CN115141148A - 双咪唑类配体、带有不同烷氧链的咪唑配体的钌超分子自组装化合物及制备方法和应用 - Google Patents
双咪唑类配体、带有不同烷氧链的咪唑配体的钌超分子自组装化合物及制备方法和应用 Download PDFInfo
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Abstract
一种双咪唑基类配体，其结构如下式所示。本发明还提供了该配体与金属钌自组装体的制备方法，包括：将新制备的双咪唑基配体与带有金属钌的及受体以1:1的量加入反应容器内，加入适量的甲醇/二氯甲烷的混合溶剂，在常温常压下反应一段时间，反应结束后将反应液浓缩到适宜的体积然后缓慢的加入乙醚静置一段时间，析出的固体即为含有双咪唑基配体的超分子钌类化合物。该化合物是一种新型的钌自组装化合物，并且该化合物对肿瘤细胞系的A549和MDA‑MB‑231具有良好的抑制效果。
Description
技术领域
本发明涉一种不同烷氧链的咪唑基配体的合成以及与钌配合物的制备方法，该含有咪唑基配体的钌超分子自组装化合物在生物医药中的应用。
背景技术
化疗是目前治疗恶性肿瘤的一个主要措施，而且彻底治愈难度较大。1967年Barnett率先发现了顺铂具有抗癌活性，于是将铂类化合物进行了开发。目前，在临床上使用的化疗药物比较有限，因此亟待开发一些新型化疗药物以弥补化疗药物少的空白。
发明内容
本发明的第一个方面，提供一种新的双咪唑基类配体，其结构式如下式所示：
其中，n为0、2或3。
作为本发明的第二个方面，提供双咪唑基配体的制备方法，具体步骤如下：
S1：3,5-二溴苯酚在弱碱和加热的条件下与碘甲烷反应，待反应结束后处理得到如下式所示的产物a
S2：将产物a溶于有机溶剂中，加入催化剂以及咪唑，反应结束后经后处理得下式所示产物L1；
S3：通过对甲基苯磺酰氯与二乙二醇甲醚(二缩三乙二醇)在室温下反应，反应结束后经过后处理得到产物如下式所示b
其中，n＝1或n＝2；
S4：将产物b与3,5-二溴苯酚在弱碱和加热的条件下，反应结束后得到产物c
其中，n＝1或n＝2；
S3：将产物c溶于有机溶剂中，加入催化剂以及咪唑，反应结束后经后处理得下式所示产物L1或L2
其中，L2,n＝1或L3,n＝2；
作为本发明的第三个方面，还提供了含上述不同烷氧链的双咪唑基类配体与钌接受体的自组体的制备方法，具体步骤如下：
S1：接受体钌的制备方法如下；
S2：将上述S1制备化合物A1-A3与专利1所诉不同烷氧链的的双咪唑基配体中其一置于反应的容器中加入适量的以甲醇/二氯甲烷等比的混合溶剂，在磁力搅拌器下搅拌反应一段时间，反应结束后通过旋转蒸发仪浓缩至0.5mL以下缓慢的加入乙醚待沉淀出含不同烷氧链的双咪唑基配体钌的组装体。
作为本发明的第四个方面，提供了在本方法下的方法合成了双咪唑基配体的钌组装体的合成。
作为本发明的第五个方面，提供了带有不同烷氧链的双咪唑基类配体的钌作为抗肿瘤药物对癌细胞的抑制作用的应用。
与目前现有的技术相比，本发明的有益效果：
本发明提供了一种含有不同烷氧链的咪唑基配体，该类配体具有较好的亲脂性，是一种新型的双咪唑基的双齿配体；
本发明还提供了上述配体与钌接受体组装，该自组装体是一种全新的自组装化合物，对 A549和MDA-MB-231癌细胞具有较好的抑制效果。
附图说明
图1为本发明实施例3中的咪唑配体L1-L3及钌组装体M1-M9的紫外-可见吸收光谱测试的结果；
图2为本发明实施例4中的钌组装体的脂水分配系数的测试结果。
具体实施方式：
下面参照附图对本发明做进一步描述。
实施例1
不同烷氧链的咪唑基配体的结构：
其中n＝0(L1),n＝2(L2)n＝3(L3)
2、合成步骤如下：
