CN104961752A - 一种双核铜(ii)–唑来膦酸配合物及应用 - Google Patents
一种双核铜(ii)–唑来膦酸配合物及应用 Download PDFInfo
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- -1 zoledronic acid coordination complex Chemical class 0.000 title abstract description 10
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- 229910052802 copper Inorganic materials 0.000 claims abstract description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Abstract
本发明公开了一种双核铜(II)–唑来膦酸配合物，其化学式为Cu2(Cl)(H2O)(H2zdn)(bipy)2·4H2O，式中H2zdn为唑来膦酸根离子，bipy为2,2’–联吡啶，此配合物具有特定的晶体结构，不仅以唑来膦酸较高的骨亲和力，能被快速传递至骨代谢活跃部位，具有性能优异的骨靶向功能和治疗效果，又具有良好的抗癌活性，该铜配合物晶体能够与靶分子DNA结合，产生链内或链间交联，进而干扰DNA正常复制，导致癌细胞死亡，相比于顺铂有较低的毒副作用和耐药性。
Description
技术领域
本发明涉及唑来膦酸配合物，具体涉及一种双核铜(II)–唑来膦酸配合物及应用。
背景技术
唑来膦酸(Zoledronic Acid)为新一代的双膦酸类药物，是破骨细胞前体的高强度骨吸收抑制剂，唑来膦酸及其衍生物表现出良好的骨靶向性，因为唑来膦酸药物含有膦酸根上的氧原子及氨基端上的氮原子，均能与金属离子等配位作用，即唑来膦酸药物含有多个配位点；如唑来膦酸可与顺铂、来曲唑、多西紫杉醇等抗肿瘤靶向药物协同发挥抗肿瘤作用，降低未发生骨转移的肺癌患者的复发率与骨转移的发生率。如公开号为CN102603812的发明专利申请，就公开了双核铂(II)–唑来膦酸配合物，该唑来膦酸配合物以2个乙二胺分子为螯合剂，使唑来膦酸与抗肿瘤作用的2个顺铂配位，形成双核铂-唑来膦酸配合物，其具有优异的骨靶向性，提高了顺铂的抗肿瘤性，降低了顺铂的毒副作用和耐药性。
发明内容
本发明所要解决的技术问题是提供一种双核铜(II)–唑来膦酸配合物及应用，其为一种新的唑来膦酸金属配合物，其具有优异的骨靶向功能和抗癌活性。
本发明解决上述技术问题所采用的技术方案为：一种双核铜(II)–唑来膦酸配合物，其化学式为Cu2(Cl)(H2O)(H2zdn)(bipy)2·4H2O，式中H2zdn为唑来膦酸，bipy为2,2’–联吡啶，其结构式如下所示：
该双核铜(II)–唑来膦酸配合物的晶胞参数如下： α＝105.76(3)°，β＝96.63(3)°，γ＝105.69(3)°，为三斜晶系，空间群。
该双核铜(II)–唑来膦酸配合物在制备抗肿瘤药物中的应用。
与现有技术相比，本发明的优点在于一种双核铜(II)–唑来膦酸配合物，其化学式为Cu2(Cl)(H2O)(H2zdn)(bipy)2·4H2O，式中H2zdn为唑来膦酸根离子，bipy为2,2’–联吡啶，此配合物具有特定的晶体结构，不仅以唑来膦酸较高的骨亲和力，能被快速传递至骨代谢活跃部位，具有性能优异的骨靶向功能和治疗效果，又具有良好的抗癌活性，该铜配合物晶体能够与靶分子DNA结合，产生链内或链间交联，进而干扰DNA正常复制，导致癌细胞死亡，相比于顺铂有较低的毒副作用和耐药性。
附图说明
图1为本发明双核铜(II)–唑来膦酸配合物的单晶型晶体结构图。
具体实施方式
以下结合附图、实施例对本发明作进一步详细描述。
实施例1
称取0.145g(0.5mmol)一水合唑来膦酸粉末，0.171g(1mmol)二水合氯化铜，0.126g(1mmol)2,2’–联吡啶，不断搅拌下，依次溶于9mL水与9mL乙醇的混合溶剂中，制备得浅蓝色悬浊液。随后滴加1mL(1mol/L)氢氧化钠溶液调节混合液的pH为2.5，悬浊液大部分溶解，且颜色加深。搅拌30min后全部转移到25mL带有聚四氟乙烯内衬的不锈钢水热反应釜内，于160℃恒温反应72h。然后取出冷却至室温，经过滤得蓝色滤液，在室温下静置培养，一周后析出大量深蓝色块状晶体和少量绿色条状晶体。过滤，干燥，手工挑选出适合X射线分析的深蓝色块状晶体即为本发明的双核铜(II)–唑来膦酸配合物，其分子式为Cu2(Cl)(H2O)(H2zdn)(bipy)2·4H2O，式中H2zdn为唑来膦酸，bipy为2,2’–联吡啶，其单晶型晶体结构如图1所示，产率：64％。该双核铜(II)–唑来膦酸配合物的晶胞参数如下：α＝105.76(3)°，β＝96.63(3)°，γ＝105.69(3)°，为三斜晶系，空间群。
