CN109232663B - 一种钌配合物的制备方法及其艾滋病毒逆转录酶抑制应用 - Google Patents
一种钌配合物的制备方法及其艾滋病毒逆转录酶抑制应用 Download PDFInfo
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Abstract
本发明属于艾滋病毒抑制剂研发领域,公开了一种多吡啶钌配合物的制备方法及其在艾滋病毒逆转录酶抑制中的应用。本发明设计了新的多吡啶钌配合物的合成方法,所得的化合物纯度高、收率高,具有良好的水溶性和优异的光谱性质。本发明的多吡啶钌配合物具有对艾滋病毒RNA上的TAR区域选择性结合的能力,并能够阻断逆转录酶对病毒RNA的逆转录过程,抑制病毒RNA的复制。该多吡啶钌配合物是一种具有高亲和力的艾滋病毒RNA选择性结合试剂和高活性的艾滋病毒逆转录酶抑制剂,是极具应用潜力的艾滋病毒药物。
Description
技术领域
本发明属于艾滋病毒逆转录酶抑制剂和艾滋病毒药物研发领域,尤其涉及多吡啶钌配合物的制备方法及其在艾滋病毒逆转录酶抑制中的应用。
背景技术
艾滋病是一种严重危害人类健康生活的疾病。我国报告艾滋病毒感染者和病人多达65.4万例,累计死亡20.1万例。艾滋病死亡数已经是我国传染病死亡数的第一位。抑制逆转录酶对病毒RNA的逆转录作用,就可以控制病毒的产生和扩散,从而起到对艾滋病等暂时无法治愈的,而又与逆转录酶和病毒RNA密切相关的疾病的治疗和早期防治作用(Science,1992,256,1783-1790;Biochemistry,2011,50,5042-5057)。因此,艾滋病毒逆转录酶成为当前抗艾滋病药物设计的首要靶点(Curr.Top.Med.Chem.,2004,4,1045-1057)。
目前,作为药物在临床中应用的逆转录酶抑制剂主要分为两类,即“核苷类逆转录酶抑制剂”和“非核苷类逆转录酶抑制剂”。核苷类逆转录酶抑制剂为核苷类似物,与病毒RNA逆转录形成的病毒DNA竞争结合逆转录酶,使病毒的复制得到一定程度上的抑制。然而,核苷类逆转录酶抑制剂的长期给药会产生严重的毒副作用(如抑制骨髓生长等)和出现明显的抗药性现象,面临着被淘汰的命运。通过大量新化合物的大规模活性筛选,人们陆续发现了一些结构各异的小分子化合物表现出较好的逆转录酶抑制活性,称其为非核苷类的逆转录酶抑制剂。它们对“酶-底物”复合物的亲和力比对酶的亲和力高,通过与逆转录酶的相互作用可以引起酶的构型变化,从而使底物活性部位的亲和性降低。由于非核苷类逆转录酶抑制剂不会直接损坏底物结合区域的功能,因此细胞毒性较小,并且在极低浓度即可抑制逆转录酶病毒的活性(Chem.Soc.Rev.,2012,41,4657-4670)。
TAR和RRE是艾滋病病毒RNA上两个重要的功能区域,对病毒RNA的逆转录活性起着至关重要的作用(Mol.Cell Biol.,1988,8,2555-2561)。最近,一种氨基噻唑类化合物表现出了较好的TAR RNA选择性(Chem.Eur.J.,2014,20,2071-2079;Chem.Commun.,2010,46,6162-6164)。该类化合物可以排除DNA和tRNA的影响,选择性的结合TAR RNA的U-A碱基对部位,抑制HIV-1菌株的生长,而对正常细胞的生长没有明显的影响。