配体L1的合成及表征：称量3,5-二溴苯酚(6.23g,25mmol)，1.8mL的碘甲烷(4.25g, 30mmol)，碳酸钾(2.88g,30mmol)，于100mL的梨形瓶中，加入35mL的丙酮，置换氮气三次，插上氮气球，在65℃下过夜。待反应体系冷却至室温，硅藻土过滤，乙酸乙酯洗涤，用旋转蒸发仪除去多余的溶剂得到粗产物。用PE/EA＝25/1进行柱层析得到固体产物3,5-二溴苯甲醚5.3g，产率为80％。称取3,5-二溴苯甲醚(2.65g,10mmol)，咪唑(3.4 g,50mmol)，碳酸钾(6.9g,50mmol)，氧化亚铜(0.20g,2.5mmol)100mL的梨形瓶中，加入25mL的DMSO，在150℃下回流4天。待反应体系冷却至室温，硅藻土过滤，二氯甲烷洗涤，减压蒸馏得到粗产物，用DCM/MEOH＝100/1进行柱层析得到白色固体2.04g，产率为85％。表征为1H NMR(400MHz,CDCl3):δ＝7.92(s,2H),7.31(s,2H),7.26(s,2H), 7.24(s,1H),7.02(t,J＝2.0Hz,2H),6.92(d,J＝2.0Hz,2H),3.92(s,2H).13C NMR(101MHz, CDCl3):δ＝161.8,139.6,135.6,131.0,118.2,107.0,106.3,56.12.ESI-MS:m/z Calcd for [L1+H]+:241.1084；found:241.1084.Elemental analysis:Calcd(％)for C13H12ON4:C,62.85；H,4.860；N,22.15.Found:C,64.99；H,5.03；N,23.32.
配体L2的合成及表征：称取对甲苯环酰氯(4.18g,22mmol)，二乙二醇甲醚(2.4g,20 mmol)于100mL的梨形瓶中，加入35mL的DCM，加入三乙胺(2.18g,21.6mmol)室温下反应2h。待反应结束后用1M盐酸水溶液洗涤，用饱和碳酸氢钠水溶液液洗三次，无水硫酸钠干燥，旋干得黄色液体b1 4.66g。称取b1(6.5g,2.4mmol)，间二溴苯酚(0.51g, 2mmol)，碳酸钾(0.54g,4.2mmol)于100mL的梨形瓶中，加入DMF中100℃过夜反应。待反应体系冷却至室温，水、EA萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，旋干溶剂即得透明液体产物c10.52g，产率为75％。称取c1(0.29g,0.82mmol)，咪唑(1.045g, 4mmol)，碳酸钾(2.11g,5mmol)，氧化亚铜(60mg,0.25mmol)在100mL的梨形瓶中，加入25mL的DMSO，在150℃下回流4天。待反应体系冷却至室温，硅藻土过滤，二氯甲烷洗涤，减压蒸馏得到粗产物，用DCM/MeOH＝100/1进行柱层析得到固体产物0.2g，产率为74％。1H NMR(400MHz,CDCl3):δ＝7.89(s,2H),7.30(s,2H),7.23(s,2H),7.01(s, 1H),6.96(s,2H),4.27–4.23(m,2H),3.92–3.88(m,2H),3.74–3.71(m,2H),3.60–3.56(m, 2H),3.38(s,2H).13C NMR(101MHz,CDCl3):δ＝161.0,139.4,135.5,130.9,118.1,106.8,71.9, 70.9,69.6,68.3,59.1.ESI-MS:m/zcalcd for[L2+H]+:329.1609；found:329.1608.Elemental analysis:Calcd(％)forC17H20O3N4:C,63.00；H,5.731；N,16.85.Found:C,62.18；H,6.14；N, 17.06.
