韓學(xué)鋒 蔡紅新 賈磊＊, 吳偉娜＊, 張鑫 徐君 張照坡 王元

兩個(gè)吡咯酰腙銅配合物的制備、結(jié)構(gòu)及抗腫瘤活性

韓學(xué)鋒1蔡紅新2賈磊＊,2吳偉娜＊,2張鑫3徐君2張照坡2王元2

(1河南理工大學(xué)人事處，焦作454000)
(2河南理工大學(xué)物理化學(xué)學(xué)院，焦作454000)
(3中國農(nóng)業(yè)大學(xué)農(nóng)業(yè)與生物技術(shù)學(xué)院，北京454000)

合成并通過X-射線單晶衍射表征了2個(gè)銅配合物[Cu(H2L)2(THF)](1)和[Cu2(L)Cl(CH3OH)]·H2O(2)(H3L=3,4-二甲基吡咯-5-甲?；?2-甲酸乙酯-2-羥基-4-甲基苯甲酰腙)。結(jié)果表明在配合物1中，中心金屬離子與周圍2個(gè)提供N2O配位原子的酰腙陰離子和1個(gè)四氫呋喃分子配位，具有扭曲的四方錐配位構(gòu)型。然而，在雙核配合物2中，酰腙配體脫去3個(gè)質(zhì)子，通過NO和N2O2配位原子分別橋聯(lián)2個(gè)具有平面正方形配位構(gòu)型的銅中心。2個(gè)配合物對人肺癌細(xì)胞A549，人食管癌細(xì)胞ECA109和人胃癌細(xì)胞SGC7901展現(xiàn)出顯著的抗腫瘤活性。

酰腙；銅(Ⅱ)配合物；吡咯；抗腫瘤活性

In recent years,the interest in coordination chemistry ofacylhydrazone ligands has been increased due to their variable bonding modes towards transition metal ions and wide range of biological properties, such as antioxidant,anti-inflammatory,antibacterial and antitumor activities[1-7].It has been noted that the presence of a heterocyclic ring in the synthesized hydrazones plays a major role in extending their pharmacological properties.Furthermore,in some cases,coordination to metal ions results in improvement of the pharmacological activity oforganic compounds.Thus,extensive efforts have been made to design and synthesize transition metal complexes of acylhydrazone ligands with various heterocyclic rings, such as pyridine[1-5,7-9]and funan[10]et al.However, complexes of the acylhydrazone ligands bearing pyrrole unithave notreceived as much attention[11-12].

In fact,as we previously reported,several Cu(Ⅱ) complexes of acylhydrazone ligands derived from 5-formyl-3,4-dimethyl-pyrrole-2-carboxylate and benzoyl hydrazide[11]or 4-hydoxylbenzoyl hydrazide[12]show excellent antibacterial or antitumor activity.This encourages us to further investigate the structureactivity relationship of such series of potential antitumor drugs.Therefore,as a continuation of our research,we report here the syntheses,crystal structures,and antitumor activities of two Cu(Ⅱ) complexes with a 2-hydoxyl-4-methylbenzoyl hydrazone ligand(Fig.1).

Fig.1 Synthesis route of H3L

1 Experimental

1.1 Materials and measurements

Solvents and starting materials for synthesis were purchased commercially and used as received.The melting point of the ligand was determined on a XT4-100A microscopic melting point apparatus (uncorrected,made in Beijing,China).Elemental analyses were carried out on an Elemental Vario EL analyzer.The IR spectra(λ=4 000～400 cm-1)were determined by the KBr pressed disc method on a Bruker V70 FTIR spectrophotometer.1H NMR spectra of H3L was acquired with Bruker AV400 NMR instrument using DMSO-d6solvent.In vitro cytotoxicity assays about inhibit tumor cell growth against human lung cancer(A549),human gastric cancer(BGC823)and human gastric cancer (SGC7901)cells were carried out by using MTT method[7].

