四氯合钯(Ⅱ)喹诺酮配合物的合成及与DNA的作用和抗增殖活性

在酸性条件下,分别合成了四氯合钯(Ⅱ)离子与2种喹诺酮(诺氟沙星,NFLX=C16H18N3O3F;环丙沙星,CPLX=C17H18N3O3F)离子形成的配合物(NFLXH)2[PdCl4]·2H2O(1)和(CPLXH)2[PdCl4]·2H2O(2).用元素分析、IR、UV以及摩尔电导测定等方法对其进行了表征.配合物1的晶体结构经X射线单晶衍射确定,结构参数:三斜晶系,P-1空间群,a=0.84561(17)nm,b=0.94191(19)nm,c=1.2832(3)nm;α=111.26(3)°,β=97.23(3)°,γ=96.38(3)°,V=0.9312(4)nm3,Z=1,最后吻合因子R=0.040,wR=0.088.利用紫外光谱法、荧光光谱法对配合物与小牛胸腺DNA(ct-DNA)的作用进行了研究,研究表明,配合物对DNA的作用模式为插入作用,与DNA的结合常数kb分别为:kb(1)=2.06×104,Kb(2)=2.43×104.其后测试了配合物对体外肿瘤细胞的抗增殖活性.经采用四甲基偶氮唑蓝分析法(MTT 法)测试后发现配合物1和2对人肺腺癌A549细胞、人原髓细胞白血病HL-60细胞的增殖抑制作用显著强于相应的喹诺酮分子本身,其中配合物2对人肺腺癌A549细胞增殖有明显的抑制作用,抑制率可高达(95.4±3.7)%,半数抑制浓度(IC50,72 h)为(124.5±10.3) μmol·L-1.     

三元配合物钯(II)-联喹啉-丙二酸根的合成及其生物活性研究

合成了三元配合物 [Pd(biqu) (mal) ]·H2 O (biqu为 2 ,2′ 联喹啉 ,mal2 -为丙二酸根 ) .测定了配合物对肺腺癌细胞AGZY 83a的抑制活性 ,IC50 值为 2 1 9μg/mL .用荧光光谱、紫外光谱和圆二色谱测定了配合物与鱼精DNA的作用规律 .求出配合物与DNA的键合常数KM 为 2 0 3× 10 8.测定了配合物与pBR3 2 2质粒DNA作用的凝胶电泳图谱 .多种实验结果表明 ,配合物主要以插入方式与DNA发生键合作用 .     

三元配合物钯(Ⅱ)-联喹啉-丙二酸根的合成及其生物活性研究

合成了三元配合物[Pd(biqu)(mal)]·H2O (biqu为2,2′-联喹啉,mal2-为丙二酸根).测定了配合物对肺腺癌细胞AGZY-83a的抑制活性,IC50值为21.9 μg/mL.用荧光光谱、紫外光谱和圆二色谱测定了配合物与鱼精DNA的作用规律.求出配合物与DNA的键合常数KM为2.03×108.测定了配合物与pBR322质粒DNA作用的凝胶电泳图谱.多种实验结果表明,配合物主要以插入方式与DNA发生键合作用.     

诺氟沙星-铜(Ⅱ)-TBZ/HPB配合物的合成、抗菌活性及与DNA作用

合成了2个新的配合物:[Cu(NFA)(TBZ)(H2O)](NO3).(H2O)0.5(1)和[Cu(NFA)(HPB)(H2O)]NO3(2)[NFA=1-乙基-6-氟-1,4-二氢-4-氧代-7-(哌嗪-1-基)-3-喹啉羧酸(诺氟沙星),TBZ=2-(噻唑-4′-基)苯并咪唑,HPB=2-(吡啶-2-基)-苯并咪唑]。用元素分析、摩尔电导率、红外光谱和紫外可见光谱等方法对配合物进行了表征;通过二倍稀释法研究了配合物对枯草杆菌、大肠杆菌和沙门氏菌的抑制作用;用电子吸收光谱、荧光光谱和粘度测定等方法研究了配合物与CT-DNA的作用。结果表明,这2种配合物均具有良好的抗菌活性,能以插入方式与CT-DNA结合,且抗菌活性与DNA结合能力大小一致:配合物21。     