配体L3的合成及表征：与配体L2相同，将二乙二醇甲醚换成二缩三乙二醇，得白色固体粉末，0.79g，率为79％。1H NMR(400MHz,CDCl3):δ＝8.04(s,2H),7.55(s,2H),7.28(s,1H),7.12(s,2H),7.08(s,2H),4.27–4.23(m,2H),3.84–3.79(m,2H),3.66–3.60(m,2H),3.59–3.52(m,4H),3.45(dd,J＝5.7,3.5Hz,2H),3.27(s,3H).13C NMR(100MHz,CDCl3):δ＝161.7,140.3,136.7,131.0,119.1,106.7,106.6,72.5,71.3,71.0,70.9,70.0,69.3,58.8.ESI-MS: m/z calcd for[L3+H]+:373.1870；found:373.1870.Elemental analysis:Calcd(％)for C17H20O3N4:C,59.96；H,5.821；N,14.31.Found:C,61.28；H,6.50；N,15.04.
配体L4的合成及表征：称取咔唑(25mmol,4.18g)，1.8mL的碘甲烷(4.25g,30mmol)，叔丁醇钾(4.2g,37.5mmol)，于100mL的梨形瓶中，加入35mL的四氢呋喃，在50℃下反应12h。待反应体系冷却至室温，硅藻土过滤，乙酸乙酯洗涤，用旋转蒸发仪除去多余的溶剂得到产物。用PE/EA＝100/1进行柱层析得到白色片状固体产物4.78g，产率为 88％。称取上一步固体产物(4.53g,25mmol)，加入100mL的梨形瓶中，置换氮气三次，加入无水无氧的DMF，插上氮气球，置于冰水浴中搅拌，待反应体系冷却至0℃，称取 NBS(9.24g,30mmol)溶于5mLDMF中缓慢滴加到梨形瓶中，室温下反应2h。待反应结束后，将反应液缓慢并且不停搅拌倒入冰水中，过滤收集白色固体，用二氯甲烷溶解固体，用无水硫酸钠干燥溶液，用旋转蒸发仪除去多余的溶剂得到粗产物。用PE/EA ＝100/1 进行柱层析得到淡黄色固体产物，产率为90％。称取上一步反应所得产物(5mmol,0.33g)， 4-硼酸吡啶(12.5mmol,1.54g)，氯化钯二茂铁(0.4mmol,0.326g)，置换氮气三次，加入 DMF/H2O＝(3:1)15mL，在110℃下反应3h。待反应体系冷却至室温，硅藻土过滤，二氯甲烷洗涤，用旋转蒸发仪除去多余的溶剂得到粗产物。用PE/EA进行柱层析得到固体产物1.0g，产率为60％。表征为1H NMR(400MHz,CD2Cl2):δ＝8.68(d,J＝5.2Hz,1H),8.45 (d,J＝1.6Hz,1H),7.82(dd,J＝8.4,1.7Hz,1H),7.66(d,J＝5.2Hz,1H),7.53(d,J＝8.4Hz, 1H),3.94(s,1H).13C NMR(101MHz,CD2Cl2):δ＝150.1,148.7,142.0,129.2,125.2,123.3, 121.4,118.9,109.5,29.4.ESI-MS:m/z calcdfor[L4+H]+:336.1495；found:336.1494.Elemental analysis:Calcd(％)for C23H17N3:C,82.99；H,4.697；N,11.85.Found:C,82.36；H,5.10；N, 12.52.
