CN116583497A - 作为后期促进复合物/环体(APC/C)抑制剂的N-苄基-α-氨基酰胺 - Google Patents
作为后期促进复合物/环体(APC/C)抑制剂的N-苄基-α-氨基酰胺 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及式(I)的后期促进复合物/环体(APC/C)抑制剂,其中R1和R2如说明书中所公开的。这些化合物可用于治疗癌症,特别是用于治疗乳腺癌。
Description
技术领域
本发明涉及为后期促进复合物/环体(cyclosome,细胞周期体)(APC/C)抑制剂的式I化合物及其药物组合物,其用于治疗癌症,特别是治疗乳腺癌。此外,本发明涉及与proTAME联合给药的式I化合物的组合物。
背景技术
癌症是一种影响许多人的疾病,并且是人类死亡的主要原因。癌症的部分特征在于不受控制的细胞增殖(参见Golias,CH.,Charalabopoulos,A.,Charalabopoulos,K.Cellproliferation and cell cycle control:a mini review.Int J Clin Pract,2004,58,12,1134-1141)。因此,破坏细胞分裂(例如有丝分裂)的化合物可以是癌症化疗药物的一部分。例如,目前临床使用的一些有丝分裂破坏剂,如紫杉醇,似乎靶向微管,因此可以破坏有丝分裂纺锤体功能(参见Wang,T-H.,Hsin-Shih Wang,MD.,Soong,YK.Paclitaxel-inducedcell death.Cancer 1,2000,88(11))。实际上,延长的有丝分裂破坏可能导致细胞经历凋亡。然而,一些肿瘤通过纺锤体组装检查点(SAC)的失活而产生对微管破坏药物的抗性,纺锤体组装检查点(SAC)是由一些蛋白质(如蛋白质Cdc20)协调的高度复杂的信号传导网络,其确保在细胞分裂期间染色体的准确和及时分离。将SAC蛋白募集到着丝粒(染色体附着到微管聚合物的位点,所述微管聚合物在细胞分裂期间将姊妹染色单体拉开)对于SAC的完全活性和最佳功能是必需的。Cdc20与BubR1的结合介导Cdc20向着丝粒的募集,而Cdc20与后期促进复合物/环体(APC/C)的结合调节APC/C与特异性泛素底物的相互作用,用于它们随后在细胞周期进程期间被蛋白酶体降解,从而以单向方式控制细胞周期向前(参见MeadowsJC,Millar JB.Sharpening the anaphase switch.Biochem Soc Trans 2015,43:19-22;Izawa D,Pines J.The mitotic checkpoint complex binds a second CDC20 toinhibit active APC/C。Nature2015,517:631-34;Di Fiore B.等,The ABBA motif bindsAPC/Cactivators and is shared by APC/C substrates and regulators.Dev Cell2015,32:358-72;Zich J,Hardwick KG.Getting down to the phosphorylated'nuts andbolts'of spindle checkpoint signalling.Trends Biochem Sci.2010,35:18-27;和WO2012/149266)。为了能够开发更有效的对抗乳腺肿瘤的治疗方法,开发新的化学抑制剂将是必需的,所述化学抑制剂在Cdc20异常过量产生的癌细胞中以及在与异常SAC信号传导和染色体分离缺陷相关的肿瘤中影响对SAC功能(包括APC/C调节)重要的Cdc20蛋白-蛋白相互作用。Cdc20蛋白可以作为癌蛋白起作用而促进乳腺癌的发展。迄今为止,只有化合物Apcin与ProTAME组合是作为癌症治疗策略的Cdc20的靶标(参见Lixia Wanga,JinfangZhangb,Lixin Wanb,Xiuxia Zhoua,Zhiwei Wanga,Wenyi Wei.Targeting CDC20 as anovel cancer therapeutic strategy.Pharmacol Ther.2015;151:141-151;PCTUS2011050203;和US 2013/0230458)。Apcin(APC/C抑制剂)结合Cdc20并阻止APC/C底物识别,从而抑制APC/C底物泛素化。
因此,需要开发用于治疗癌症,特别是用于治疗乳腺癌的新的APC/C抑制剂。
发明内容
本发明的第一方面涉及式I的化合物:
或其药用盐,其中:
R1表示H、芳基、C1-C20烷基、-CF3、CCl3或-CBr3;
R2表示任选被-NH2-或Cy1取代的C1-C6烷基;
Cy1表示任选被-OH取代的苯基(-Ph)。
因此,式I的化合物可以是游离的或盐的形式。式I化合物的盐的阴离子的实例尤其包括氯阴离子(Cl-)和阴离子TFA(CF3CO2 -)。