本发明将多吡啶钌配合物的结构引入上述的噻唑类化合物,进一步设计和优化分子结构,得到了一种具有良好水溶性和光谱性质的、具有对艾滋病毒RNA具有特异性识别作用的氨基噻唑功能基团的多吡啶钌配合物,使其能够选择性结合艾滋病毒RNA的TAR区域,并显著抑制艾滋病毒逆转录酶的活性。该多吡啶钌配合物不仅是艾滋病毒RNA的特异性结合试剂,还是艾滋病毒逆转录酶的特异性抑制剂,是潜在的高活性的艾滋病特异性药物。
发明内容
本发明的目的在于针对当前尚未攻克的艾滋病药物研究,提供一种既具有良好水溶性和光谱性质,又具有特异性的艾滋病毒RNA识别作用和优秀的艾滋病毒逆转录酶抑制能力的多吡啶钌配合物。
本发明的第二个目的是提供所述多吡啶钌配合物的制备方法。
本发明的第三个目的是提供所述多吡啶钌配合物在制备艾滋病毒TAR RNA特异性识别中的应用。
本发明的第四个目的是提供所述多吡啶钌配合物在制备艾滋病毒逆转录酶抑制中的应用。
本发明的上述目的通过如下技术方案予以实现:
一种钌配合物,由阳离子和阴离子组成,所述阳离子结构式如式I,所示:
本发明所述钌配合物并不限定阴离子的种类,本领域常规阴离子均能实现本发明目的,尤其是无机盐阴离子,如PF6 -、ClO4 -、Cl-等,作为一种最优选方案,本发明所述钌配合物的阴离子为PF6 -。
上述钌配合物的制备方法,包括以下步骤:
S1.化合物4,4'-二甲基-2,2'-联吡啶先经过二氧化硒氧化成醛基取代联吡啶,再经过硝酸银氧化成羧基取代联吡啶,并进一步与氨基噻唑化合物在1-羟基-7-偶氮苯并三氮唑(HOAt)、1-乙基-碳酰二亚胺盐酸盐(EDCI)、4-二甲氨基吡啶(DMAP)的作用下发生缩合得到含有氨基噻唑功能基团的联吡啶配体L1,如式II所示:
S2.化合物4,4'-二甲基-2,2'-联吡啶在二异丙基氨基锂的作用下分别与溴乙腈、溴丁腈以及溴己腈反应,得到氰基取代的联吡啶化合物,经过盐酸水解,生成羧基取代的联吡啶化合物,进一步与氨基噻唑化合物在1-羟基-7-偶氮苯并三氮唑(HOAt)、1-乙基-碳酰二亚胺盐酸盐(EDCI)、4-二甲氨基吡啶(DMAP)的作用下发生缩合得到含有氨基噻唑功能基团的联吡啶配体L2、L3和L4。
S3.上述配体L1~L4分别与前体化合物cis-[Ru(bpy)2Cl2]·2H2O在乙二醇中回流,反应结束后加入六氟磷酸铵饱和水溶液,过滤所得沉淀,无水***洗涤,真空干燥,中性氧化铝柱层析,乙腈洗下唯一红色组分,即得所述多吡啶钌配合物Ru1~Ru4。
本发明具有以下有益效果:
本发明提供了一种新型多吡啶钌配合物,可作为艾滋病毒RNA选择性结合试剂和艾滋病毒逆转录酶抑制剂。本发明合成的多吡啶钌配合物结构稳定,具有良好的光谱性质、良好的艾滋病毒RNA选择性结合和艾滋病毒逆转录酶抑制能力,是新型的艾滋病毒逆转录酶抑制剂。
本发明合成的一种新型多吡啶钌配合物在艾滋病毒逆转录酶抑制剂中的应用,具有以下优势:(1)具有良好的水溶性和稳定性;(2)具有正电荷,有利于与带负电荷的RNA相互作用;(3)具有良好的光谱性质,能够对RNA进行光谱响应;(4)与氨基噻唑有机类化合物相比,具有更强的艾滋病毒逆转录酶抑制能力。
附图说明
图1为本发明所制备的多吡啶钌配合物Ru1的合成途径;
图2为本发明所制备的多吡啶钌配合物Ru2~Ru4的合成途径;
图3为本发明所制备的多吡啶钌配合物与tat蛋白竞争结合TAR RNA实验的凝胶电泳图;
图4为本发明所制备的多吡啶钌配合物抑制艾滋病毒逆转录酶的酶联免疫实验数据图;
图5为本发明所制备的多吡啶钌配合物与DNA相互作用的紫外可见光谱滴定图;