配体L5的合成及表征：称取咔唑(20mmol,3.34g)，溴乙烷(40mmol,4.36g)，氢氧化钠(60mmol,2.4g)，于100mL的梨形瓶中，加入35mL的四氢呋喃，在50℃下反应 12h。待反应体系冷却至室温，硅藻土过滤，乙酸乙酯洗涤，用旋转蒸发仪除去多余的溶剂得到产物。用PE/EA＝100/1进行柱层析得到白色固体产物，产率为90％。其余部分与配体L4相同。1H NMR(400MHz,CD2Cl2):δ＝8.65(d,J＝5.5Hz,4H),8.51(d,J＝1.8Hz,2H), 7.86(dd,J＝8.5,1.8Hz,2H),7.70–7.67(m,4H),7.59(d,J＝8.5Hz,2H),4.46(q,J＝7.2Hz, 2H),1.49(t,J＝7.2Hz,3H).13C NMR(101MHz,CD2Cl2):δ＝152.18,150.59,142.93,131.16, 127.11,125.44,123.33,120.97,111.47,39.96,15.62.ESI-MS:m/z calcd for[L5+H]+:350.1651；found:350.1642.Elemental analysis:Calcd(％)for C24H19N3:C,81.31；H,5.088；N,11.50. Found:C,82.49；H,5.48；N,12.02.
配体L6的合成及表征：与L5合成方法相同只是将溴乙烷换成溴丙烷，最终产率为63％。1H NMR(400MHz,CD2Cl2):δ＝8.65(d,J＝5.1Hz,4H),8.50(s,2H),7.85(d,J＝8.5Hz,2H), 7.69(s,4H),7.58(d,J＝8.5Hz,2H),4.36(t,J＝7.1Hz,2H),1.97(h,J＝7.3Hz,2H),1.00(t,J ＝7.4Hz,3H).13C NMR(101MHz,CD2Cl2):δ＝152.17,150.58,143.49,131.12,127.07,125.32, 123.32,120.90,111.74,46.88,24.30,13.45.ESI-MS:m/z calcd for[L6+H]+:350.1651；found: 350.1642.Elemental analysis:Calcd(％)for C24H21N3:C,81.27；H,5.487；N,10.86.Found:C, 82.61；H,5.82；N,11.56.
实施例2
钌自组装化合物M1-M9，通用结构如下：
苯组装体由两个配体(上，下)和两个钌接受体(左，右)，具体合成步骤如下：
A1的合成：称取二氯双(4-甲基异丙基苯基)钌(II)(612.4mg,1mmol)，草酸铵(124.2 mg,1mmol)于100mL的梨形瓶中，加入甲醇与二氯甲烷的混合溶剂30mL，在氮气氛下回流过夜，待反应结束冷却至室温后，旋干后溶于二氯甲烷，过滤并旋干得到黄色粉末。将上诉的黄色粉末溶于甲醇中，加入2倍物质的量的三氟甲磺酸银，室温搅拌6h，过滤浓缩后加入乙醚析出黄色粉末，即为A1。
钌受体A2和A3的合成：合成方法与A1类似，将草酸铵换成苯醌和奈醌，A2为红色固体粉末，A3为墨绿色为的固体粉末。
组装体M1-M9的合成及表征：
组装体M1的合成及表征：用千万分之一的电子天平准确称取钌受体A13(4mmol，3.4269mg)和配体L1(4mmol,0.960mg)加入到反应瓶内然后加入6mL的二氯甲烷/甲醇的混合溶剂，反应结束后，在氮气线下浓缩至0.5mL以下加入乙醚后析出固体粉末，乙醚洗涤，将组装体真空干燥，产率为81％，数据表征为1H NMR(400MHz,CD3OD):δ＝8.34(s, 2H),7.75(s,2H),7.05–6.97(m,6H),6.60(s,8H),5.96(d,J＝6.2Hz,8H),5.80(d,J＝6.2Hz, 8H),3.94(s,6H),2.82(p,J＝6.9Hz,4H),2.23(s,12H),1.34(d,J＝6.9Hz,24H).13C NMR(100MHz,CD3OD):δ＝172.4,163.3,139.1,138.6,130.6,121.2,106.3,104.2,102.7,99.3,83.7, 81.8,56.8,32.4,22.5,18.2.Elemental analysis:Calcd(％)forC74H80O22N8S4F12Ru4:C,40.65；H, 3.448；N,5.06.Found:C,40.51；H,3.68；N,5.11.