一些式I的化合物可具有可产生各种立体异构体的手性中心。本发明涉及这些立体异构体中的每一种及其混合物。
式I化合物的基团R1可以在任何可用的邻位、间位或对位。
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中Cy1表示在对位被-OH取代的苯基(-Ph)。
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中R1是-CF3、CCl3或-CBr3,并且优选其中R1是-CF3。
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中R2是被-NH2取代的C1-C4烷基。
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中R2是式R2-a的基团:
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中R2是式R2-b的基团:
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中式I的化合物选自:
在另一个实施方案中,本发明涉及如上定义的式I的化合物,其中式I的化合物选自:
本发明的另一个方面涉及药物组合物,其包含如上定义的式I化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
式I的化合物或其药学上可接受的盐可以单独施用或与前药组合施用,所述前药优选为pro-N-4-甲苯磺酰基-L-精氨酸甲酯(proTame)。
因此,本发明的另一个方面涉及药物组合物,其包含如上定义的式I的化合物与选自pro-N-4-甲苯磺酰基-L-精氨酸甲酯(proTame)的其他化合物的组合。
本发明的另一个方面涉及式I的化合物或其药学上可接受的盐,用于治疗中。
本发明的另一个方面涉及式I的化合物:
其中:
R1表示H、芳基、C1-C20烷基、-CF3、CCl3、-CBr3或-Cl3;
R2表示任选被-NH2或Cy1取代的C1-C6烷基;
Cy1表示任选被-OH取代的苯基(-Ph),
用于治疗癌症。
在另一个实施方案中,本发明涉及用于如上所定义的用途的式I的化合物,其中式I的化合物选自:
在另一个实施方案中,本发明涉及用于如上所定义的用途的式I的化合物,其中式I的化合物选自:
在另一个实施方案中,本发明涉及用于如上所定义的用途的式I的化合物,用于治疗乳腺癌。
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。与本文所述的那些类似或等同的方法和材料可用于本发明的实践中。在整个说明书和权利要求书中,词语“包括”及其变体并不旨在排除其他技术特征、添加剂、组分或步骤。本发明的其他目的、优点和特征对于本领域技术人员而言在阅读说明书后将变得显而易见,或者可以通过实践本发明来学习。以下实施例和附图以说明的方式提供,并不旨在限制本发明。
附图说明
图1.显示复合物Cdc20-o-TFB-Tyr的3D结构,接触o-TFB-Tyr Cdc20和复合物Apcin,o-TFB-Tyr-Cdc20。
图2.显示了通过MTT测定对测试的化合物对抗三阴性乳腺癌细胞的细胞毒性分析,使用Cdc20抑制剂apcin进行比较。用选择的第三代化合物o-TFB-Tyr处理24小时后,非同步化HCC-38三阴性乳腺癌细胞的细胞毒性分析。将HCC-38细胞暴露于25μM和5μM浓度的化合物o-TFB-Tyr(图A)和1μM浓度的化合物o-TFB-Tyr(图B),单独和与proTAME组合。使用的阴性对照是未处理的细胞(培养基),而使用的阳性对照是单独的25μM Apcin和10μM的proTAME以及25μMApcin与10μM的proTAME的组合。通过单因素方差分析和Dunnett检验分析了数据,所有柱与阴性对照柱(培养基)相比,p<0.001。进行了重复实验。
图3.显示了5μM、1μM、0.5μM和100nM浓度的化合物o-TFB-Tyr的细胞毒性分析。将HCC-38癌细胞暴露于单独的化合物o-TFB-Tyr和与proTAME组合的化合物o-TFB-Tyr。使用的阴性对照是未处理的细胞(培养基),而使用的阳性对照是Apcin 25μM与proTAME 10μM组合。通过单因素方差分析和Dunnett检验分析了数据,所有柱与阴性对照柱(培养基)相比,p<0.001。进行了重复实验。
图4.显示了形成ADME研究的一部分的细胞膜渗透性测试的原理。
图5.显示了与Reversine(逆转素)和Apcin相比,不同浓度的化合物o-TFB-Tyr在HeLa细胞中的相对细胞毒性,Reversine是Mps1激酶的小化合物抑制剂,SAC的上游调节剂,Apcin是Cdc20的小尺寸结合剂和通过Cdc20的APC/C激活的抑制剂。该研究证实了化合物o-TFB-Tyr对抗不同组织来源的不同类型的癌症表现出更高的细胞毒性作用。
