喷昔洛韦-铜(Ⅱ)配合物的合成、晶体结构及DNA键合作用（英文）
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摘要
将具有生物活性的铜(Ⅱ)离子与临床抗病毒药物喷昔洛韦(PCV)配位,合成了首个喷昔洛韦的金属配合物[Cu(PCV)_2(H_2O)_3]SO_4(1),并通过红外光谱、元素分析和X射线单晶衍射分析方法对其结构进行了表征。初步测试了其针对多种典型人肿瘤细胞株的体外抗肿瘤活性。测试结果表明,喷昔洛韦-铜(Ⅱ)配合物1对各种肿瘤细胞株均显示出显著高于喷昔洛韦的增殖抑制活性,其中对于较为敏感的人肝癌细胞BEL-7404,配合物1的增殖抑制活性是喷昔洛韦的3倍以上。进一步,针对抗肿瘤首要靶点DNA,通过紫外-可见吸收光谱、荧光发射光谱以及DNA粘度实验对配合物1与小牛胸腺DNA的键合作用方式进行了探讨。由实验结果推测,DNA应该是配合物1的抗肿瘤活性的重要靶点,其与DNA之间存在典型的插入结合方式。
The first metal complex of the clinical antivirus agent, penciclovir(PCV), was synthesized and structurally characterized by IR, elemental analysis and X-ray single crystal diffraction analysis. In this complex,copper(Ⅱ) was selected as the bioactive metal center, which was coordinated by two PCV molecules to form a new copper(Ⅱ) complex of PCV, [Cu(PCV)_2(H_2O)_3]SO_4(1). The in vitro antitumor activity of complex 1 towards a variety of typical human tumor cell lines has been explored. The results indicated that complex 1 showed enhanced antitumor activity comparing with PCV alone towards all the tested cell lines, in which the human hepatoma cell line BEL-7404 was the most sensitive one to complex 1(Inhibition ratio(55.83±16.41)%). The inhibitory activity of complex 1 is more than 3 times that of PCV(Inhibition ratio(17.38±5.53)%). Furthermore, the DNA binding mechanism of complex 1 was also studied and discussed by means of UV-Vis absorption and fluorescence emission spectral analyses, as well as the DNA viscosity experiment. The results suggested that DNA, as the primary antitumor target, should be an important binding target of complex 1. And the classic intercalative binding mode might exist between complex 1 and CT-DNA.
The first metal complex of the clinical antivirus agent, penciclovir(PCV), was synthesized and structurally characterized by IR, elemental analysis and X-ray single crystal diffraction analysis. In this complex,copper(Ⅱ) was selected as the bioactive metal center, which was coordinated by two PCV molecules to form a new copper(Ⅱ) complex of PCV, [Cu(PCV)_2(H_2O)_3]SO_4(1). The in vitro antitumor activity of complex 1 towards a variety of typical human tumor cell lines has been explored. The results indicated that complex 1 showed enhanced antitumor activity comparing with PCV alone towards all the tested cell lines, in which the human hepatoma cell line BEL-7404 was the most sensitive one to complex 1(Inhibition ratio(55.83±16.41)%). The inhibitory activity of complex 1 is more than 3 times that of PCV(Inhibition ratio(17.38±5.53)%). Furthermore, the DNA binding mechanism of complex 1 was also studied and discussed by means of UV-Vis absorption and fluorescence emission spectral analyses, as well as the DNA viscosity experiment. The results suggested that DNA, as the primary antitumor target, should be an important binding target of complex 1. And the classic intercalative binding mode might exist between complex 1 and CT-DNA.