组装体M2的合成步骤同上，得黄色固体粉末，产率为75％，数据表征为1H NMR(400MHz,CD3OD):δ＝8.33(t,J＝1.4Hz,4H),7.75(t,J＝1.6Hz,4H),7.01(s,6H),6.59(t,J＝1.4 Hz,4H),5.96(d,J＝6.1Hz,8H),5.80(d,J＝6.1Hz,8H),4.27-4.24(m,4H),3.95–3.88(m, 4H),3.76–3.71(m,4H),3.63–3.57(m,4H),2.82(p,J＝6.9Hz,4H),2.23(s,12H),1.34(d, J＝6.9Hz,24H).13C NMR(100MHz,CD3OD):δ＝172.4,162.7,139.2,138.6,130.7,121.3, 107.1,104.4,102.6,99.4,83.8,81.8,73.0,71.6,70.7,69.9,59.1,32.5,22.8,18.2.Elemental analysis:Calcd(％)for C78H96O26N8S4F12Ru4:C,41.57；H,3.780；N,4.71.Found:C,40.34；H, 4.17；N,4.83.
组装体M3的合成步骤同上，得黄色固体粉末，产率为70％，数据表征为1H NMR(400MHz,CD3OD):δ＝8.34(s,4H),7.75(s,4H),7.02(s,6H),6.59(s,4H),5.96(d,J＝6.3Hz,8H), 5.80(d,J＝6.3Hz,8H),4.31–4.23(m,4H),3.95–3.90(m,4H),3.77–3.75(m,4H),3.71–3.69(m,4H),3.67–3.65(m,4H),3.34(s,6H),2.85–2.79(m,4H),2.23(s,12H),1.34(d,J＝7.0Hz,24H).13C NMR(100MHz,CD3OD):δ＝172.4,162.7,139.1,138.5,130.6,121.2,107.2,104.3,102.6,99.3,83.8,81.7,72.9,71.7,71.5,71.3,70.6,69.9,59.1,32.4,22.6,18.2. Elemental analysis:Calcd(％)for C86H104O28N8S4F12Ru4:C,39.85；H,3.723；N,4.41.Found:C, 42.02；H,4.26；N,4.56.
组装体M4的合成步骤同上，得红色固体粉末，产率为76％，数据表征为1H NMR(400MHz,CD3CN):δ＝8.06(d,J＝2.1Hz,4H),7.53(d,J＝1.7Hz,4H),7.03(t,J＝1.9Hz,2H),6.80(d,J＝1.8Hz,4H),6.76(s,4H),5.91(d,J＝6.0Hz,8H),5.76(s,4H),5.73(d,J＝6.0Hz, 8H),3.84(s,6H),2.80(p,J＝6.9Hz,4H),2.18(s,12H),1.29(d,J＝6.9Hz,24H).13CNMR (100MHz,CD3CN):δ＝184.0,161.4,138.2,137.4,130.1,120.1,106.4,105.2,102.5,101.4, 99.1,83.6,80.9,56.2,31.1,21.5,17.5.Elemental analysis:Calcd(％)forC82H96O22N8S4F12Ru4: C,40.77；H,3.339；N,4.68.Found:C,42.71；H,4.20；N,4.86.
组装体M5的合成步骤同上，得红色固体粉末，产率为70％，数据表征为1H NMR(400MHz,CD3CN):δ＝7.94(d,J＝1.9Hz,4H),7.58–7.53(m,4H),7.10(d,J＝2.0Hz,2H),6.76(d,J＝1.6Hz,4H),6.54(d,J＝1.8Hz,4H),5.92(d,J＝6.1Hz,8H),5.82(s,4H),5.74(d,J＝6.1Hz,8H),4.03–3.98(m,4H),3.90(dd,J＝5.5,2.6Hz,4H),3.80–3.74(m,4H),3.59– 3.53(m,4H),3.24(s,6H),2.83–2.74(m,4H),2.19(s,12H),1.27(d,J＝6.9Hz,24H).13C NMR(100MHz,CD3CN):δ＝183.9,160.0,138.2,137.2,130.1,120.3,107.2,106.0,102.1,101.4,99.2,83.8,80.7,71.7,70.4,69.1,68.6,58.0,31.2,21.5,17.6.Elementalanalysis:Calcd(％) for C90H112O26N8S4F12Ru4:C,43.03；H,3.903；N,4.80.Found:C,43.54；H,4.55；N,4.51.
