CN101125865B - 手性钌配合物及其作为抗肿瘤药物的应用 - Google Patents
手性钌配合物及其作为抗肿瘤药物的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
本发明公开了一种手性钌配合物及其作为抗肿瘤药物的应用。手性钌配合物的通式为:A-[Ru(bpy)2L](PF6)2,其中,A为Δ或Λ;L为tFPIP、IPBP、IPBH或PYNI。该手性钌配合物以钌作为中心金属离子,具有刚性八面体空间结构的络离子;分子中有两个联吡啶基团作为辅助配体;以2-取代苯基咪唑[4,5-f][1,10]菲咯啉作为主配体;具有上述结构特点的金属配合物的手性异构体,具有旋光性。这些钌配合物对肝癌细胞株BEL-7402等具有明显的抑制活性,能用于制备抗肿瘤药物。
Description
技术领域
本发明涉及钌配合物,具体的说,涉及手性钌配合物及其作为抗肿瘤药物的应用。
背景技术
恶性肿瘤是危害人类健康的主要疾病之一,在各种疾病导致的死亡中,癌症的死亡率仅次于心血管疾病的死亡率,在某些发达国家占死亡原因的首位,90年代我国每年新发病例超过200万人。临床上普遍采用化疗、手术治疗以及放射治疗等手段对肿瘤进行治疗。
1969年Rosenberg发现顺铂(cisplatin)具有抗肿瘤活性,并很快发展成为临床上广泛使用的抗肿瘤药物。顺铂临床上用于治疗膀胱癌、前列腺癌、肺癌、头颈部癌、乳腺癌、恶性淋巴癌和白血病等。但该药物水溶性差,且仅能注射给药,缓解期短,并伴有严重的肾、胃肠道毒性、耳毒性及神经毒性,长期使用会产生耐药性。因此研制新的具有抗肿瘤活性的金属配合物引起人们的重视。近年来已经证实铂、铑、锗、锡等,特别是钌的化合物具有抗肿瘤活性。
发明内容
本发明的目的在于提供一种手性钌配合物,以克服现有技术存在的不足。
本发明的另一个目的是提供上述手性钌配合物在制备抗肿瘤药物中的应用。
本发明设计合成了一系列的手性钌配合物,具有以下结构特点:1)以钌作为中心金属离子;具有刚性八面体空间结构的络离子;2)分子中有两个联吡啶基团作为辅助配体;3)以2-取代苯基咪唑[4,5-f][1,10]菲咯啉作为主配体;4)具有上述结构特点的金属配合物的手性异构体,具有旋光性。
上述手性钌配合物的通式为:A-[Ru(bpy)2L](PF6)2,
其中,A为Δ或Λ;L为tFPIP、IPBP、IPBH或PYNI。
上述手性钌配合物的优选化合物为:
Δ-[Ru(bpy)2(tFPIP)](PF6)2、Λ-[Ru(bpy)2(tFPIP)](PF6)2、
Δ-[Ru(bpy)2(IPBP)](PF6)2、Λ-[Ru(bpy)2(IPBP)](PF6)2、
Δ-[Ru(bpy)2(IPBH)](PF6)2、Λ-[Ru(bpy)2(IPBH)](PF6)2、
Δ-[Ru(bpy)2(PYNI)](PF6)2、Λ-[Ru(bpy)2(PYNI)](PF6)2。
上述手性钌配合物具有很好的抗肿瘤活性,能用于制备抗肿瘤药物。
与现有技术相比,本发明具有如下有益效果:本发明设计合成了一系列的手性钌配合物,体外细胞实验结构表明,这些钌配合物对肝癌细胞株BEL-7402等具有明显的抑制活性,能用于制备抗肿瘤药物。
具体实施方式
实施例1Δ-[Ru(bpy)2(tFPIP)](PF6)2(Δ-1)的合成
Δ-[Ru(bpy)2(FPIP)](PF6)2(Δ-1)的合成路线见式(Ⅰ):
1.1菲罗啉5,6-二酮的合成
1,10-邻菲罗啉(4g,21.88mmol)与KBr(4g,33.9mmol)置于冰浴上,搅拌下缓慢滴加H2SO4和HNO3的混酸溶液,滴加完毕后移去冰浴,加热回流40分钟。反应结束后,使溴逸去,将反应液转移至烧杯中,加入6mol·L-1NaOH溶液,小心调节溶液pH值约为7(溶液中有大量金黄色沉淀生成),用3×100mL氯仿萃取,合并有机相后,用50ml水洗涤1-2次,无水硫酸钠干燥过夜。减压蒸去氯仿,得橙黄色粗产品。用乙醇溶解粗产品,过60-100目硅胶柱,收集黄色色带,乙醇中重结晶,得黄色针状晶体,产率74.8%。
1.2 2-(2-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉(tFPIP)的合成
菲罗啉5,6-二酮(2.6g,12mmol)和2-三氟基苯甲醛(2.5g,18mmol),乙酸铵(19g,25mmol)和冰乙酸(100ml),搅拌回流4h,冷却至室温,加入蒸馏水,用浓氨水调pH值至中性,有大量橙黄色沉淀生成时,用3×20mL氯仿萃取。旋干,真空干燥,得粗产品。粗产品以甲醇溶解,过硅胶柱,甲醇淋洗,收集黄色洗脱液,浓缩干燥,得灰黄色固体,产率86.7%。
1.3 cis-[Ru(bpy)2Cl2]·2H2O的合成