图6为本发明所制备的多吡啶钌配合物与总RNA相互作用的紫外可见光谱滴定图;
图7为本发明所制备的多吡啶钌配合物与tRNA相互作用的紫外可见光谱滴定图;
图8为本发明所制备的多吡啶钌配合物与poly(A)RNA相互作用的紫外可见光谱滴定图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明。实施例仅用以解释本发明,并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备,所用试剂和材料均为市购。
实施例1多吡啶钌配合物的制备
1、多吡啶钌配合物Ru1的制备:
按照图1所示的途径合成。将4,4'-二甲基-2,2'-联吡啶(1.5g,8mmol)和二氧化硒(887.68mg,8mmol)在100ml 1,4-二氧六环中回流24小时,冷却至室温,滤除黑色固体,蒸去溶剂,得到白色固体。该固体用100ml乙酸乙酯搅拌溶解,滤除不溶物,滤液用20ml 1.0M的碳酸钠溶液洗涤三次,有机相用50ml 0.3M的焦亚硫酸钠溶液萃取三次,合并水相,用碳酸钠溶液调节pH至10,用20ml氯仿萃取四次,合并有机相,无水硫酸钠干燥,蒸去溶剂,得粗产品。粗产品利用柱层析提纯,用石油醚/乙酸乙酯(1:4)洗脱,得到醛基取代的联吡啶398mg,收率25%。将所得醛基取代的联吡啶全部溶于20ml乙醇,加入4ml硝酸银水溶液搅拌,缓慢加入10ml 1.0M的氢氧化钠水溶液,室温下反应15小时,蒸去溶剂,固体分别用4ml 1.3M的氢氧化钠和4ml水洗涤2次,合并的滤液用10ml氯仿萃取三次,水相用4M的盐酸pH至3.5,过滤产生的白色固体,真空干燥,得羧基取代的联吡啶258mg,收率60%。将所得羧基取代的联吡啶(1.3mmol)全部溶于20ml DMF中,加入氨基噻唑化合物(300mg,1.3mmol)、1-羟基-7-偶氮苯并三氮唑(1.3mmol,177mg)、4-二甲氨基吡啶(1.3mmol,146mg)、1-乙基-碳酰二亚胺盐酸盐(1.3mmol,87mg),室温搅拌6小时,过滤所得固体,用25ml水洗涤四次,真空干燥,得到氨基噻唑功能基团取代的多吡啶配体(L1)457mg,产率82%。将所得全部L1(1.06mmol)与化合物cis-[Ru(bpy)2Cl2]·2H2O(442mg,0.85mmol)在20ml乙二醇、氩气保护条件下回流8小时,冷却至室温,加入10ml饱和六氟磷酸铵水溶液,过滤所得橙色沉淀,用15ml水洗涤一次,30ml无水***洗涤三次,真空干燥,得粗产品。粗产物用中性氧化铝柱层析,乙腈洗脱唯一橙色组分,得到所述目标多吡啶配合物Ru1,产量616mg,收率64%。1H-NMR(300MHz,DMSO-d6):δ(ppm)12.28(s,1H),10.79(s,1H),9.21(d,J=1.4Hz,1H),8.95–8.79(m,5H),8.41(t,J=1.9Hz,1H),8.20(ddt,J=7.9,6.5,1.8Hz,4H),7.99–7.85(m,2H),7.85–7.66(m,5H),7.66–7.48(m,7H),7.49–7.38(m,2H),2.58(s,3H),2.18(s,3H)。ESI-MS[CH3CN,m/z]=421.6(理论值:421.5,[M-2PF6]2+)。
2、多吡啶钌配合物Ru2的制备:
