CN107955024B - 以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物及其合成方法和抗肿瘤应用 - Google Patents
以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物及其合成方法和抗肿瘤应用 Download PDFInfo
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Abstract
本发明公开了一种以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物及其合成方法和抗肿瘤应用。该簇合物的的化学式为：[[Ag15(N‑triphos)4(Cl4)](NO3)3]；其为如下式(I)所示为具有六帽体心立方体结构，其制备方法为：取如下式(II)所示化合物和硝酸银，溶于极性溶剂中，按摩尔比进行配位反应，并用硼氢化钠还原，即得到目标产物。本发明所述的Ag15簇合物表现出比配体NP3及顺铂更强的抗肿瘤活性，具有较好的潜在药用价值，可制备成抗肿瘤药物而得到应用。式(I)和式(II)所示结构如下：(I)
Description
技术领域
本发明涉及医药技术领域，具体涉及一种以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物及其合成方法、结构和抗肿瘤应用。
背景技术
恶性肿瘤（通称癌症）是危害人类健康的重大疾病之一。世界上每年新增的癌症患者约为1100万，全球每年因肿瘤死亡的人数约为700多万。恶性肿瘤的防御和治疗已经成为世界医药学界重点关注的焦点。通过放射治疗、化学治疗、手术治疗等都可以不同程度抑制肿瘤的生长。
银作为生物安全性高、稳定性好的金属材料备受广大研究者的关注。在已报道的文献中，人们发现银的纳米材料不仅有显著的抗菌活性，而且还有抗病毒、抗肿瘤等生物活性，它可以通过改变线粒体膜的通透性从而促进细胞凋亡。
随着纳米银生物活性越来越深入的研究，关于纳米银的抗肿瘤活性的研究也越来越热。Foldbjerg R等用人肺癌细胞A549研究了纳米银对肿瘤细胞的增殖抑制作用，结果显示纳米银确实能抑制肿瘤细胞的增殖。但关于其抗肿瘤的作用机制目前还没有明确的定论，它可以通过不同的途径进入细胞内，并产生活性氧簇（ROS），这能使细胞的某些成分受到损坏，比如DNA双链发生破坏并影响核糖体亚基蛋白的表达，从而使细胞凋亡或死亡。关于银及纳米银化合物作用于肿瘤细胞的研究有很多，但由于银化合物的稳定性问题一直困扰其成药的开展应用，本发明开展了一种稳定且目前尚未见报道的以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物及其合成方法、结构和应用的相关报道。
发明内容
本发明的目的是提供一种新的十五核银簇合物，即以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物以及它的合成方法、结构和抗肿瘤应用。
本发明一种以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物的化学式为：[[Ag15(N-triphos)4(Cl4)](NO3)3] ；
其为如下式 (I) 所示化合物或其药学上可接受的盐，该簇合物具有六帽体心立方体结构：
(I)。
上述式 (I) 所示簇合物的合成方法为：取如下结构式 (II) 所示化合物和硝酸银，溶于极性溶剂中，按摩尔比进行配位反应，并用硼氢化钠还原，即得到目标产物；
。
上述合成方法中涉及的式 (II) 所示化合物作为配体参与反应，其化学名称为三（（二苯膦）亚甲基）胺（tris((diphenylphosphino)methyl)amine），简称NP3。
上述合成方法中，所述的极性溶剂为甲醇或乙醇；所述硝酸银和式 (II)所示化合物的摩尔比为6-8:1，优选7:1。
本发明所述的式(I) 所示簇合物的合成方法，具体步骤如下：
1）取0.35mmol硝酸银溶解于少量蒸馏水中，待完全溶解后加入2.5-3 mL甲醇或乙醇，待完全溶解后加入0.05mmol NP3置于磁力搅拌器继续搅拌30min，完全反应后加入6mL新配置的硼氢化钠溶液，室温下搅拌反应20h；
2）反应结束后置于高速离心机10000r/min离心2min，弃其上清反应液，用7mL氯仿、7mL二氯甲烷或1mL无水甲醇加6mL氯仿溶解萃取，于室温下扩散培养晶体，一周可得产品。
本发明所述的式 (I) 所示簇合物具体合成时，可直接加入3mL甲醇或乙醇，后加NP3，优选是先用少量蒸馏水溶解硝酸银，再加入配体进行配位。