图6.与相同浓度的化合物Apcin、m-TFB-Tyr、p-TFB-Tyr和o-TFB-Lys相比,化合物o-TFB-Tyr在HeLa细胞中的相对细胞毒性的比较。化合物o-TFB-Tyr、m-TFB-Tyr和p-TFB-Tyr在化学结构方面密切相关。比较研究证实了化合物o-TFB-Tyr对培养物中的癌细胞表现出更高的细胞毒性作用。因此,揭示了o-TFB-Tyr和异构体m-TFB-Tyr、p-TFB-Tyr的关键立体化学特征,其影响o-TFB-Tyr和结构相关分子的抗癌活性。比较分析还显示了所要求保护的化合物o-TFB-Tyr、m-TFB-Tyr、p-TFB-Tyr和o-TFB-Lys的R2残基的化学性质影响这些分子的癌细胞细胞毒性。
图7.用DMSO(1.2%v/v)、Mps1激酶抑制剂Reversine、Cdc20结合剂Apcin和化合物o-TFB-Tyr处理的HCC-38细胞的克隆形成测定。在37℃下孵育12天后对克隆进行染色。用化合物处理HCC38细胞24小时后,每48小时更换培养基。在这个测定中,在用Reversine和o-TFB-Tyr处理的细胞中一致地观察到较低数量的三阴性乳腺癌细胞克隆,证实了后一种化合物在癌细胞中所需的细胞毒性活性。
图8.然后使用配备用于DIC成像和荧光成像的Axiozoom Zeiss Axioplan荧光显微镜扫描克隆形成测定的每个孔,并使用ImageJ2图像处理软件(Fiji)进行分析。在此显示了由图像处理软件生成的代表性图片。
图9.蛋白质印迹显示了化合物o-TFB-Tyr通过APC/C引起细胞周期蛋白B泛素化的抑制。因此,非泛素化的细胞周期蛋白B逃避蛋白酶体的降解。该分析还显示了Apcin作为通过Cdc20的APC/C激活的拮抗剂的有效性相对低于化合物o-TFB-Tyr。在本研究中使用密度为200,000个细胞/孔的HCC-38细胞。
具有实施方案
计算
展示了将具有化学结构I的柔性配体对接(Maestro Suite,Schrodinger)到Cdc20蛋白(刚性)的结合位点的技术。(图1)该方法基于预先生成的一组化合物(o-、m-、p-TFB-aa、配体)的构象和蛋白质结合位点中配体的最终的基于柔性梯度的优化。受体结合位点被定义为立方体盒,并将化合物置于结合袋的中心。对于所有情况,盒足够大以保证对接结果与结合位点定义的独立性。对接参数(分数对接kcal/mol)给出了最佳复合化合物-蛋白质的概念。
o-、m-或p-三氟苄基L-氨基酸衍生物(o-TFB-Tyr、o-TFB-Lys和m-TFB-Tyr、p-TFB-Tyr)的合成。
1.用叔丁氧基羰基保护L-氨基酸的氨基:
在氩气下,将L-氨基酸悬浮于水和二噁烷的1:1混合物(程序A)或2-丙醇(程序B)中。之后,在恒定搅拌下加入氢氧化钠(程序A)或氢氧化钾(程序B)的水溶液。加入碳酸二叔丁酯后,将反应在室温下搅拌。反应完成时,在减压下除去溶剂直至一半体积,然后加入硫酸氢钾直至溶液达到pH=2。反应溶液用乙酸乙酯萃取,有机相用饱和氯化钠溶液和水洗涤。将溶液经硫酸钠干燥,然后过滤。将滤液浓缩至干。我们将产物不经进一步纯化用于下一反应。
2.Boc-L-氨基酸和三氟苄胺的偶联反应。
2.1.使用2-三氟苄胺作为偶联剂
在氩气下将Boc-L-氨基酸溶于无水DMF中。此后,将二异丙基乙胺(程序A)或2,4,6-三甲吡啶(程序B)和HBTU在室温(r.t.)下依次加入并搅拌30min。然后,在r.t.下加入三氟苄胺。并将反应在r.t.下搅拌过夜。反应完成时,减压除去溶剂。然后通过硅胶色谱纯化粗产物。
(2S)-2,6-双[(叔丁氧基羰基)氨基]-N-[2-(三氟甲基)苄基]己酰胺(3)
1H-NMR(500MHz,CDCl3):δ7.63(1H,d,J=7.5Hz),7.54-4.47(2H,m),7.36(1H,t,J=7.5Hz),6.65(1H,b.s.),5.17(1H,b.s.),4.65-4.56(2H,m),4.07(1H,b.s.),3.09(2H,m),1.89-1.81(1H,m),1.69-1.59(1H,m),1.53-1.44(2H,m),1.42(9H,s),1.40(9H,s),1.40-1.39(2H,m)ppm.13C-NMR(125MHz,CDCl3):δ172.1,156.2,155.8,136.4,132.3,130.1,128.0(q,J=30.9Hz),127.5,125.9(q,J=5.8Hz),124.4(q,J=273.9Hz),80.2,79.2,54.6,39.9(q,J=2.5Hz),39.7,31.5,29.7,28.4,28.2,22.6ppm.LRMS(ESI-ES+):m/z 504(M+H)+,526(M+Na)+.IR(KBr):ν3318,3080,2978,2934,2867,1693,1610,1525,1457,1392,1367,1315,1250,1166,1121,1059,1039,867,769,655cm-1.
