该化合物的分子量为448,分子式为C21H20O11(基于下表中的1H和13C NMR数据),确定为litvinolin。
化合物litvinolin的1H和13C NMR数据(DMSO)
位置 | 1H NMR | 13C NMR |
2 | 147.44 | |
3 | 8.78(1H,brs OH) | 135.81 |
4 | 176.41 | |
5 | 11.90(1H,brs OH) | 151.66 |
6 | 6.59(1H,s) | 98.38 |
7 | 9.45(1H,brs OH) | 148.02 |
8 | 127.13 | |
9 | 144.54 |
10 | 104.61 | |
1′ | 121.83 | |
2′ | 8.15(1H,brs) | 129.83 |
3′ | 6.95(1H,brs) | 115.46 |
4′ | 10.13(1H,brs,OH) | 159.39 |
5′ | 6.95(1H,brs) | 115.46 |
6′ | 8.15(1H,brs) | 129.83 |
Rha | ||
1″ | 5.48(1H,brs) | 99.49 |
2″ | 3.95(1H,m) | 70.11 |
3″ | 3.82(1H,m) | 70.11 |
4″ | 3.34(1H,m) | 71.78 |
5″ | 3.82(1H,m) | 69.93 |
6″ | 1.23(3H,brs) | 17.91 |
6-O-没食子酰基松香(F199-C22):
该化合物的分子量为448,分子式为C22H24O10(基于下表中的1H和13C NMR数据),确定为6-O-没食子酰基松香。
化合物6-O-没食子酰基松香的1H和13C NMR数据(CD3OD)
4′-甲氧基草质素(F199-C23):
该化合物的分子量为316,分子式为C16H12O7(基于下表中的1H和13C NMR数据),确定为4′-甲氧基草质素。
化合物4′-甲氧基草质素的1H和13C NMR数据(DMSO)
位置 | 1H NMR | 13C NMR |
2 | 154.53 | |
3 | 136.00 | |
4 | 178.18 | |
5 | 155.00 | |
6 | 6.49(1H,s) | 95.82 |
7 | 148.80 | |
8 | 127.89 | |
9 | 145.47 | |
10 | 105.10 | |
1′ | 124.23 | |
2′ | 8.22(1H,d,J=8.0Hz) | 131.31 |
3′ | 6.93(1H,d,J=8.0Hz) | 116.57 |
4′ | 160.94 | |
5′ | 6.93(1H,d,J=8.0Hz) | 116.57 |
6′ | 8.22(1H,d,J=8.0Hz) | 131.31 |
4′-OCH3 | 3.97 | 57.28 |
6-O-没食子酰基熊果酚甙(F199-C34):
该化合物的分子量为424,分子式为C19H20O11(基于下表中的1H和13C NMR数据),确定为6-O-没食子酰基熊果酚甙。
化合物6-O-没食子酰基熊果酚甙的1H和13C NMR数据(CD3OD)
表没食子儿茶素-3-没食子酸酯(F199-C35):
该化合物的分子量为458,分子式为C22H18O11(基于下表中的1H和13C NMR数据),确定为表没食子儿茶素-3-没食子酸酯。
化合物表没食子儿茶素-3-没食子酸酯的1H和13C NMR数据(CD3OD)
山奈酚-3-O-β-D-吡喃木糖基(l→3)β-D-吡喃葡萄糖苷(F199-C42):
该化合物的分子量为580,分子式为C26H28O15(基于下表中的1H和13C NMR数据),确定为山奈酚-3-O-β-D-吡喃木糖基(l→3)β-D-吡喃葡萄糖苷。
化合物山奈酚-3-O-β-D-吡喃木糖基(l→3)β-D-吡喃葡萄糖苷的1H和13C NMR数据(CD3OD)
Isomericitrin(F199-C57):
该化合物的分子量为460,分子式为C21H16O12(基于下表中的1H和13C NMR数据),确定为isomericitrin。
化合物isomericitrin(DMSO)的1H NMR数据
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尽管已经对本发明的基本新特征描述且指出为用于其中的优选实施方案,但是可以理解的是,本领域的普通技术人员可以作出多种省略和替换以及变化(以示例性的实施方案的形式和详情),而不背离本发明的精神。本发明并不限于上文作为实施例显示的所述的实施方案,还包括在随附的专利权利要求所限定的包括范围内的多种变化。
Claims (19)
3.一种药物组合物,其包含药学有效量的权利要求1所述的化合物和一种或多种药学上可接受的赋形剂。
4.权利要求3所述的药物组合物,其包含药学有效量的权利要求2所述的化合物和一种或多种药学上可接受的赋形剂。
6.权利要求5所述的方法,其中所述化合物选自由F119-C6、F199-C16、F199-C23、F199-C35、F199-C42和F199-C57组成的组。
7.权利要求5所述的方法,其中所述化合物的R1、R2和R3独立地为H、OH或OCH3。
9.权利要求5所述的方法,其中所述化合物的R7为OH或O-葡萄糖基。
10.权利要求5所述的方法,其中所述化合物的R5为H或=O。
11.权利要求5所述的方法,其用于治疗或预防与异常Cdk5活性相关的疾病或病症。
12.权利要求11所述的方法,其中所述疾病或病症为神经性疼痛、中风、脑外伤、癫痫或神经退行性疾病。
13.权利要求12所述的方法,其中所述神经退行性疾病为肌萎缩侧索硬化、阿尔茨海默氏病、帕金森病或亨廷顿病。
14.权利要求5所述的方法,其中所述化合物如权利要求1所定义。
15.权利要求5所述的方法,其中所述化合物如权利要求2所定义。
16.一种抑制人类细胞Cdk5酶的方法,其包括将所述Cdk5酶与一定量的选自由F199-C4、F199-C34和F199-BU组成的组中的物质接触的步骤。
17.权利要求16所述的方法,其用于治疗或预防与异常Cdk5活性相关的疾病或病症。
18.权利要求17所述的方法,其中所述疾病或病症为神经性疼痛、中风、脑外伤、癫痫或神经退行性疾病。
19.权利要求18所述的方法,其中所述神经退行性疾病为肌萎缩侧索硬化、阿尔茨海默氏病、帕金森病或亨廷顿病。
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CN111107869A (zh) * | 2017-09-18 | 2020-05-05 | 麻省理工学院 | 细胞周期蛋白依赖性激酶5(cdk5)抑制肽 |
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KR20210130991A (ko) | 2020-04-23 | 2021-11-02 | 단국대학교 천안캠퍼스 산학협력단 | 헤르바세틴을 유효성분으로 포함하는 뇌전증지속증 또는 신경퇴행 예방 또는 치료용 조성물 |
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