组装体M6的合成步骤同上，得红色固体粉末，产率为55％，数据表征为1H NMR(400MHz,CD3CN):δ＝7.94–7.89(m,4H),7.56(s,4H),7.11(d,J＝1.9Hz,2H),6.74(d,J＝1.4Hz,4H),6.47(d,J＝1.8Hz,8H),5.93(d,J＝6.1Hz,8H),5.84(s,4H),5.74(d,J＝6.1Hz,4H), 4.04–3.95(m,4H),3.93–3.91(m,4H),3.85–3.79(m,4H),3.71–3.63(m,4H),3.55–3.48(m,4H),3.38–3.31(m,4H),3.03(s,4H),2.78(p,J＝6.9Hz,4H),2.21(s,12H),1.27(d,J＝6.9Hz,24H).13C NMR(100MHz,CD3CN):δ＝183.9,159.9,138.4,137.2,130.0,122.8,120.4,119.6,107.3,106.3,101.9,101.4,99.4,84.1,80.7,71.3,70.2,70.1,57.8,31.2,21.6,17.6. Elemental analysis:Calcd(％)for C94H120O28N8S4F12Ru4:C,43.05；H,3.946；N,4.41.Found:C, 43.92；H,4.71；N,4.36.
组装体M7的合成步骤同上，得墨绿色固体粉末，产率为67％，数据表征为1H NMR(400 MHz,CD3OD):δ＝8.42(s,2H),7.52(s,4H),7.19(s,8H),7.15(d,J＝3.4Hz,4H),6.85(s,4H), 5.85(d,J＝5.9Hz,8H),5.63(d,J＝5.9Hz,8H),3.85(s,6H),2.82(p,J＝6.8Hz,4H),2.12(s, 12H),1.31(d,J＝6.9Hz,24H).13C NMR(100MHz,CD3OD):δ＝170.9,137.8,137.1,129.1, 119.7,111.5,106.1,102.6,100.0,99.7,84.9,84.7,81.4,55.5,30.7,21.1,16.2,14.0.Elemental analysis:Calcd(％)for C90H100O22N8S4F12Ru4:C,45.93；H,3.710；N,4.35.Found:C,44.92；H, 4.19；N,4.66.
组装体M8的合成步骤同上，得墨绿色固体粉末，产率为61％，数据表征为1H NMR(400 MHz,CD3OD):δ＝8.24(s,4H),7.54(d,J＝1.6Hz,4H),7.19(s,8H),7.14(s,4H),6.90(s,4H), 6.49(d,J＝1.8Hz,4H),5.84(d,J＝6.1Hz,8H),5.61(d,J＝6.1Hz,8H),3.97(d,J＝5.4Hz, 4H),3.93(d,J＝4.9Hz,4H),3.81–3.77(m,4H),3.60–3.56(m,4H),3.27(s,6H),2.87– 2.71(m,4H),2.13(s,12H),1.29(d,J＝6.9Hz,24H).13C NMR(100MHz,CD3OD):δ＝170.8, 160.3,137.9,137.5,137.2,129.8,120.0,111.4,107.1,102.5,99.9,84.6,81.4,71.7,71.5,70.2, 69.0,68.4,57.7,30.7,21.1,16.2.Elemental analysis:Calcd(％)forC98H116O26N8S4F12Ru4:C, 45.04；H,3.874；N,4.48.Found:C,45.58；H,4.53；N,4.34.