按照图2所示的途径合成。在火焰烘干的烧瓶中加入预先干燥的4,4'-二甲基-2,2'-联吡啶(3.0mmol,552.7mg)和20ml无水四氢呋喃,在-78℃下缓慢加入1.8ml 2.0M二异丙基氨基锂,密封反应器,于-78℃下反应1小时。将溶于5ml无水四氢呋喃的溴乙腈(3.6mmol,431.8mg)用注射器缓慢加入反应物中,将反应器缓慢恢复至室温,继续反应12小时后,加入20ml水淬灭反应。反应液用稀盐酸中和后,用50ml乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,蒸除溶剂,得到的粗产物用硅胶进行柱层析,乙酸乙酯/石油醚(1:2)洗下主要组分,得到含氰基联吡啶。将其加入到6ml浓盐酸中回流12小时,冷却至室温,用氢氧化钠调节pH至4.5,用50ml氯仿萃取三次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,蒸除溶剂,得到含羧基联吡啶393mg。进一步将其溶于20ml DMF,加入氨基噻唑化合物(454mg,1.95mmol)、1-羟基-7-偶氮苯并三氮唑(272mg,2mmol)、4-二甲氨基吡啶(224mg,2.0mmol)、1-乙基-碳酰二亚胺盐酸盐(384mg,2.0mmol)室温搅拌12小时。过滤沉淀,25ml水洗三次,真空干燥,得到氨基噻唑功能基团取代的多吡啶配体(L2)670mg,三步总收率49%。将配体L2(667mg 1.46mmol)与化合物cis-[Ru(bpy)2Cl2]·2H2O(632mg,1.22mmol)在20ml乙二醇、氩气保护条件下回流8小时,冷却至室温,加入10ml饱和六氟磷酸铵水溶液,过滤所得橙色沉淀,用15ml水洗涤一次,30ml无水***洗涤三次,真空干燥,得粗产品。粗产物用中性氧化铝柱层析,乙腈洗脱唯一橙色组分,得到所述目标多吡啶配合物Ru2,产量864mg,收率61%。1H-NMR(300MHz,DMSO-d6):δ(ppm)12.24(s,1H),10.03(s,1H),8.92–8.75(m,6H),8.71(d,J=7.9Hz,1H),8.28–8.02(m,5H),7.71(dt,J=13.3,6.2Hz,4H),7.52(tq,J=20.0,6.1Hz,12H),7.36(d,J=8.3Hz,4H),3.14(t,J=7.3Hz,2H),2.83(d,J=7.6Hz,2H),2.17(s,3H)。ESI-MS[CH3CN,m/z]=435.6(理论值:435.6,[M-2PF6]2+)。
3、多吡啶钌配合物Ru3的制备:
制备步骤同多吡啶钌配合物Ru2的制备,不同点在于将其中的溴乙腈替代为溴丁腈(3.6mmol,533mg),得到多吡啶配体(L3)626mg,三步总收率43%。进一步与化合物cis-[Ru(bpy)2Cl2]·2H2O(572mg,1.1mmol)反应得到目标多吡啶配合物Ru3,产量706mg,收率54%。1H-NMR(300MHz,DMSO-d6):δ(ppm)12.22(s,1H),9.96(s,1H),8.82(d,J=8.2Hz,4H),8.75(d,J=7.6Hz,2H),8.23(s,1H),8.15(t,J=7.7Hz,4H),7.83–7.62(m,4H),7.54(q,J=5.7Hz,7H),7.48–7.20(m,5H),2.82(t,J=7.7Hz,2H),2.39(t,J=7.6Hz,2H),2.17(s,3H),1.73(m,4H)。ESI-MS[CH3CN,m/z]=449.6(理论值:449.6,[M-2PF6]2+)。