(2S)-2-[(叔丁氧基羰基)氨基]-3-{4-[(叔丁氧基羰基)羟基]苯基}-N-[2-(三氟甲基)苄基]丙酰胺(4)
1H-NMR(500MHz,CDCl3):δ7.60(1H,d,J=7.6Hz),7.47(1H,t,J=7.8Hz),7.37-7.30(2H,m),7.14(2H,d,J=8.4Hz),7.03(2H,d,J=8.4Hz),6.34(1H,b.s.),5.03(1H,b.s.),4.57(1H,dd,J=15.6,6.4Hz),4.52(1H,dd,J=15.6,6.4Hz),4.34(1H,b.s.),3.11-3.00(2H,m),1.55(9H,s),1.38(9H,s)ppm.13C-NMR(125MHz,CDCl3):δ171.0,155.4,151.8,150.0,136.1,133.9,132.2,130.2,130.1,128.0(q,J=31.3Hz),127.5,125.9(q,J=6.5Hz),124.3(q,J=274.0Hz),121.4,83.6,80.4,55.8,39.9,37.4,28.2,27.7ppm.LRMS(EI):m/z 538(M+,0.1),321(100),231(6),159(22),136(21)
(2S)-2-[(叔丁氧基羰基)氨基]-3-[4-(羟基)苯基]-N-[2-(三氟甲基)苄基]丙酰胺(5)
1H-NMR(400MHz,CDCl3):δ7.58(1H,d,J=7.6Hz),7.43(1H,t,J=7.6Hz),7.32(1H,t,J=7.6Hz),7.22(1H,b.s.),6.93(2H,d,J=8.1Hz),6.66(2H,d,J=8.1Hz),6.41(1H,t,J=6.2Hz),5.19(1H,b.s.),4.59(1H,dd,J=15.4,6.1Hz),4.46(1H,dd,J=15.5,5.6Hz),4.31(1H,b.s.),2.97(1H,J=14.3,6.5Hz),2.92(1H,dd,J=14.3,7.8Hz),1.39(9H,s)ppm.13C-NMR(100MHz,CDCl3):δ171.5,155.6,155.1,135.9,132.2,130.3,130.0(q,J=3.3Hz),127.9(q,J=29.7Hz),127.8,127.5,125.8(q,J=5.1Hz),124.3(q,J=274.3Hz),115.6,80.6,56.2,39.9,37.5,28.2ppm.LRMS(EI):m/z 438(M+,0.5),321(100),231(5).
2.2.使用3-或4-三氟苄胺作为偶联剂
在氩气下将Boc-L-酪氨酸溶于无水DMF中。此后,在r.t.下依次加入2,4,6-三甲基吡啶和HBTU,并搅拌30分钟。然后,在r.t.下加入3-三氟苄胺(程序A)或4-三氟苄胺(程序B),并将反应在r.t.下搅拌过夜。反应完成时,在减压下除去溶剂。通过硅胶色谱纯化粗产物。
(2S)-2-[(叔丁氧基羰基)氨基]-3-{4-[(叔丁氧基羰基)羟基]苯基}-N-[3-(三氟甲基)苄基]丙酰胺(6)
1H-NMR(500MHz,CDCl3):δ7.48(1H,d,J=7.5Hz),7.43(1H,s),7.61(1H,t,J=7.5Hz),7.27(1H,b.s.),7.15(2H,d,J=8.3Hz),7.04(2H,d,J=8.3Hz),6.58(1H,b.s.),5.16(1H,b.s.),4.36(3H,s),3.05(2H,s),1.54(9H,s),1.36(9H,s)ppm.13C-NMR(125MHz,CDCl3):δ171.3,155.5,151.8,150.0,138.8,134.0,130.9,130.7(q,J=32.9Hz),130.2,129.1,124.3,124.2,123.9(q,J=271.3Hz),121.4,83.5,80.4,55.8,42.9,37.6,28.2,27.6ppm.LRMS(EI):m/z 321(100),231(6),159(34),136(22).
(2S)-2-[(叔丁氧基羰基)氨基]-3-[4-(羟基)苯基]-N-[3-(三氟甲基)苄基]丙酰胺(7)
1H-NMR(500MHz,CDCl3):δ7.92(1H,b.s.),7.47(1H,d,J=7.7Hz),7.41(1H,s),7.36(1H,t,J=7.7Hz),7.20(1H,b.s.),6.97(1H,b.s.),6.95(2H,d,J=8.4Hz),6.65(2H,d,J=8.4Hz),5.38(1H,b.s.),4.38(1H,dd,J=15.5,5.2Hz),4.31(1H,dd,J=15.5,5.6Hz),4.24(1H,q,J=7.1Hz),2.91(2H,d,J=7.1Hz),1.36(9H,s)ppm.13C-NMR(125MHz,CDCl3):δ171.9,155.7,155.4,138.7,130.9(×2C),130.3,129.0,127.4,124.2,124.1(q,J=3.1Hz),123.9(q,J=272.3Hz),115.4,80.4,56.1,42.8,37.7,28.1ppm.LRMS(EI):m/z438(M+,0.3),321(100),231(3),159(54),136(24).
(2S)-2-[(叔丁氧基羰基)氨基]-3-{4-[(叔丁氧基羰基)羟基]苯基}-N-[4-(三氟甲基)苄基]丙酰胺(8)
1H-NMR(300MHz,CDCl3):δ7.55(2H,d,J=8.1Hz),7.20(2H,d,J=8.5Hz),7.18(2H,d,J=8.1Hz),7.07(2H,d,J=8.5Hz),6.23(1H,b.s.),5.00(1H,b.s.),4.41(2H,d,J=6.3Hz),4.32(1H,q,J=7.1Hz),3.14(1H,dd J=13.7,7.1Hz),3.02(1H,dd,J=13.7,7.1Hz),1.57(9H,s),1.41(9H,s)ppm.13C-NMR(125MHz,CDCl3):δ171.1,155.4,151.9,150.1,141.7,133.9,130.2,129.6(q,J=33.8Hz),127.7,125.6(q,J=3.7Hz),124.0(q,J=272.9Hz),121.5,53.6,80.5,56.0,42.9,37.6,28.2,27.6ppm.LRMS(EI):m/z 538(M+,0.1),321(100),231(4),159(20),136(15).