司帕沙星及均三嗪衍生物铜(II)配合物与DNA作用及其抗肿瘤活性

DNA是抗肿瘤药物的重要靶点,研究药物分子与DNA之间的作用有助于设计靶向DNA类抗肿瘤药物.合成和表征了新的三元铜（II）配合物[Cu（Sf）（PyTA）（H₂O）]·ClO₄·3.5H₂O[Sf=司帕沙星,5-氨基-1-环丙基-7-（顺-3,5-二甲基-1-哌嗪基）-6,8-二氟-1,4-二氢-4-氧-3-喹啉羧酸、PyTA=2,4-二氨基-6-（2'-吡啶基）-1,3,5-均三嗪].利用电子吸收光谱、KI荧光猝灭光谱、粘度测定以及分子对接技术研究了配合物与DNA之间作用,发现配合物以插入模式与DNA结合,结合常数K_b=1.23×10⁴ L/mol.此外,应用MTT[3-（4,5-二甲基噻唑-2）-2,5-二苯基四氮唑溴盐]比色法检测了配合物的细胞毒性作用,发现配合物对癌细胞A549、Bel-7402和Eca-109等表现出良好的抑制作用[IC₅₀=（57.0±1.6）~（77.6±1.4）μmol/L].尤为重要的是,通过单细胞凝胶电泳、Hoechst 33342染色、Annexin V-FITC/PI双染流式细胞术、测定线粒体膜电位、检测细胞色素C和胞内Ca²⁺水平及细胞周期分析探究了配合物抗肿瘤作用机制,结果表明,配合物通过DNA结合及线粒体功能障碍途径诱导细胞凋亡,使细胞S和G2/M周期发生阻滞并造成DNA损伤.     

钯(II)配合物和氯化锌在DMF中阴极还原的动力学

烯丙基化合物在钯催化下与碳亲核试剂的反应已成为碳一碳键合成的手段.1989年王志勤等研究报导,在DMF溶液中和氯化锌存在下,钯催化醋酸烯丙酯与羰基化合物电化学还原生成高产率的醇.我们对此反应的机理进行了研究,首先用线性电势扫描法确定各电还原反应的还原电势,得出在实验条件下,氯化锌比π-烯丙基钯配合物容易还原,然后     

一种含芴基的钌(II)配合物的合成及DNA键合性质

合成了一种新的钌(II)配合物[Ru(bpy)2(Hfip)](ClO4)2, 其中bpy代表2,2′-联吡啶, Hfip代表2-(9H-芴-2-基)-1H-咪唑-[4,5-f]-[1,10]-邻菲啰啉. 通过紫外可见光谱、荧光光谱、稳态荧光淬灭、与溴化乙锭的竞争实验、粘度测量和DNA热变性研究了该配合物与小牛胸腺DNA的键合性质. 结果表明, 该配合物能嵌入键合DNA, 键合常数Kb=8.6×105 L·mol-1 (50 mmol·L-1 NaCl).     

全反式维甲酸合铜(II)配合物对DNA的切割和键合作用

以荧光法、粘度法、凝胶电泳和电化学方法研究了全反式维甲酸合铜(II)配合物与DNA的作用.结果表明,该配合物能在生理条件下有效切割质粒DNA,加入H_2O_2后发现该配合物的切割活性增强,说明该配合物对DNA的切割机理可能有两种:氧化和水解.同时可使DNA的粘度增加,使EB-DNA体系的荧光强度降低.DNA的存在能导致该配合物氧化还原峰电流降低.据此推断,该配合物主要以嵌入方式与DNA作用.     