氯化钌(RuCl3·nH2O)(1.56g,6mmol),联吡啶(1.87g,12mmol)和氯化锂(2.42g,57.6mmol),溶于15ml DMF中,氩气保护下加热回流8小时。冷却至室温,加入50ml丙酮,摇匀,置冰箱冷冻过夜。过滤,得紫黑色微晶,以冰水洗至近无色,干燥,产率71.0%(以联吡啶计算)。
1.4 cis-[Ru(bpy)2(py)2]Cl2的合成
2.0g cis-[Ru(bpy)2Cl2]·2H2O,23ml吡啶和46ml水,加热搅拌回流4小时。减压蒸去全部溶剂后,用46ml甲醇溶解得到红色固体,然后加入300ml乙醚,室温放置1小时,洗出大量的红色晶体。抽滤,用乙醚洗涤数次,得到红色晶体,产率84.5%。
1.5Δ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成
1.95g cis-[Ru(bpy)2(py)2Cl2]溶于30ml水中,室温搅拌下加入0.5M的O,O’-二苯甲酰基-D-酒石酸钠溶液19.0ml,搅拌10分钟,将所得溶液敞口置于通风橱中,约一个星期后析出大量红色晶体,产率79.3%。
1.6Δ-[Ru(bpy)2(FPIP)](PF6)2(Δ-1)的合成
Δ-[Ru(bpy)2(py)2][O,O’-dibenzoyl-d-tartrate]·12H2O,tFPIP以及乙二醇和水的混合溶液加热回流6小时,冷至室温后加水稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈-甲苯溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到橘红色固体,产率79%。ESI-MS(m/e):777.2;389.2。CD(in Tris-HCl,pH=7.2,λmax):-291.0nm。
实施例2Λ-[Ru(bpy)2(tFPIP)](PF6)2(Λ-1)的合成
Λ-[Ru(bpy)2(FPIP)](PF6)2(Λ-1)的合成路线见式(Ⅱ):
菲罗啉5,6-二酮,2-(2-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉(tFPIP),cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2的合成同实施例1。
2.1Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-L-酒石酸]·12H2O的合成
1.95g cis-[Ru(bpy)2(py)2Cl2]溶于30ml水中,室温搅拌下加入0.5M的O,O’-二苯甲酰基-L-酒石酸钠溶液19.0ml。搅拌10分钟,将所得溶液敞口置于通风橱中,约一星期后析出大量红色晶体,产率73%。
2.2Λ-[Ru(bpy)2(tFPIP)](PF6)2(Λ-1)的合成
Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-L-酒石酸]·12H2O(0.13g,0.1mmol),tFPIP(0.105g,0.28mmol)以及乙二醇和水的混合溶剂加热回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈-甲苯溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到橘红色固体,产率76%。ESI-MS(m/e):777.3;389.3。CD(in Tris-HCl,pH=7.2,λmax):+291.0nm。
实施例3Δ-[Ru(bpy)2(IPBP)](PF6)2(Δ-2)的合成
Δ-[Ru(bpy)2(IPBP)](PF6)2(Δ-2)的合成路线见式(Ⅲ):
菲罗啉5,6-二酮,cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2,Δ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成同实施例1。
3.1 2-(4-甲基-1-苯并吡喃-2-酮)咪唑[4,5-f][1,10]菲咯啉)(IPBP)的合成
菲罗啉-5,6-二酮0.315g(1.5mmol),3-醛基色酮0.261g(1.5mmol),乙酸铵2.31g(30mmol)和冰乙酸20mL的混合物于油浴中加热回流2小时。冷却至室温后,用80mL水稀释,然后滴加浓氨水中和至近中性,即析出大量黄色沉淀。抽滤,先后用水,乙醇洗涤数次,烘干即得粗产物,无水乙醇中重结晶,产率73%。
3.2Δ-[Ru(bpy)2(IPBP)](PF6)2(Δ-2)的合成