1.2 Synthesis of H3L

According to the relevantliteratures[11-12],the ligand H3L was prepared by condensation of ethyl 5-formyl-3,4-dimethyl-pyrrole-2-carboxylate(0.97 g,5mmol) and 2-hydroxy-4-methylbenzoyl benzoyl hydrazide (0.83 g,5mmol)in ethanol(20ml)solution at 60℃for 4 h.The separated solids were filtered and suitable crystals for X-ray diffraction measurement were obtained by recrystallization of H3L from ethanol/water (1∶1,V∶V)solution.Yield:1.52g(73%).m.p:236～238℃.Elemental analysis for H3L(C18H21N3O4)(%): Calcd.C 62.96,H 6.16,N 12.24;Found C 63.17,H 5.94,N 12.11.FTIR(cm-1):(O-H)3 423,(N-H)3 257,(O=C-O)1 709,(O=C-N)1 663,(C=N)1615.1H NMR(400 MHz,DMSO-d6)δ:12.16(1H,s,OH), 11.80(1H,s,NH),11.61(1H,s,NH),8.44(1H,s,CH= N),7.82～7.84(1H,d,Ar-H),6.77～6.78(2H,d,Ar-H), 4.24～4.29(2H,q,J=8.0 Hz,CH2CH3),2.30(3H,s, CH3),2.22(3H,s,CH3),2.09(3H,s,CH3),1.29～1.33 (3H,t,J=8.0 Hz,CH3CH2).

1.3 Syntheses of complexes 1 and 2

Complexes 1 and 2 were synthesized by reacting H3L(0.5 mmol)with Cu(OAc)2·2H2O(nligand∶nmetal=2∶1) and CuCl2·2H2O(nligand∶nmetal=1∶1)in methanol/THF(20 mL,1∶1,V∶V)solution,respectively.The block crystalssuitable for X-ray diffraction analysis were obtained by evaporating the reaction solutions at room temperature.Both complexes are soluble in DMF and DMSO,slightly soluble in THF,methanol,ethanol, ethyl acetate and acetone,insoluble in water and ether.

1:brown block,yield:62%.Elemental analysis for C36H44CuN6O10(%):Calcd.C 55.13,H 5.65,N 10.72;Found C 55.35,H 5.23,N 11.05.FTIR(cm-1): (O-H)3 443,(N-H)3 179,(O=C-O)1 688,(N=C-O) 1 633,(N=C-N)1 596.

2:brown block,yield:43%.Elementalanalysis for C19H24ClCu2N3O6(%):Calcd.C 41.27,H 4.37,N 7.60; Found C 41.34,H 4.21,N 7.57.FTIR(cm-1):(N-H) 3 224,(O=C-O)1 705,(N=C-O)1 639,(N=C-N)1 581.

1.4 X-ray crystallography

The X-ray diffraction measurement for H3L·H2O· CH3CH2OH,1 and 2 were performed on a Bruker SMART APEXⅡCCD diffractometer equipped with a graphite monochromatized Mo Kαradiation(λ= 0.710 73 nm)by usingφ-ωscan mode.Semiempirical absorption correction was applied to the intensity data using the SADABS program[13].The structures were solved by direct methods and refinedby full matrix least-square on F2using the SHELXTL-97 program[14].The hydrogen atoms for O5 in H3L· H2O·CH3CH2OH and O1 in complex 1 are located from difference Fourier map and refined with restraints in bond length and thermal parameters.All the other H atoms were positioned geometrically and refined using a riding model.A summary of crystal data and details of the structure refinements are listed in Table 1.

Table 1 Selected crystallographic data for H3L·H2O·CH3CH2OH,1 and 2

CCDC:1040334,H3L·H2O·CH3CH2OH;1040335, 1;1040336,2.