全反式维甲酸合铜(II)配合物对DNA的切割和键合作用

以荧光法、粘度法、凝胶电泳和电化学方法研究了全反式维甲酸合铜(II)配合物与DNA的作用. 结果表明, 该配合物能在生理条件下有效切割质粒DNA, 加入H₂O₂后发现该配合物的切割活性增强, 说明该配合物对DNA的切割机理可能有两种: 氧化和水解. 同时可使DNA的粘度增加, 使EB-DNA体系的荧光强度降低. DNA的存在能导致该配合物氧化还原峰电流降低. 据此推断, 该配合物主要以嵌入方式与DNA作用.     

新型的去甲斑蝥酸根合镨(Ⅲ)、钐(Ⅲ)配合物的晶体结构、与DNA和BSA的作用及抗增殖活性

合成了两种2-氨甲基苯并咪唑(ambi)和去甲基斑蝥酸(H2DCA=7-氧杂二环[2.2.1]庚烷-2,3-二甲酸)与镨(Ⅲ)、钐(Ⅲ)的配合物。应用元素分析、摩尔电导、红外光谱及X射线单晶衍射法对配合物的组成和结构进行了表征,配合物的组成为:(Hambi)[Ln(DCA)2(H2O)3]·3H2O(Ln=Pr(III)(1),Sm(III))(2);Hambi为质子化的ambi。DCA离子的醚键和羧酸根的氧原子参与配位,为三齿配体,稀土离子的配位数为9。通过紫外光谱法、荧光光谱法和粘度法研究了配合物与DNA和牛血清白蛋白(BSA)的相互作用。结果表明:配合物能通过部分插入模式与DNA发生较强的结合作用(Kb:1.56×104(1)和1.85×104L·mol-1(2))。配合物能与BSA发生强烈的相互作用(KA:9.33×104L·mol-1(1)和1.52×106L·mol-1(2)),结合位点数为1。测试了配合物对人肝癌细胞(SMMC7721)的体外抗增殖活性。结果显示,配合物的抗癌活性较去甲基斑蝥素有明显提高。     

Palladium(II) 4,5-Diphenylimidazole Cyclometalated Complexes: DNA Interaction

In this paper, we show the synthesis of palladium(II) 4,5-phenylimidazole cyclometalated complexes. They have been characterized by IR, ¹H- and ¹³C-NMR spectroscopy. The cyclometalated dimer compound 2 [Pd(C₁₅H₁₁N₂)(μ-OAc)]₂ and the cyclometalated monomer compound 5 [PdBr(SEt₂)(C₁₅H₁₁N₂)], having OAc and Br as leaving groups, interact with DNA, modifying its secondary structure (as measured by T_m and CD), without modifying its tertiary structure (as determined by measurement of the electrophoretic mobility in agarose gels). The monomeric compound 5 seems to be the one that induces the highest alterations in DNA secondary structure since it strongly modifies the CD spectrum of the DNA. Melting data of drug–DNA complexes suggest that, at low drug concentration, the 4,5-Imd ligand intercalates between the base pairs in the DNA molecule, increasing the T_m, while at high drug concentrations the palladium(II) centers destabilize the double helix, producing a lowering in T_m values. These results indicate that complexes containing planar structures might selectively bind to DNA that is not supercoiled, and that therefore it only has a secondary structure. © 1997 John Wiley & Sons, Ltd.     

8-O-烯丙基-4,4'-二甲基花椒毒酚的合成及其抗增殖活性

以焦性没食子酸和乙酰乙酸乙酯为原料,经Pechmann反应、Williamson成醚、环化、还原和脱水等反应合成了新化合物8-O-烯丙基-4,4'-二甲基花椒毒酚(5),总收率32.0%,其结构经1H NMR,13C NMR和ESI-MS表征。抗增殖活性测试结果表明:5对人类肝癌细胞Hep G2、结肠癌细胞HCT和子宫癌细胞SA具有一定的抗增殖活性,其中对Hep G2的抑制活性最高,IC50为(27.57±1.00)μmol·L-1。     

Pd(II) and Pt(II) Complexes of 2-Phenyl- and 2-Benzyl-imidazoline: Synthesis,Structural Characterization,DNA Modification and in vitro Antileukaemic Activity