Δ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O(0.26g,0.2mmol),IPBP(0.210g,0.56mmol)以及乙二醇和水的混合溶剂加热回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈-甲苯溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到红色固体,产率70%。ESI-MS(m/e):791.3.CD(in Tris-HCl,pH=7.2,λmax):-291.0nm。
实施例4Λ-[Ru(bpy)2(IPBP)](PF6)2(Λ-2)的合成
Λ-[Ru(bpy)2(IPBP)](PF6)2(Λ-2)的合成路线见式(Ⅳ):
菲罗啉5,6-二酮,cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2的合成同实施例1;Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成同实施例2;IPBP的合成同实施例3。
Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-L-酒石酸]·12H2O(0.26g,0.2mmol),IPBP(0.210g,0.56mmol)以及乙二醇和水的混合溶剂加热回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈-甲苯溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到红色固体,产率72%。ESI-MS(m/e):937.0;791.3;396.27。CD(in Tris-HCl,pH=7.2,λmax):+291.0nm。
实施例5Δ-[Ru(bpy)2(IPBH)](PF6)2(Δ-3)的合成
Δ-[Ru(bpy)2(IPBH)](PF6)2(Δ-3)的合成路线见式(Ⅴ):
菲罗啉5,6-二酮,cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2,Δ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成同实施例1。
5.12-(4H-1-二氧六环并苯基)咪唑[4,5-f][1,10]菲咯啉(IPBH)的合成
邻菲咯啉-5,6-二酮0.315g(1.5mmol),3-醛基苯并二恶烷0.246g(1.5mmol),乙酸铵2.31g(30mmol)和冰乙酸20mL的混合物于油浴中加热回流2小时。冷却至室温后,用80mL水稀释,然后滴加浓氨水中和至近中性,即析出大量棕黄色沉淀。抽滤,先后用水,乙醇洗涤数次,烘干即得粗产物,无水乙醇中重结晶,产率67.1%。
5.2Δ-[Ru(bpy)2(IPBH)](PF6)2(Δ-3)的合成
Δ-[Ru(bpy)2(py)2][O,O’-dibenzoyl-d-tartrate]·12H2O(0.13g,0.1mmol),IPBH(0.107g,0.3mmol)以及乙二醇和水的混合溶剂加热回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈-甲苯溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到橘黄色固体,产率74%。ESI-MS(m/e):913.0;767.2;384.3。CD(in Tris-HCl,pH=7.2,λmax):-292.0nm。
实施例6Λ-[Ru(bpy)2(IPBH)](PF6)2(Λ-3)的合成
Λ-[Ru(bpy)2(IPBH)](PF6)2(Λ-3)的合成路线见式(Ⅵ):
菲罗啉5,6-二酮,cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2的合成同实施例1;Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成同实施例2;IPBP的合成同实施例5。
Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-L-酒石酸]·12H2O(0.13g,0.1mmol),IPBH(0.107g,0.3mmol)以及乙二醇和水的混合溶剂加热回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈-甲苯溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到橘黄色固体,产率76%。ESI-MS(m/e):912.87;767.3;384.3。CD(in Tris-HCl,pH=7.2,λmax):292.0nm.