4、多吡啶钌配合物Ru4的制备:
制备步骤同多吡啶钌配合物Ru2的制备,不同点在于将其中的溴乙腈替代为溴己腈(3.6mmol,630mg),得到多吡啶配体(L4)585mg,三步总收率38%。进一步与化合物cis-[Ru(bpy)2Cl2]·2H2O(494mg,0.95mmol)反应得到目标多吡啶配合物Ru4,产量531mg,收率46%。1H-NMR(300MHz,DMSO-d6):δ(ppm)12.24(s,1H),9.93(s,1H),8.82(d,J=8.3Hz,4H),8.76(s,1H),8.71(s,1H),8.25(s,1H),8.15(t,J=7.9Hz,4H),7.79–7.64(m,4H),7.64–7.43(m,8H),7.43–7.22(m,4H),2.76(d,J=8.1Hz,2H),2.33(t,J=7.2Hz,2H),2.16(s,3H),1.64(d,J=23.9Hz,4H),1.38(s,4H)。ESI-MS[CH3CN,m/z]=463.6(理论值:463.6,[M-2PF6]2+)。
实施例2多吡啶钌配合物识别艾滋病毒TAR RNA的电泳实验
在1:1的艾滋病毒TAR RNA(上海生工生物)和TAR结合蛋白tat(上海强耀生物)体系中,加入不同浓度的多吡啶钌配合物,进行聚丙烯酰胺凝胶电泳实验,4S Gel Red染色,FluorChemFC3上进行凝胶成像。如图3所示,随着多吡啶钌配合物浓度的升高,结合了tat蛋白的TAR RNA逐渐减少,最终完全消失,说明钌配合物与tat竞争结合同一位点。配合物结合TAR RNA的能力依次为Ru1>Ru2>Ru3>Ru4,说明随着TAR RNA识别基团与钌配合物中心的距离(连接链的长度)增加,会使配合物结合TAR RNA的能力降低。另一方面,钌配合物Ru1表现出比tat蛋白更强的结合TAR RNA的能力,说明含有两个正电荷的钌配位中心的增强了分子与负电性的RNA之间的作用。
实施例3多吡啶钌配合物抑制艾滋病毒逆转录酶的酶联免疫实验
采用Roche试剂盒(Reverse Transcriptase Assay,colorimetric),对本发明制备的多吡啶钌配合物对重组的HIV-1艾滋病毒逆转录酶的抑制活性进行了基于酶联免疫法的实验测定,记录405nm的吸收值(以490nm的吸收值为参考)。经单指数曲线拟合,多吡啶钌配合物Ru1~Ru4抑制半数艾滋病毒逆转录酶活性的浓度(IC50)分别为2.38、5.42、5.87、8.20μM,显著高于未连接钌配合物的氨基噻唑化合物。因此,本发明制备的多吡啶钌配合物具有很高的艾滋病毒逆转录酶抑制活性,是艾滋病等与逆转录酶密切相关的疾病的潜在药物。
实施例4配合物与核酸的相互作用
称取适量的小牛胸腺DNA,溶于缓冲液当中,超声波振荡15分钟之后抽滤,将滤液按需要稀释之后,测量260nm和280nm的吸光度值。A260/A280在1.8~1.9范围内,表明基本不含蛋白质和RNA。总RNA、酵母tRNA和poly(A)RNA三种不同的RNA溶液参考DNA溶液配制方法配制。准确的核酸浓度由各自的特征吸收峰对应的摩尔消光系数计算。多吡啶钌配合物Ru1~Ru4与小牛胸腺DNA(图5)、总RNA(图6)、酵母tRNA(图7)三种核酸分别相互作用的紫外光谱滴定图均没有明显的减色或红移,配合物Ru1~Ru4与小牛胸腺DNA、总RNA、酵母tRNA三种含有共轭双链结构的核酸的作用模式可能是通过静电作用、氢键作用等,而不是通过***碱基对的方式。