2 Result and discussion

2.1 Crystalstructure of H3L·H2O·CH3CH2OH

Fig.2(a)ORTEP drawing of H3L·H2O·CH3CH2OH with 30%thermal ellipsoids;the dimer(b)and ladder-like structure (c)formed by hydrogen bonds in H3L·H2O·CH3CH2OH

Table 2 Selected bond lengths(nm)and angles(°)in H3L·H2O·CH3CH2OH,1 and 2

Table 3 Hydrogen bonds in H3L·H2O·CH3CH2OH,1 and 2

As shown in Fig.2(a),the ligand H3L in the crystal structure of H3L·H2O·CH3CH2OH,is in a ketone form,in which the bond lengths of carbonyl C8-O1(0.124 8(4)nm)and amide C8-N1(0.134 6(4) nm)(Table 2)are comparable to those of some reported arylhydrazones[11-12].In the crystal,two arylhydrazone molecules are linked by both neighboring crystal water molecules through intermolecular O-H…O,N-H…O and O-H…N hydrogen bonds(Fig.2(b)), forming a centrosymmetric dimer.Intermolecular N-H…O hydrogen bonds between the ethanol molecule and the dimmers are also present.A further ladderlike structure(Fig.2(c))is constructed via pairs of O-H…O hydrogen bonds between the crystal ethanol and water molecules.

2.2 Crystal structure of 1 and 2

Fig.3 ORTEP drawing of 1(a)and 2(b)with 30%thermal ellipsoids;(c)the chain-like structure along the c axis formed by hydrogen bonds in complex 2

As shown in Fig.3a,the asymmetric unit of complex 1 contains one halfofa molecule with Cu ion and oxygen atom(O5)ofcoordinated THF lying on the two fold rational axis.In our previous work[11-12],the central copper center in 1 are coordinated by two L-anions via NO donor sets and an additional binding of THF molecule.According to the Addison rule[15],the geometric indexτvalue is 0.261,indicating that the coordination geometry of Cu(Ⅱ)ion is best described as a distorted square pyramidal.Strong intramolecular N-H…O and O-H…N hydrogen bonds are observed in the crystalof1.

Generally,only mononuclear complexes with pyrrole arylhydrazones could be obtained using either Cu(OAc)2or CuCl2[11-12].However,the structuralanalysis reveals that the crystal of 2 is build of one neutral binuclear unit and one crystal water molecule(Fig.3 (b)).The deprotonated ligand L3-acts as a trianionic hexadentate ligand,one phenolate oxygen,one ester carbonyl oxygen,one enolizated imine nitrogen and one pyrrole nitrogen in the ligand are bound to one Cu(Ⅱ)ion,and one enolizated carbonyl oxygen plus the other imine nitrogen in the same ligand are chelated to an adjacent Cu(Ⅱ)ion,which is also coordinated by one chloride anion and one methanol molecule.Both of the Cu(Ⅱ)ions have square planar coordination geometry.It should be noted that the pyrrole nitrogen and estercarbonyloxygen atomsdid not take part in coordination in our reported mononuclear complexes[Cu(L1)(DMF)Cl]and[Cu(L2)(CH3OH)Cl] (HL1=2-ethoxycarbonyl-5-formyl-3,4-dimethylpyrrole 4-hydroxylbenzoylhydrazone,HL2=2-ethoxycarbonyl-5 -formyl-3,4-dimethylpyrrole benzoylhydrazone)[11-12]. Furthermore,the configuration ofthe pyrrole imine C=N bond in complex 1(E configuration)are similar as those in[Cu(L1)2(CH3OH)]·CH3OH and[Cu(L2)2(THF)],but different from that in 2,[Cu(L1)(DMF)Cl]and[Cu(L2) (CH3OH)Cl](Z configuration)[11-12].In the crystal structure of 2,crystal water molecules link the complex molecules into chains along the c axis via intermolecular O-H…O between the acylhydrazone ligands and water molecules,together with O-H…Cl hydrogen bonds(Fig.3c).