实施例7Δ-[Ru(bpy)2(PYNI)](PF6)2(Δ-4)的合成
Δ-[Ru(bpy)2(PYNI)](PF6)2(Δ-4)的合成路线见式(Ⅶ)。
cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2,Δ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成同实施例1。
7.12-(2′-吡啶)萘并咪唑(PYNI)的合成
2-氰基-吡啶0.312g(3mmol),2,3-二氨基萘0.47g(3mmol),多聚磷酸6ml,加热到175℃6小时,停止反应,冷至80℃,迅速将反应混合物倒入50ml水中,用25%氨水中和,得到棕绿色沉淀,用乙醇重结晶,真空干燥得棕绿色粉末。产率76.2%。
7.2Δ-[Ru(bpy)2(PYNI)](PF6)2(Δ-4)的合成
Δ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O(0.13g,0.1mmol),IPBH(0.0735g,0.3mmol)以及乙二醇和水的混合溶剂(9∶1,v/v,20ml)于120℃回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈∶甲苯(10∶1,v/v)溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到棕色固体,产率80%。ESI-MS(m/e):658.2;583.9;329.7。CD(in Tris-HCl,pH=7.2,λmax):-294nm。
实施例8Λ-[Ru(bpy)2(PYNI)](PF6)2(Λ-4)的合成
Λ-[Ru(bpy)2(PYNI)](PF6)2(Λ-4)的合成路线见式(Ⅷ):
cis-[Ru(bpy)2Cl2],cis-[Ru(bpy)2(py)2]Cl2的合成同实施例1;Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-D-酒石酸]·12H2O的合成同实施例2;PYNI的合成同实施例7。
Λ-[Ru(bpy)2(py)2][O,O’-二苯甲酰基-L-酒石酸]·12H2O(0.13g,0.1mmol),IPBH(0.0735g,0.3mmol)以及乙二醇和水的混合溶剂(9∶1,v/v,20ml)于120℃回流6小时,冷至室温后加水40ml稀释,过滤得到深红色滤液,向滤液中加入饱和NH4PF6溶液,得到大量橙黄色沉淀,抽滤,沉淀分别用水、乙醚洗涤数次,真空干燥,得到橙红色粗品。将干燥后得粗品用5ml乙腈溶解,过中性氧化铝柱,乙腈∶甲苯(10∶1,v/v)溶液淋洗下主要的红色组分,减压旋干,乙腈-甲苯中重结晶,得到棕色固体,产率79%。ESI-MS(m/e):658.2;583.8;329.8。CD(in Tris-HCl,pH=7.2,λmax):+294nm。
实施例9钌配合物对肿瘤细胞生长的抑制
以5-氟尿嘧啶为阳性对照。研究钌配合物对人肝癌细胞株(BEL-7402),结肠癌细胞株(HCT-8)和人肺腺癌细胞株(A-549)(细胞实验均由中国医学科学院药物研究所筛选中心进行)。
一般实验方法:选用对数生长周期的贴壁肿瘤细胞,胰酶消化后,用10%小牛血清的RPMI1640培养液配成5000个/ml的细胞悬液,接种在96孔培养板中(每孔接种100μl),37℃,5%CO2条件下培养24h。待细胞长满单层后,实验组加样品10μl,然后加入RPMI-1640培养液(Flow Laboratories,美国)至每孔终体积为200μl。37℃,5%CO2条件下继续培养72h后,将细胞培养板中的营养液弃掉,每孔加入100μl新鲜配制的0.5mg/ml MTT无血清培养液,37℃,5%CO2条件下继续培养4h。小心弃上清,加入200μl DMSO溶解MTT formazon沉淀,微型超声振荡器混匀,酶标仪上测定波长544nm处的光密度值(OD值),按下式计算配合物对肿瘤细胞生长的抑制率:
肿瘤细胞生长抑制率(%)=(OD对照-OD实验)/(OD对照-OD空白)×100%
不同浓度目标化合物对人肝癌细胞株(BEL-7402),结肠癌细胞株(HCT-8)和人肺腺癌细胞株(A-549)肿癌细胞生长的抑制率(%)见表1。
表1钌配合物对BEL-7402,HCT-8和A-549肿瘤细胞株的抑制活性