对于单链poly(A)RNA,配合物Ru1产生了明显的光谱响应,可见Ru1对单链RNA具有特异性的识别作用。另一方面,Ru2~Ru4与单链poly(A)RNA作用前后没有明显的光谱变化。这是由于Ru1具有π轨道共轭结构,能够将氢键结合位点上的电子和分子轨道的变化有效的传递到配位中心钌上,从而引起配体到金属的电荷转移跃迁(MLCT)的明显变化。而Ru2~Ru4虽然也可能具有这种识别作用,但由于连接链为脂肪链,无法如共轭π轨道的结构一样有效传递氢键结合前后电子和分子轨道的能级变化,因此光谱上没有显示出明显的变化。
因此,本发明制备的多吡啶钌配合物是特异性的RNA结合试剂,并能够识别艾滋病毒TAR RNA上与tat蛋白结合的位点,并高效的抑制艾滋病毒逆转录酶的活性,是艾滋病等与逆转录酶目前相关的疾病的潜在的高活性药物分子。
Claims (6)
2.根据权利要求1所述多吡啶钌配合物,其特征在于,所述阴离子为无机盐离子。
3.根据权利要求2所述多吡啶钌配合物,其特征在于,所述无机盐离子为PF6 -,ClO4 -或Cl-。
4.权利要求1所述多吡啶钌配合物的制备方法,其特征在于,制备步骤如下:
S1.化合物4,4'-二甲基-2,2'-联吡啶先经过二氧化硒氧化成醛基取代联吡啶,再经过硝酸银氧化成羧基取代联吡啶,并进一步与氨基噻唑化合物在1-羟基-7-偶氮苯并三氮唑(HOAt)、1-乙基-碳酰二亚胺盐酸盐(EDCI)、4-二甲氨基吡啶(DMAP)的作用下发生缩合得到含有氨基噻唑功能基团的联吡啶配体L1,如式II所示:
S2.化合物4,4'-二甲基-2,2'-联吡啶在二异丙基氨基锂的作用下分别与溴乙腈、溴丁腈以及溴己腈反应,得到氰基取代的联吡啶化合物,经过盐酸水解,生成羧基取代的联吡啶化合物,进一步与氨基噻唑化合物在1-羟基-7-偶氮苯并三氮唑(HOAt)、1-乙基-碳酰二亚胺盐酸盐(EDCI)、4-二甲氨基吡啶(DMAP)的作用下发生缩合得到含有氨基噻唑功能基团的联吡啶配体L2、L3和L4,如式II所示;
S3.上述配体L1~L4分别与前体化合物cis-[Ru(bpy)2Cl2]·2H2O在乙二醇中回流,反应结束后加入六氟磷酸铵饱和水溶液,过滤所得沉淀,无水***洗涤,真空干燥,中性氧化铝柱层析,乙腈洗下唯一红色组分,即得多吡啶钌配合物。
5.权利要求1中所述的多吡啶钌配合物在制备艾滋病毒TAR RNA选择性识别试剂的应用。
6.权利要求1中所述的多吡啶钌配合物在制备艾滋病毒逆转录酶抑制剂的应用。
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CN101864291A (zh) * | 2010-05-26 | 2010-10-20 | 上海大学 | 荧光纳米粒子Ru(bpy)3/SiO2、其制备方法及应用 |
CN103502475A (zh) * | 2011-05-06 | 2014-01-08 | 凯杰有限公司 | 包含内部标记引物的核酸的测序、扩增和检测方法 |
CN107337699A (zh) * | 2017-08-30 | 2017-11-10 | 华南师范大学 | 一种电化学发光探针三联吡啶钌‑cbt及其制备方法与应用 |
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