本发明还包括上述式 (I) 所示化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
本发明还包括上述式 (I) 所示化合物或其药学上可接受的盐为活性成分制备的抗肿瘤药物。
与现有技术相比，本发明提供了一种新的稳定的十五核银簇合物，即以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物簇合物，以及它的合成方法和应用。并通过考察其对多种肿瘤细胞株的抑制作用，结果表明以三（（二苯膦）亚甲基）胺为配体的Ag15簇合物表现出比其配体更强的抗肿瘤活性，具有较好的潜在药用价值，有望制备成抗肿瘤药物而得到应用。
附图说明
图1为本发明实施例1制得的最终产物的红外图；
图2为本发明实施例1制得的最终产物的紫外光谱图；
图3为本发明实施例1制得的最终产物的电喷雾质谱图；
图4为本发明实施例1制得的最终产物的X射线单晶结构图。
具体实施方式
下面结合具体实施例对本发明内容作进一步的详述，以更好地理解本发明的内容，但本发明并不限于以下实施例。
实施例1：簇合物[Ag15(N-triphos)4(Cl4)](NO3)3 的合成
1) 取0.35mmol硝酸银溶解于0.5mL蒸馏水中，待完全溶解后加入2.5mL甲醇中，待完全溶解后加入0.05mmolNP3置于磁力搅拌器继续搅拌30min，完全反应后加入6mL新配置的硼氢化钠溶液，室温下反应20h；
2)反应结束后至于高速离心机10000r/min离心2min，弃其上清反应液，用7mL氯仿溶解萃取，乙醚汽相扩散一周后得黑色晶体即为产品。
对所得黑色晶体进行电喷雾质谱和单晶衍射分析。具体电喷雾质谱数据如下：
（1）ESI-MS m/z:1402 [Ag15(N-triphos)4(Cl)4]3+ 、2220 {[Ag15(N-triphos)4(Cl)4]Cl}2+，如图3。
（2）X射线单晶衍射分析，确定其结构如图4所示，具有六帽体心立方体结构。
参照图1-4，可确定上述黑色晶体产物即为簇合物[Ag15(N-triphos)4(Cl4)](NO3)3。
实施例2：
1）取0.35mmol硝酸银溶解于3mL乙醇中，待完全溶解后加入0.05mmolNP3置于磁力搅拌器继续搅拌30min，待完全反应后加入6mL新配置的硼氢化钠溶液，溶液从无色透明迅速变成黑色，室温下搅拌反应20h；
2)反应结束后至于高速离心机10000r/min离心2min，弃其上清反应液，用1mL无水甲醇和6mL氯仿溶解萃取，乙醚液相扩散五天后得黑色晶体即为产品。对所得黑色晶体进行电喷雾质谱和单晶衍射分析，确定为目标簇合物[Ag15(N-triphos)4(Cl4)](NO3)3。
实施例3：
与实施例2不同的是反应结束后，用旋转蒸发仪旋干溶剂，再加入7mL氯仿溶解萃取，乙醚扩散可得黑色晶体即为产品。
对所得黑色晶体进行电喷雾质谱和单晶衍射分析，确定为目标簇合物[Ag15(N-triphos)4(Cl4)](NO3)3。
为了充分说明本发明所述的以三（（二苯基膦基）甲基）胺为配体的Ag15簇合物在制药中的用途，对其进行了抗肿瘤活性实验。
实验例1：以三（（二苯基膦基）甲基）胺为配体的Ag15簇合物对多种人类肿瘤株进行体外抑制活性实验
1、细胞株与细胞培养
本实验选用T24（人膀胱癌细胞）、SK-OV-3(人卵巢腺癌细胞株) 、MGC803(人胃癌细胞)在含10 %牛胎血清、1%青链霉素混合液的DMEM培养液内，放入37℃含体积浓度5% CO2孵箱中培养。A549 (人肺腺癌细胞) 、Hela（人宫颈癌细胞）、NCI-H-460（人大细胞肺癌）在含10 %牛胎血清、1%青链霉素混合液的RPMI-1640培养液，放入37℃含体积浓度5% CO2孵箱中培养。
2、MTT法测抑制率及IC50
化合物以DMSO助溶为2mM储液，用无血清培养基稀释至终浓度为100μmol/L，50μmol/L，25μmol/L，12.5μmol/L，6.25μmol/L的中间浓度液体，取每个中间浓度20μL，准备加入已有180μL细胞液96孔板。
将各株处于对数生长期的系列肿瘤细胞株以每孔180 μL分别接种于96孔板，边缘孔加200μLPBS（磷酸缓冲盐粉剂配制溶液），细胞浓度约为1×104/孔，，待细胞贴壁培养16小时后，加入20μL中间浓度的化合物液体，终浓度为10μmol/L，5μmol/L，2.5μmol/L，1.25μmol/L，0.625 μmol/L。化合物每个浓度平行设5个复孔，其中DMSO终浓度小于等于1%，同时设相应的阴性对照组（培养液中只有细胞和等量DMSO，无药物）和空白对照组（培养液中只有等量的药物，无细胞），每个组也平行设5个复孔，药物作用时间为48小时。