从表1数据可以看到,高浓度(50μg/ml)条件下;钌配合物(约50μM)对实验肿瘤细胞均表现出明显的生长抑制作用;特别是Δ-1(88.3%;86.2%);Λ-1(88.8%;88.9%);Δ-2(86.8%;83.4%);Λ-2(64.9%;53.7%)对人肝癌细胞株BEL-7402和结肠癌细胞株HCT-8生长抑制率均超过50%。在低浓度5μg/ml条件下,钌配合物Δ/Λ-[Ru(bpy)2(FPIP)]2+(约5μM),对人肝癌细胞株BEL-7402肝癌细胞、HCT-8结肠癌和A-549肺腺癌细胞生长的抑制均超过了阳性对照药5-FU(约38μM)。实验条件下,钌配合物对人肝癌细胞株BEL-7402肝癌细胞的抑制率要比HCT-8结肠癌和A-549肺腺癌的强一些,而对肝癌细胞的活性比结肠癌更大,尤其是左旋配合物,对肝癌细胞的选择性更为明显。
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KR102016699B1 (ko) * | 2017-12-20 | 2019-09-02 | 서울대학교산학협력단 | 신규 루테늄 착화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
CN109456365B (zh) * | 2018-12-05 | 2020-09-25 | 湖南文理学院 | 一种钌配合物荧光探针、制备方法和用途 |
CN115057889A (zh) * | 2022-05-26 | 2022-09-16 | 广东药科大学 | 一种生物素修饰钌(ii)配合物及其制备方法和应用 |
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US5112974A (en) * | 1985-01-18 | 1992-05-12 | The Trustees Of Columbia University In The City Of New York | Mixed ligand complexes and uses thereof as binding agents to DNA |
US4699978A (en) * | 1985-01-18 | 1987-10-13 | The Trustees Of Columbia University In The City Of New York | Site-specific chiral ruthenium (II) and cobalt (III) antitumor agents |
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Liu,Yun-Jun;et al..Interaction of polypyridyl ruthenium (II) complex containingasymmetric ligand with DNA.Journal of Inorganic Biochemistry99 2.2005,99(2),530-537, 全文, 特别是实验部分. * |
Liu,Yun-Jun;et al..Photoinduced cleavage and DNA-binding of theruthenium(II)polypyridyl complex [Ru(phen)2(ipbd)](ClO4)2.Transition Metal Chemistry32 3.2007,32(3),332-337, 全文, 特别是实验部分. * |
邓洪等.配体的空间构型及疏水性对钌(II)多吡啶配合物与DNA作用的影响.化学学报60 12.2002,60(12),2159-2166,全文,特别是实验部分. * |
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US20100216993A1 (en) | 2010-08-26 |
US8357678B2 (en) | 2013-01-22 |
WO2009043223A1 (fr) | 2009-04-09 |
CN101125865A (zh) | 2008-02-20 |
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