In this paper we describe the synthesis and chemical characterization of three new Pd(II)–imidazoline complexes: [PdCl₂ (C₆H₅–CH₂–C₃H₅N₂)₂] (2), [PdCl(SEt₂) (C₆H₄-C₃H₅N₂)] (5) and [Pd(C₆H₄-C₃H₅N₂) (μ-Br)]₂ (6). We have also analyzed the DNA modifications and in vitro antileukaemic activity of these compounds and of their previously reported analogs [Pd Cl₂ (C₆H₅–C₃H₅N₂)₂] (1), [Pd (C₆H₄–C₃H₅N₂) (μ-OAc)]₂ (3), [Pd (C₆H₄–C₃H₅N₂) (μ-Cl)]₂ (4) and [Pt(C₆H₄–C₃H₅N₂)(μ-Cl] (7). All these compounds modify the DNA secondary structure since they alter the melting temperature (T_m) of the DNA. Circular dichroism spectra indicated, moreover, that compounds 3, 5 and 6 induced higher modification on the double helix than compounds 1, 2 and 4. While compounds 1, 2 and 5 seem to induce slight changes in the electrophoretic mobility of the open and covalently closed circular forms of pUC8 DNA at high r_i (input molar ratio of Pd or Pt to nucleotides), compounds 3, 6 and 7 do not modify at any r_i the tertiary structure of the plasmid DNA. Antileukaemic tests suggest that compounds 1, 4 and 7 exhibit important cytotoxic activity since their IC₅₀ values against HL-60 human leukaemic cells were below 10 μg ml⁻¹. © 1997 John Wiley & Sons, Ltd.     

新型肟基取代豆甾类化合物的合成及其抗肿瘤活性

以豆甾醇为原料,通过臭氧化将豆甾醇的C20—C22键断裂,再经过官能团转换,合成了22-肟基取代的单肟基化合物(3和9),6,22-二肟基取代的双肟基化合物(13和14)及3,6,22-三肟基化合物(17),其中涉及4个中间体(5~8)及目标化合物9,13,14和17共8个新化合物,其结构经~1H NMR,~(13)C NMR,IR和HR-MS(ESI)表征。采用MTT法测试了化合物对人胃癌细胞(SGC-7901)、人肝癌细胞(Bel-7404)和人体乳腺癌细胞株(He La)的体外抗肿瘤活性。结果表明,具有22-肟基取代的3-羟基-5-烯结构的豆甾化合物3对受试细胞均有一定活性,IC50分别为34±2μmol·L~(-1),32±1μmol·L~(-1)和38±3μmol·L~(-1)。但是进一步在甾核上引入肟基或羟基的其他几种类型化合物的抗肿瘤活性没有提高。     

Synthesis,interaction with double-helical DNA and biological activity of new Pt(II) and Pd(II) complexes with phenylglycine

The mononuclear palladium(II) (1) and platinum(II) (2) complexes containing phenylglycine have been synthesized and characterized by elemental analysis, IR spectra, and ¹H NMR spectra. The structure of 1 was determined by X-ray diffractometry. The interaction between the complexes and fish sperm DNA (FS-DNA), adenosine-5′-triphosphate (ATP), and adenine (Ade) were investigated by UV absorption spectra, the interaction mode of the complex binding to DNA was studied by fluorescence spectra and viscometry. The results indicate that the two complexes have different binding affinities to DNA, complex 2 > complex 1. Gel electrophoresis assay demonstrates that the two complexes have the ability to cleave pBR322 plasmid DNA. Cytotoxicity experiments were carried out toward four different cancer cell lines, and 1 shows lower inhibitory efficiency than 2, consistent with the binding affinities towards DNA.     

Amidine- and Amidoxime-Substituted Heterocycles: Synthesis,Antiproliferative Evaluations and DNA Binding

The novel 1,2,3-triazolyl-appended N- and O-heterocycles containing amidine 4–11 and amidoxime 12–22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC₅₀ values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6, 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.     