组装体M9的合成步骤同上，得墨绿色固体粉末，产率为55％，数据表征为1H NMR(400 MHz,CD3OD):δ＝8.19(s,4H),7.54(s,4H),7.21(s,8H),6.89(s,4H),6.36(s,4H),5.86(d,J＝ 6.0Hz,8H),5.63(d,J＝6.0Hz,8H),3.95(d,J＝3.4Hz,4H),3.86(q,J＝4.6Hz,4H),3.70(t,J ＝4.5Hz,4H),3.63(dd,J＝5.6,3.3Hz,4H),3.57(q,J＝4.5Hz,4H),3.40(dd,J＝5.7,3.3Hz, 4H),3.08(d,J＝0.9Hz,4H),2.81(p,J＝7.0Hz,4H),2.15(s,12H),1.30(d,J＝6.8Hz,24H). 13C NMR(100MHz,CD3OD):δ＝170.8,160.0,138.2,137.5,137.3,129.9,122.0,120.1,118.8, 111.5,107.2,102.4,100.1,84.8,81.3,71.3,70.5,70.2,69.9,68.4,57.5,30.7,21.1,16.2. Elemental analysis:Calcd(％)forC106H124O28N8S4F12Ru4:C,44.06；H,3.819；N,4.25.Found:C, 46.82；H,4.60；N,4.12.
实施例3光谱性质测试
接受体A1-A3以及组装体M1-M9在甲醇溶液中进行紫外可见光光谱测试，将化合物配置成统一的浓度(1×10-5M)在室温下测试(图1)。接受体A1在206nm处有一个较弱的吸收峰，A2在255nm,287nm,375nm三个吸收峰，A3在320nm,442nm处有两个吸收峰，三种接受体中出现的不同的吸收峰这是由于接受体内部金属钌(II)与配体之间的电子转移的结果。
组装后的化合物有三种类型的分别是草酸型、苯醌型和萘醌型，自组装体M1在λmax ＝217nm处出现强吸收峰；组装体M2在λmax＝216nm处出现强吸收峰；组装体M3在λ max＝217nm处出现强吸收峰；对比配体与接受体的峰的强度明显增加，主要表现为接受体的电子的跃迁而且移动了11nm，从图中也可以看出在291nm处有一个肩峰这是由于组装以后峰变高变宽无法出现一个全峰，通过峰的强度变大峰型变宽也可以证明组装后的化合物形成一个闭环。自组装体M4在226nm,302nm,496nm处出现强吸收峰；组装体M5 在226nm,399nm,495nm处出现强吸收峰；组装体M6在224nm,298nm,495nm处出现强吸收峰；峰型与接受体A3相同都是三种吸收峰，强度明显增加，出现这一情况是因为形成了闭环的结构，配体L1-L3上的电子可能受到金属离子的吸引加速了电子的跃迁。自组装体M7在225nm,296nm,447nm处出现强吸收峰；组装体M8在226nm,296nm,447nm 处出现强吸收峰；组装体M9在226nm,296nm,447nm处出现强吸收峰。综上所诉接受体 A1-A3组装之后电子跃迁的能力显著增强，可以说明组装的化合物是一个闭环的结构。
实施例4稳定性测试
将组装体M1-M3的固体样品于真空线下抽真空，一天以后发现固体样品的状态没有发生任何改变仍然为黄色的固体粉末，后又将固体粉末敞口暴露于环境中物理状态也没有变化。将上述组装体溶于氘带甲醇溶液中分别测试不同时间段的氢谱。通过0h,12h,24h的氢谱变化，可以看出组装体的化学结构没有变化；说明组装体在与空气接触和真空状态下是稳定的。
实施例5细胞毒性测试