(2S)-2-[(叔丁氧基羰基)氨基]-3-[4-(羟基)苯基]-N-[4-(三氟甲基)苄基]丙酰胺(9)
1H-NMR(500MHz,CDCl3):δ7.45(2H,d,J=7.0Hz),7.35(1H,b.s.),7.11-7.04(3H,m),6.93(2H,d,J=8.3Hz),6.65(2H,d,J=8.3Hz),5.56(1H,b.s.),4.37(1H,dd,J=15.5,6.0Hz),4.27-4.14(2H,m),2.85(2H,d,J=7.0Hz),1.33(9H,s)ppm.13C-NMR(125MHz,CDCl3):δ172.0,155.6,152.0,141.8,130.2,129.3(q,J=34.5Hz),127.6,127.1,125.2,(q,J=4.2Hz),124.0(q,J=272.0Hz),115.3,80.2,56.0,42.6,37.7,28.0ppm.LRMS(EI):m/z 438(M+,0.5),321(100),231(5),159(25),136(25).
3.Boc-三氟苄基氨基酸衍生物的脱保护反应
在氩气下在r.t.下将Boc-三氟苄基酰胺衍生物溶于CH2Cl2:TFA[2:1]混合物中,并在该温度下搅拌溶液。反应完成时,在减压下除去溶剂。通过两种程序纯化粗反应产物:1)程序A:使用reveleris柱SRC C18的反相色谱。2)程序B:使用Dowex 50WX4树脂的阴离子交换色谱,然后进行硅胶色谱。
(2S)-2,6-二氨基-N-[2-(三氟甲基)苄基]己酰胺(o-TFB-Lys-TFA)(程序A)(10)
1H-NMR(500MHz,D2O):δ7.79(1H,d,J=7.8Hz),7.65(1H,t,J=7.5Hz),7.54(1H,d,J=7.5Hz),7.52(1H,t,J=7.8Hz),4.70(1H,d,J=15.4Hz),4.57(1H,d,J=15.4Hz),4.04(1H,t,J=6.6Hz),2.94(2H,t,J=7.8Hz),1.98(2H,m),1.72-1.63(2H,m),1.43-1.34(2H,m)ppm.13C-NMR(125MHz,D2O):δ170.1,135.4(q,J=1.7Hz),133.2,130.7,128.8,128.1(q,J=30.7Hz),127.0(q,J=6.0Hz),125.0(q,J=274.4Hz),53.6,41.2(q,J=2.8Hz),39.6,31.0,26.9,21.8ppm.LRMS(ESI-ES+):m/z304(M+H)+,326(M+Na)+.IR(KBr):ν3080,2882,2824,1673,1433,1316,1203,1128,1061,1040,840,800,770,723cm-1.
(2S)-2-氨基-N-[2-(三氟甲基)苄基]-3-[4-(羟基)苯基]丙酰胺(o-TFB-Tyr-TFA)(程序A)(11)
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1H-NMR(500MHz,CD3OD):δ7.72(1H,d,J=7.7Hz),7.56(1H,t,J=7.5Hz),7.50(1H,t,J=7.7Hz),7.13(1H,d,J=7.5Hz),6.97(2H,m),6.66(2H,m),4.64(1H,d,J=15.3Hz),4.28(1H,d,J=15.3Hz),4.14(1H,dd,J=10.0,5.9Hz),3.17(1H,dd,J=13.6,5.9Hz),2.94(1H,dd,J=13.6,10.0Hz)ppm.13C-NMR(125MHz,CD3OD):δ167.9,154.0,133.6,131.6,129.7,129.5,127.2,126.5(q,J=30.1Hz),125.3(q,J=5.1Hz),124.4,123.4(q,J=273.6Hz),114.8,53.7,39.2,35.2ppm.LRMS(ESI-ES+):m/z 339(M+H)+,361(M+Na)+,699(2M+Na)+.IR(KBr):ν3416,3089,2928,1677,1615,1518,1439,1370,1317,1204,1122,1061,1041,840,801,770,723cm-1.
(2S)-2-氨基-N-[2-(三氟甲基)苄基]-3-[4-(羟基)苯基]丙酰胺(o-TFB-Tyr)(程序B)(12)
1H-NMR(500MHz,CDCl3):δ7.69(1H,t,J=6.1Hz),7.63(1H,d,J=7.6Hz),7.50(1H,dd,J=7.7,7.4Hz),7.43(1H,d,J=7.7Hz),7.37(1H,dd,J=7.6,7.4Hz),7.02(2H,m),6.77-6.74(2H,m),4.62(2H,d,J=6.1Hz),3.61(1H,dd,J=8.8,4.3Hz),3.13(1H,dd,J=13.8,4.3Hz),2.68(1H,dd,J=13.8,8.8Hz),3.05(3H,b.s.)ppm.13C-NMR(125MHz,CDCl3):δ147.7,155.2,136.4,132.3,130.6,130.4,128.7,128.2(q,J=30.6Hz),127.6,126.0(q,J=6.3Hz),124.4(q,J=274.2Hz),115.7,56.4,40.0,39.8(q,J=2.1Hz)ppm.LRMS(EI):m/z321(34),231(25),159(56),136(100).