实施例2
人肺癌细胞株A549(购自中国科学院上海细胞生物学研究所)用含10％新生胎牛血清，100U/mL青霉素，100U/mL链霉素的RPMI1640培养基于37℃、5％CO2，饱和湿度条件下培养。采用一种常用的检测细胞存活和生长的方法，即MTT法，检测细胞生长抑制。将培养至对数生长期的肺癌细胞以10×103/ml密度接种于96孔无菌培养板(每孔加200uL)，置于37℃、5％CO2培养箱中培养。为防止边缘细菌污染，周边孔加200uL的灭菌水。过夜，肺癌细胞完全贴壁后，设置五组测试组，分别加入100uL不同终浓度(10ug/mL为测试组1、20ug/mL为测试组2、40ug/mL为测试组3、80ug/mL为测试组4、100ug/mL为测试组5)的实施例1的双核铜(II)–唑来膦酸配合物的溶液，对照组只加100uL培养液不加药物，每组设置5个复孔。48h或72h后加入2ug/mL的MTT液(50uL/孔)，放置5％CO2培养箱中继续培养3h。终止培养，选用检测波长为492nm，震荡10s的测试条件，用酶标仪检测各孔OD值(被检测物吸收掉的光密度值)。记录结果(该试验重复3次)，综合平均，得到不同浓度的双核铜(II)–唑来膦酸配合物对人肺癌细胞平均存活表；测试结果如下表1所示：
表1：不同浓度的双核铜(II)–唑来膦酸配合物对人肺A549细胞存活表
测试结果处理与分析：采用Excel和Graphpad Prism5软件计算双核铜(II)–唑来膦酸配合物的细胞存活率与半数抑制浓度(IC50)值，其对A549细胞作用48h和72h的IC50值分别为21.14±0.68uM和12.18±0.20uM。从剂量依赖性看，该药物在10–100uM系列浓度下对A549细胞抑制率随浓度的增加而增大；从时间依赖性看，72h后产生的抑制作用比48h产生的抑制作用强。说明该配合物对人肺癌细胞具有明显的抑制作用，在很小的给药剂量时就可达到不错的作用效果，是具有较好应用前景的抗肿瘤药物，也可以在制备治疗乳腺癌、肾癌、人骨肉瘤及其他原因导致骨性转移药物中有潜在的应用，在此不一一列举。
Claims (3)
1.一种双核铜(II)–唑来膦酸配合物，其特征在于化学式为
Cu2(Cl)(H2O)(H2zdn)(bipy)2·4H2O，式中H2zdn为唑来膦酸，bipy为2,2’–联吡啶，其结构式如下所示：
2.如权利要求1所述的一种双核铜(II)–唑来膦酸配合物，其特征在于该双核铜(II)–唑来膦酸配合物的晶胞参数如下：α＝105.76(3)°，β＝96.63(3)°，γ＝105.69(3)°，为三斜晶系，P1空间群。
3.权利要求1所述的一种双核铜(II)–唑来膦酸配合物在制备抗肿瘤药物中的应用。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848676A (zh) * | 2020-08-21 | 2020-10-30 | 郑州大学 | 一种基于苯并咪唑双膦配体的发光铜化合物及其制备方法 |
| CN111892628A (zh) * | 2020-08-21 | 2020-11-06 | 郑州大学 | 一种基于吡啶并咪唑双膦衍生物的发光铜(i)配合物及其制备方法 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848676A (zh) * | 2020-08-21 | 2020-10-30 | 郑州大学 | 一种基于苯并咪唑双膦配体的发光铜化合物及其制备方法 |
| CN111892628A (zh) * | 2020-08-21 | 2020-11-06 | 郑州大学 | 一种基于吡啶并咪唑双膦衍生物的发光铜(i)配合物及其制备方法 |
| CN111892628B (zh) * | 2020-08-21 | 2021-05-11 | 郑州大学 | 一种基于吡啶并咪唑双膦衍生物的发光铜(i)配合物及其制备方法 |
| CN111848676B (zh) * | 2020-08-21 | 2021-06-29 | 郑州大学 | 一种基于苯并咪唑双膦配体的发光铜化合物及其制备方法 |
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