引文
[1]Parker W B.Chem.Rev.,2009,109:2880-2893
[2]Schaeffer H J,Beauchamp L,de Miranda P,et al.Nature,1978,272:583-585
[3]Sime J T,Barnes R D,Elson S W,et al.J.Chem.Soc.Perkin Trans.,1992,1:1653-1658
[4]Elion G B,Furman P A,Fyfe J A,et al.Proc.Natl.Acad.Sci.USA,1977,74:5716-5720
[5]Kim H O,Baek H W,Moon H R,et al.Org.Biomol.Chem.,2004,2:1164-1168
[6]Freeman S,Gardiner J M.Mol.Biotechnol.,1996,5:125-137
[7]TAN Zai-You(谭载友),JIANG Tao(江涛),TANG Chun-Ping(唐春萍),et al.Chinese Journal of New Drugs(中国新药杂志),2003,12(7):529-531
[8]Zhong M G,Xiang Y F,Qiu X X,et al.RSC Adv.,2013,3:313-328
[9]Siakallis G,Spandidos D A,Sourvinos G.Antiviral Ther.,2009,14:1051-1064
[10]Greco A,Diaz J J,Thouvenot D,et al.Infect.Disord.:Drug Targets,2007,7:11-18
[11]Brem S.Cancer Control,1999,6:436-458
[12]Yang D Z,Wang A H J.Prog.Biophys.Molec.Biol.,1996,66:81-111
[13]Takahara P M,Rosenzweig A C,Frederick C A.Nature,1995,377:649-652
[14]Takahara P M,Frederick C A,Lippard S J.J.Am.Chem.Soc.,1996,118:12309-12321
[15]Reedijk J.Chem.Commun.,1996:801-806
[16]HAI Shi-Kun(海士坤),LOU Shu-Fang(娄淑芳),QIU XiaoYang(仇晓阳).Chinese J.Inorg.Chem.(无机化学学报),2016,32:906-912
[17]HAN Xue-Feng(韩学锋),CAI Hong-Xin(蔡红新),JIA Lei(贾磊),et al.Chinese J.Inorg.Chem.(无机化学学报),2015,31:1453-1459
[18]Lewis A,McDonald M,Scharbach S,et al.J.Inorg.Biochem.,2016,157:52-61
[19]Sheldrick G M.SHELX-97,Program for the Solution and the Refinement of Crystal Structures,University of G?ttingen,Germany,1997.
[2]Schaeffer H J,Beauchamp L,de Miranda P,et al.Nature,1978,272:583-585
[3]Sime J T,Barnes R D,Elson S W,et al.J.Chem.Soc.Perkin Trans.,1992,1:1653-1658
[4]Elion G B,Furman P A,Fyfe J A,et al.Proc.Natl.Acad.Sci.USA,1977,74:5716-5720
[5]Kim H O,Baek H W,Moon H R,et al.Org.Biomol.Chem.,2004,2:1164-1168
[6]Freeman S,Gardiner J M.Mol.Biotechnol.,1996,5:125-137
[7]TAN Zai-You(谭载友),JIANG Tao(江涛),TANG Chun-Ping(唐春萍),et al.Chinese Journal of New Drugs(中国新药杂志),2003,12(7):529-531
[8]Zhong M G,Xiang Y F,Qiu X X,et al.RSC Adv.,2013,3:313-328
[9]Siakallis G,Spandidos D A,Sourvinos G.Antiviral Ther.,2009,14:1051-1064
[10]Greco A,Diaz J J,Thouvenot D,et al.Infect.Disord.:Drug Targets,2007,7:11-18
[11]Brem S.Cancer Control,1999,6:436-458
[12]Yang D Z,Wang A H J.Prog.Biophys.Molec.Biol.,1996,66:81-111
[13]Takahara P M,Rosenzweig A C,Frederick C A.Nature,1995,377:649-652
[14]Takahara P M,Frederick C A,Lippard S J.J.Am.Chem.Soc.,1996,118:12309-12321
[15]Reedijk J.Chem.Commun.,1996:801-806
[16]HAI Shi-Kun(海士坤),LOU Shu-Fang(娄淑芳),QIU XiaoYang(仇晓阳).Chinese J.Inorg.Chem.(无机化学学报),2016,32:906-912
[17]HAN Xue-Feng(韩学锋),CAI Hong-Xin(蔡红新),JIA Lei(贾磊),et al.Chinese J.Inorg.Chem.(无机化学学报),2015,31:1453-1459
[18]Lewis A,McDonald M,Scharbach S,et al.J.Inorg.Biochem.,2016,157:52-61
[19]Sheldrick G M.SHELX-97,Program for the Solution and the Refinement of Crystal Structures,University of G?ttingen,Germany,1997.