(2S)-2-氨基-N-[3-(三氟甲基)苄基]-3-[4-(羟基)苯基]丙酰胺(m-TFB-Tyr)(程序B)(13)
1H-NMR(500MHz,CDCl3):δ7.75(1H,t,J=5.8Hz),7.50-7.44(2H,m),7.39(1H,t,J=7.5Hz),7.33(1H,d,J=7.5Hz),6.97(2H,d,J=8.2Hz),6.71(2H,d,J=8.2Hz),4.41(2H,s),3.58-3.50(1H,m),3.04(1H,dd,J=13.4,4.2Hz),2.86(3H,b.s.),2.65(1H,dd,J=13.4,9.0Hz)ppm.13C-NMR(125MHz,CDCl3):δ174.9,155.6,139.0,130.9(q,J=1.4Hz),130.8(q,J=32.3Hz),130.2,129.0,128.0,124.2(q,J=3.7Hz),124.1(q,J=3.9Hz),123.9(q,J=272.1Hz),115.5,56.3,42.5,40.0ppm.LRMS(EI):m/z 338(M+,0.2),321(50),231(26),159(95),136(100).
(2S)-2-氨基-N-[4-(三氟甲基)苄基]-3-[4-(羟基)苯基]丙酰胺(p-TFB-Tyr)(程序B)(14)
1H-NMR(500MHz,CDCl3):δ7.75(2H,J=5.6Hz),7.50(2H,d,J=8.0Hz),7.22(2H,d,J=8.0Hz),6.96(2H,d,J=8.4Hz),6.70(1H,d,J=8.4Hz),4.39(2H,s),3.51(1H,dd,J=8.3,5.0Hz),3.10(3H,s),3.00(1H,dd,J=13.8,5.0Hz),2.66(1H,dd,J=13.8,8.3Hz)ppm.13C-NMR(125MHz,CDCl3):δ174.9,155.7,142.0(q,J=1.4Hz),130.2,129.4(q,J=33.6Hz),127.9,127.6,125.4(q,J=5.4Hz),124.0(q,J=272.1Hz),115.4,56.3,42.4,40.0ppm.LRMS(EI):m/z 338(M+,0.2),321(44),231(25),159(85),136(100)107(33).
功能和药理学(ADME)测定
与靶分子相互作用的影响。
功能(生物)测试。
进行基于MTT测定的体外细胞毒性分析,以确认新的小分子量化合物对癌细胞的所需生物效应。使用三阴性乳腺癌细胞系(HCC38)测试了总共45种独特分子,因为已知Cdc20在该癌细胞系中被扩增。
第1组结果。在25和5uM下单独以及与APC/C拮抗剂proTAME组合测试了先导化合物(o-TFB-Tyr)。将报道的Cdc20抑制剂apcin用于比较(参见图2)。
第2组结果。在5uM至100nM浓度范围内单独以及与APC/C拮抗剂proTAME组合测试了先导化合物(o-TFB-Tyr)。将报道的Cdc20抑制剂apcin用于比较(参见图3)。
从图2和3中总结的功能研究中,选择了一种化合物(o-TFB-Tyr)用于药理学测试,包括细胞通透性(图4)。
药理学研究。
这些包括测定o-TFB-Tyr的ADME(吸附、分布、代谢和排泄)检测。这些测试的结果总结如下:
动力学溶解度。
这是在开始ADME测试之前进行的有价值的初始筛选,以便识别潜在问题并确定适当的浓度范围。使用浊度法测量动力学溶解度。该测试的结果示于以下表1中:
表1
这个数据证明了o-TFB-Tyr易溶于水溶液中。
吸附
这是使用Caco-2细胞(一种人结肠直肠腺癌细胞系)中的肠通透性测定来确定的(参见图4)。
该测试的结果示于以下表2中:
表2
显示化合物在两个方向上自由扩散穿过半透膜。这反过来表明该化合物不被膜蛋白(如ABC转运蛋白)主动转运,它可能限制其作为药物的用途。
分布、代谢和排泄
代谢稳定性测试
肝脏是大多数药物的主要药物代谢器官。研究药物代谢的良好体外模型基于微粒体(肝脏的亚细胞部分)的使用。
该测试的结果显示在以下表3中,并且证明化合物是稳定的,45分钟后存在8%的完整分子。
表3
药物清除率
通过代谢清除的三分之二的药物至少部分地通过细胞色素P450(CYP)酶代谢,同种型CYP3A4占所有CYP活性的几乎50%。为此,我们测试了CYP3A4是否参与o-TFB-Tyr的清除。以下表4显示了细胞色素P450(CYP3A4同种型)抑制(IC50)测定。使用咪达唑仑和睾酮作为CYP3A4底物测试先导化合物(o-TFB-Tyr)对CYP3A4的可能抑制。
表4