将液氮中的A549细胞和MDA-MB-231细胞取出，然后在37℃的水浴锅中溶解细胞，经过离心处理后加入新的培养液，摇匀后将细胞的悬浊液滴加到10％FBS胎牛血清和1％青霉素链霉素组成的DMEM培养基，然后将接种后的细胞培养基放置于37℃的5％CO2 培养箱中，培养一段时间(全程无菌操作)。将传代好的细胞吸入1mL的离心管中，弃去培养液，用PBS清洗，紧接着在离心管中加入胰酶脱壁处理，脱壁完成后将细胞均匀的分在两个离心管中。
将配体L1-L3，接受体A1-A3和组装体M1-M9与对照组分别溶于二甲基亚二甲基亚砜中浓度为5mg mL-1。将细胞加入到96孔板中，每个孔的细胞数量大约控制在0.5×104–1.0×104个，将分好细胞的孔板置于培养箱中培养24h，然后梯度加入配体，接受体以及组装体，给药后的细胞继续在培养箱中培养72h。
将MTT溶于磷酸盐缓冲液(PBS，pH＝7.2)中，每孔加入20μL的MTT溶液，在培养箱内培养4h，培养结束后弃去孔板中的多余液体，然后用二甲基亚砜溶剂细胞代谢产物，用酶标仪测试溶液的吸光度，通过吸光度的测试可以计算出IC50值
MTT实验法的检测原理是活细胞中琥珀酸脱氢酶将MTT还原为水不溶性蓝紫色结晶甲臜，然后用DMSO溶解甲臜，测溶液的吸光度来确定活细胞数。实验测得结果如下表1 所示：
可以看出，对于A549和MDA-MB-231癌细胞，组装体M7,M8和M9的抗癌效果都优于顺铂和阿霉素。组装体M7,M8以及M9对MDA-MB-231癌细胞的效果很好，而顺铂几乎没有抑制作用，通过配体与接受体的对比可以看出组装后的组装体抑癌效果明显变好，可能是因为配体与组装体的协同作用所产生的。
表1癌细胞抑制测试结果
Claims (6)
1.一种双咪唑基类配体，其特征在于，其结构式如下式所示：
其中，n＝0、2或3。
2.权利要求1中所述双咪唑基配体的制备方法，其特征在于，包括步骤：
S1：将3,5-二溴苯酚在弱碱和加热的条件下与碘甲烷反应，待反应结束后处理得到下式所示产物a
S2：将产物a溶于有机溶剂中，加入催化剂以及咪唑，反应结束后经后处理得下式所示产物L1；
S3：通过对甲基苯磺酰氯与二乙二醇甲醚(二缩三乙二醇)在室温下反应，反应结束后经过后处理得到下式所示产物b
其中，n＝1或n＝2；
S4：将产物b与3,5-二溴苯酚在弱碱和加热的条件下，反应结束后得到下式所示产物c
其中，n＝1或n＝2；
S3：将产物c溶于有机溶剂中，加入催化剂以及咪唑，反应结束后经后处理得下式所示双咪唑基类配体
其中，n＝1或2。
3.权利要求1中所述双咪唑基类配体与钌接受体的自组体的制备方法，其特征在于，包括步骤：
S1：制备下式任一所示接受体钌：
S2：将S1制备的其中一种接受体钌与权利要求1中所述双咪唑基配体中的一种置于反应的容器中，加入甲醇/二氯甲烷的混合溶剂，搅拌反应一段时间，蒸发浓缩后缓慢加入乙醚待沉淀出含不同烷氧链的双咪唑基配体钌的组装体。
4.根据权利要求3所述的方法，其特征在于，所述步骤S2包括：将S1制备其中一种接受体钌与权利要求1中所述双咪唑基配体中的一种置于反应的容器中，加入适量的以甲醇/二氯甲烷等比的混合溶剂，在磁力搅拌器下搅拌反应一段时间，反应结束后通过旋转蒸发仪浓缩至0.5mL以下缓慢的加入乙醚待沉淀出含不同烷氧链的双咪唑基配体钌的组装体。
5.由权利要求3或4所述方法制备的双咪唑基配体的钌组装体。
6.带有不同烷氧链的双咪唑基类配体的钌作在制备抗肿瘤药物中的应用。
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