Design,Synthesis and Antiproliferative Activities of Diaryl Thiourea Derivatives as Anticancer Agents

Two new series of diaryl thiourea containing sorafenib derivatives 9a – 9t were designed and synthesized, and their antiproliferative activities against PC‐3, HCT116 and MDA‐MB‐231 cell lines were evaluated. All compounds generally showed antiproliferative activity to PC‐3 cells, most of the analogs exhibited potent antiproliferative activity to HCT116 cells, and compounds 9e , 9f , 9o and 9p demonstrated inhibitory activities against all three cell lines. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

三齿多吡啶钴(II)配合物的合成、表征及其与DNA的相互作用研究

合成了两种三齿多吡啶钴(II)配合物 (A)和[Co(H₂Bzimpy)₂]Cl₂ (B), 用元素分析、IR对配合物的组成和结构进行了表征, 测定了配合物A的晶体结构. 用电子吸收光谱、荧光光谱、循环伏安法及凝胶电泳实验等方法研究了配合物与DNA的相互作用. 结果表明配合物A和B与小牛胸腺(CTDNA)的作用属部分插入和静电结合, 凝胶电泳实验表明配合物A在310 nm光辐射15 min, 可使超螺旋pBR322DNA断裂为开环缺口型和线型DNA.     

Photocytotoxic Activity of Ruthenium(II) Complexes with Phenanthroline-Hydrazone Ligands

This paper reports on the synthesis and characterization of two new polypyridyl-hydrazone Schiff bases, (E)-N′-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)thiophene-2-carbohydrazide (L¹) and (E)-N′-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)furan-2-carbohydrazide (L²), and their two Ru(II) complexes of the general formula [RuCl(DMSO)(phen)(Lⁿ)](PF6). Considering that hydrazides are a structural part of severa l drugs and metal complexes containing phenanthroline derivatives are known to interact with DNA and to exhibit antitumor activity, more potent anticancer agents can be obtained by covalently linking the thiophene acid hydrazide or the furoic acid hydrazide to a 1,10-phenanthroline moiety. These ligands and the Ru(II) complexes were characterized by elemental analyses, electronic, vibrational, ¹H NMR, and ESI-MS spectroscopies. Ru is bound to two different N-heterocyclic ligands. One chloride and one S-bonded DMSO in cis-configuration to each other complete the octahedral coordination sphere around the metal ion. The ligands are very effective in inhibiting cellular growth in a chronic myelogenous leukemia cell line, K562. Both complexes are able to interact with DNA and present moderate cytotoxic activity, but 5 min of UV-light exposure increases cytotoxicity by three times.     

Synthesis,Antiproliferative Activity and DNA-Binding Properties of Nitrogen and Sulfur Heterocyclic Norcantharidin Acylamide Acid

Three novel norcantharidin acylamide acids (L¹?N‐thiadiazole norcantharidin acylamide acid, C₁₀H₁₁N₃O₄S; L²?N‐thiazole norcantharidin acylamide acid, C₁₁H₁₂N₂O₄S and L³?N‐benzothiazole norcantharidin acylamide acid, C₁₅H₁₄N₂O₄S) were synthesized by the reactions of norcantharidin (NCTD?7‐oxabicyclo[2,2,1]heptane‐2,3‐dicarboxylic acid anhydride, C₈H₈O₄) with 2‐amino‐1,3,4‐thiadiazole (C₂H₃N₃S), 2‐aminothiazole (C₃H₄N₂S) and 2‐aminobenzothiazole (C₇H₆N₂S), respectively. Their structures were characterized by elemental analysis, IR, and NMR. The inhibition rates of L³ was much higher than those of L¹ and L² against human hepatoma cells SMMC7721 cell lines in vitro. The interaction between the compounds and DNA was studied by means of fluorescence quenching studies and viscosity measurements. The emission intensities decreased obviously with increasing concentration of the compounds in the fluorescence quenching experiments. The linear Stern‐Volmer quenching constant K_sq values were 0.62 (L¹), 0.55 (L²) and 1.08 (L³), respectively. The binding abilities followed the trend from high to low were L³, L¹ and L², respectively. The results of viscosity measurements showed that L¹ and L² might bind to DNA via partial intercalation, while L³ bound mainly in intercalation.