在两种情况下,IC50远高于已知由细胞色素P450同种型CYP3A4代谢的对照化合物。出于比较的目的,使用咪达唑仑和睾酮的对照化合物(酮康唑)的数据显示于以下表5中:
表5
总之,表4和表5中所示的数据表明细胞色素P450同种型CYP3A4似乎在o-TFB-Tyr的清除中起到边际作用。然而,需要进一步的研究来证实这些观察结果。
血浆蛋白结合测定
非特异性血浆蛋白结合可极大地影响游离药物浓度的程度,其可影响先导化合物的后续抑制潜力(参见以下表6)。
表6
在两种情况下(人和小鼠),观察到蛋白质的总回收,表明不存在非特异性血浆蛋白结合。
细胞毒性结果
关键结果
在HeLa细胞中进行的细胞毒性和克隆形成研究证实了化合物o-TFB-Tyr在这个癌细胞系中的中等细胞毒性活性(即,在200至10μM的范围内)。在HeLa细胞中观察到的细胞毒性作用(如图5和6所示)与在三阴性乳腺癌细胞系HCC-38中测定的相当。此外,用化合物o-TFB-Tyr处理的HCC-38细胞的蛋白质印迹分析证实了这种化合物对通过Cdc20的APC/C激活的抑制作用,如通过抑制细胞周期蛋白B(APC/C E3泛素连接酶的底物)所监测的。与化合物o-TFB-Tyr在结构上相关的一系列化合物的细胞毒性也在HCC-38和HeLa细胞中进行了测试,证实化合物o-TFB-Tyr的某些立体化学特征对这种化合物的所需生物活性具有重要影响。
方法学
细胞生长
以下全部方案在无菌条件下进行。HeLa细胞在补充有10%胎牛血清(FBS)(SigmaF7524)的Dulbecco改良Eagle培养基(DMEM)中培养。将细胞计数并以6,000个细胞/孔的密度接种到透明底96孔板(Greiner Bio-One)中。向每个孔中加入100μl细胞并置于培养箱中过夜。第二天,抽吸培养基,并向孔中加入100μL处理物。用对照(单独的培养基,Reversine5μM,Apcin 25μM)处理细胞。Apcin和化合物的所有储备溶液通过将固体重悬于二甲亚砜(DSMO)中来制备,然后在培养基中稀释以达到200μM的浓度,然后再次在培养基中稀释至待测试的最终浓度。
细胞毒性分析
体外细胞毒性分析涉及细胞增殖的定量测量和随后评估化合物的相对毒性。(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物(MTT)是一种广泛使用的细胞毒性测定,其测量细胞代谢活性作为细胞活力、增殖和细胞毒性的指标,通过线粒体脱氢酶将水溶性黄色四唑MTT还原为不溶性紫色甲臜晶体。将不溶性紫色晶体产物溶解于DMSO中,并通过测量吸光度(570nm)定量所得有色溶液。还原只能在线粒体还原酶有活性时发生,因此与活细胞的数量直接相关。将用化合物处理的细胞与未处理的对照细胞产生的紫色甲臜进行比较,使得能够用计算的细胞活力%确定化合物的细胞毒性。测试的处理一式三份进行。
将细胞孵育并进行72小时的处理暴露;在暴露结束前3小时,向每个孔中加入5μlMTT(5mg/mL)(Invitrogen M6494),然后将板置于培养箱中持续剩余的处理暴露时间。从每个孔中吸出溶液,然后向孔中加入100μl DMSO,并将板在室温下置于振荡器上15分钟。一旦每个孔可见均匀的颜色,就测量吸光度(570nm)(SpectraMax i3x)。将处理的细胞的细胞毒性读数相对于阴性对照(单独的培养基)归一化,并从以下等式计算细胞的%活力:
使用GraphPad Prism 7.0,GraphPad Software,Inc.,通过单因素方差分析(ANOVA)和事后Dunnet检验分析数据。对于获得的数据,将所有处理与对照(单独的培养基)进行比较,p<0.001。
克隆形成测定
以下整个程序在无菌条件下进行。将HeLa细胞计数并以500个细胞/孔(250个细胞/ml)的密度接种到透明底6孔板(Greiner Bio-One)中。向每个孔中加入2ml细胞并置于培养箱(37℃,5%CO2)中过夜。第二天,抽吸培养基,并向孔中加入1.5ml处理物。用对照(单独的培养基)和化合物处理细胞。通过将固体重悬于DMSO中制备化合物的所有储备溶液,然后在培养基中稀释至待测试的最终浓度。使用克隆形成测定法测量HeLa细胞活力,克隆形成测定法是一种基于细胞存活的测定法,其确定用细胞毒性剂处理后的细胞生殖死亡。将细胞孵育并进行72小时的处理暴露。然后从每个孔中吸出溶液,并向孔中加入2ml培养基,并将板放回培养箱中。将板再孵育9天(总共10天),用1×PBS洗涤细胞,每隔几天用2ml新鲜培养基替换每个孔中的2ml培养基。从加入处理物开始孵育10天后,从每个孔中吸出溶液,并用1×PBS洗涤细胞两次。然后将500μL的PBS中的4%多聚甲醛(Alfa Aesar J61899)加入每个孔中,并将板在室温下孵育30分钟。从每个孔中吸出溶液,然后向每个孔中加入4-5滴结晶紫(甲醇中0.5%w/v)。将板在室温下孵育15分钟。通过用水洗涤每个孔轻轻地除去溶液,并使克隆可视化。克隆形成测定结果的代表性图像显示在图7中。