培养结束前4小时每孔加入10 µL MTT，继续培养4小时后，倾去培养液，加入DMSO100 µL/孔，平板震荡器振荡7 min，使结晶物充分溶解，空白对照组调零，用酶标仪以570nm/630nm双波长测定去除本底光吸收值后的吸光度(A)值，测得抑制率，10μmol/L浓度抑制率大于50%，且符合光镜下细胞受抑（或受损）的形态变化(如细胞皱缩，破碎，漂浮等)的，则判定为初筛有效，即进入下一步骤求取IC50，结果如以下表1，表2所示：
表1：
表2：
从表中得知Ag15簇合物的抗肿瘤活性更优于配体NP3及顺铂，具有较好的潜在药用价值，可为抗肿瘤新药的研发提供新的来源，可用于抗肿瘤新药的研发。
Claims (6)
1.一种以三（（二苯膦）亚甲基）胺为配体的十五核银簇合物，其特征在于：该十五核银
簇合物的化学式为：[[Ag15(N-triphos)4(Cl4)](NO3)3]，其中N-triphos的结构为。
2.根据权利要求1所述的十五核银簇合物的合成方法，其特征在于：取硝酸银蒸馏水溶液和如下结构式 (II) 所示化合物，溶于极性溶剂中，按摩尔比进行配位反应，并用硼氢化钠还原，即得到目标产物；
所述极性溶剂为甲醇或乙醇；
所述硝酸银和式 (II)所示化合物的摩尔比为6-8:1。
3.根据权利要求2所述的十五核银簇合物的合成方法，其特征在于：所述硝酸银和式(II)所示化合物的摩尔比为7:1。
4.根据权利要求2所述的十五核银簇合物的合成方法，其特征在于：该方法的具体步骤如下：
1) 取0.35mmol硝酸银溶解于少量蒸馏水中，待完全溶解后加入2.5-3 mL甲醇或乙醇，待完全溶解后加入0.05mmol三（（二苯膦）亚甲基）胺置于磁力搅拌器继续搅拌30min，完全反应后加入6mL新配置的硼氢化钠溶液，室温下搅拌反应20h；
2)反应结束后置于高速离心机10000r/min离心2min，弃其上清反应液，用7mL氯仿、7mL二氯甲烷或1mL无水甲醇加6mL氯仿溶解萃取，于室温下扩散培养晶体，一周可得产品。
5.根据权利要求1所述的十五核银簇合物的应用，其特征在于：化学式为：[[Ag15(N-triphos)4(Cl4)](NO3)3]的化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
6.根据权利要求5所述的十五核银簇合物的应用，其特征在于：化学式为：[[Ag15(N-triphos)4(Cl4)](NO3)3]的化合物或其药学上可接受的盐为活性成分制备的抗肿瘤药物。
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| CN106565755A (zh) * | 2016-09-26 | 2017-04-19 | 广西师范大学 | 以1‑吡啶‑6‑甲氧基‑β‑咔啉为配体的硝酸铜(II)螯合物及其合成方法和应用 |
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| CN106565755A (zh) * | 2016-09-26 | 2017-04-19 | 广西师范大学 | 以1‑吡啶‑6‑甲氧基‑β‑咔啉为配体的硝酸铜(II)螯合物及其合成方法和应用 |
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| [Ag15(N-triphos)4(Cl4)](NO3)3: a stable Ag–P superatom with eight electrons (N-triphos = tris((diphenylphosphino)methyl)amine);Xue-Tao Shen等;《Nanoscale》;20171201;第10卷;2664-2669 * |
| Octahedral and Cyclic [Ag6] Cluster Cores Stabilized by {Ag3(Spz)3(N-triphos)3} Motifs [HSpz=Pyrazine-2-thiolate,N-triphos=Tris((diphenylphosphanyl)methyl)amine]:Ag•••Ag Interactions;Qing-Ling Ni等;《Z. Anorg. Allg. Chem.》;20151030;第641卷(第15期);515-519 * |
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