然后使用配备用于DIC成像和荧光成像的Axiozoom Zeiss Axioplan荧光显微镜扫描克隆形成测定的每个孔,并使用ImageJ2图像处理软件(Fiji)进行分析。由图像处理软件生成的代表性图片如下所示(图8)。
通过测量细胞周期蛋白B1水平证实Cdc20对APC/C激活的抑制
以下全部程序在无菌条件下进行。对HeLa细胞进行计数并以200,000个细胞/孔的密度以2ml的体积接种到透明底6孔板(Greiner Bio-One)中,并置于培养箱(37℃,5%CO2)中过夜。第二天,抽吸培养基,并向孔中加入1.5ml处理物。用对照(单独的培养基)和化合物处理细胞。通过将固体重悬于DSMO中制备小化合物的所有储备溶液,然后在培养基中稀释至待测试的最终浓度。通过测量APC/C-Cdc20的下游靶标细胞周期蛋白B1的水平来分析这些化合物对有丝分裂的影响。孵育细胞并进行24小时处理暴露。然后将板置于冰上,并从每个孔中吸出溶液。将细胞用PBS洗涤两次,然后向每个孔中加入300μL裂解缓冲液(50mMTris pH 8、150mM NaCl、5mM ETDA、1%Triton X-100、5mMβe,来自牛胰腺的脱氧核糖核酸酶I,cOmplete Mini无EDTA蛋白酶抑制剂混合物片剂(1片/50ml裂解液),并将板在搅拌下孵育10分钟。使用细胞刮刀将每个孔刮2分钟,然后将每个孔的溶液转移到相应的标记的Eppendorf管中。然后将管在14,500rpm、4℃下离心30分钟。将来自每个管的上清液转移到干净的Eppendorf管中,快速冷冻并储存在-20℃。图9显示了用化合物o-TFB-Tyr处理的HCC-38细胞的蛋白质印迹,其证实了Cdc20对APC/C激活的抑制,如通过细胞周期蛋白B的抑制所监测的。使用小鼠抗细胞周期蛋白B1抗体(BD Pharmingen 554177)作为一抗。AP-连接的抗小鼠IgG用作二抗(Sigma SAB3701107-1)。小鼠抗α-微管蛋白抗体(Santa CruzBiotechnology sc-32293)用作蛋白质浓度加载的内部对照。
Claims (18)
1.式I的化合物:
或其药用盐,
其中:
R1表示H、芳基、C1-C20烷基、-CF3、CCl3或-CBr3;
R2表示任选被-NH2或Cy1取代的C1-C6烷基;
Cy1表示任选被-OH取代的苯基(-Ph)。
2.根据权利要求1的式I的化合物或其药用盐,其中Cy1表示在对位被-OH取代的苯基(-Ph)。
3.根据权利要求1或2任一项的式I的化合物或其药用盐,其中R1是-CF3、CCl3或-CBr3。
4.根据权利要求3的式I的化合物或其药用盐,其中R2是被-NH2取代的C1-C6烷基。
5.根据权利要求4的式I的化合物或其药用盐,其中R1是-CF3。
6.根据权利要求1至3和5任一项的式I的化合物或其药用盐,其中R2是式R2-a的基团:
7.根据权利要求1至3和5中任一项所述的式I的化合物,其中R2是式R2-b的基团:
8.根据权利要求1的式I的化合物或其药用盐,其中式I的化合物选自:
9.根据权利要求8的式I的化合物或其药用盐,其中式I的化合物是:
10.根据权利要求1的式I的化合物或其药用盐,其中式I的化合物选自:
11.一种药物组合物,其包含根据权利要求1至10任一项的式I化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
12.一种药物组合物,其包含根据权利要求1至10任一项的式I的化合物,以及选自pro-N-4-甲苯磺酰基-L-精氨酸甲酯(proTame)的其他化合物。
13.根据权利要求1至10任一项的式I的化合物或其药学上可接受的盐,其用于治疗。
14.式I的化合物:
或其药用盐,
其中:
R1表示H、芳基、C1-C20烷基、-CF3、CCl3或-CBr3;
R2表示被-COR5、-SR6、-OH或Cy1取代的C1-C6烷基;
Cy1表示任选被-OH取代的苯基(-Ph),
用于治疗癌症。
15.式I的化合物或其药用盐,用于权利要求14的用途,其中式I的化合物选自:
16.式I的化合物或其药用盐,用于根据权利要求15的用途,其中式I的化合物是:
17.式I的化合物或其药用盐,用于根据权利要求14的用途,其中式I的化合物选自:
18.式I的化合物或其药用盐,用于根据权利要求14至17任一项的用途,用于治疗乳腺癌。
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