2.3 IR spectra

In the IR spectra ofthe ligand H3L,the vibration bands of(O-H),(N-H),(O=C-O),(O=C-N)and(C=NN)were observed at 3 423,3 257,1 709,1 663 and 1 615 cm-1,respectively[11-12].However,(O=C-N) characteristic stretching vibration absorption in both complexes are disappeared.Meanwhile,new(N=C-O) stretching vibration absorption are observed at 1 633 and 1 639 cm-1in complexes 1 and 2,respectively, which revealing that in both complexes the C=O in O=C-N moiety has enolizated and the oxygen atom coordinates to the central Cu(Ⅱ)ion[1].The(C=N-N) stretching vibration absorption of the ligand at 1 615 cm-1shifts to 1 596 and 1 581 cm-1in complexes 1 and 2,respectively,indicating that imine nitrogen atom in the ligand also takes part in the coordination[11-12].It is also observed that the vibration band of(O=C-O)in the ligand is slight higher than that in the complex 2(1 705 cm-1),showing that there is relatively weak interaction between the ester oxygen atom and the center Cu(Ⅱ)ion.This is in accordance with single-crystal XRD analysis result(the bond length of Cu1-O3 is 0.217 5(3)nm and longer than the other coordination bonds of Cu1).However,the shift of vibration band of(O=C-O)in complex 1 is rather high,probably due to the coordination between the nitrogen atoms of the pyrrole rings and Cu(Ⅱ)ions, as some reported pyrrole imine complexes[16].

Fig.4 IC50values of complexes H3L,1 and 2 against A549,ECA109 and SGC7901 cancer cells

2.4 Antitumor activity

The cytotoxicity of complexes 1 and 2 against A549,ECA109 and SGC7901 cancer cells was evaluated from the MTT assay.A dose dependentantiproliferative activity was observed in the three tested cells in the presence of both complexes.As shown in Fig.4,the IC50values for both complexes are statistically lower than that for metal-free ligand H3L in all of the tested cells,which suggests that coordinated Cu(Ⅱ)ionplays a major role in mediating potency of the complexes.However,the complex 2 which has more active Cu(Ⅱ)centers owns less cytotoxic activity than 1. Comparing with our previous work[11-12],itmay be roughly concluded thatthe E configuration ofthe pyrrole imine C=N bond in such series of complexes is responsible for high cytotoxic activity.

[1]Despaigne A A R,Parrilha G L,Izidoro J B,et al.Eur.J. Med.Chem.,2012,50:163-172

[2]El-Gammal O A,Bekheit M M,Tahoon M.Spectrochim. Acta A,2015,135:597-607

[3]Hosseini-Monfared H,Bikas R,Szymczak R,etal.Polyhedron, 2013,63:74-82

[4]Patole J,Sandbhor U,Padhye S,et al.Bioorg.Med.Chem. Lett.,2003,13:51-55

[5]Recio Despaigne A A,Da Costa F B,Piro O E,et al. Polyhedron,2012,38:285-290

[6]SathyadeviP,Krishnamoorthy P,Alagesan M,etal.Polyhedron, 2012,31:294-306

[7]Singh P,Singh D P,Singh V P.Polyhedron,2014,81:56-65

[8]Hao Z Y,Liu Q W,Xu J,et al.Chem.Pharm.Bull., 2010,58:1306-1312

[9]Manikandan R,Viswanathamurthi P,Velmurugan K,et al.J. Photochem.Photobiol.B,2014,130:205-216

[10]Cui Z N,Li Y,Ling Y,et al.Eur.J.Med.Chem.,2010,45: 5576-5584.

[11]YE Xing-Pei(葉行培),WANG Guan-Jie(王冠杰),PAN Peng (潘鵬),et al.Chinese J.Inorg.Chem.(無機(jī)化學(xué)學(xué)報(bào)), 2014,30:2789-2795

[12]Ye X P,Zhu T F,Wu W N,et al.Inorg.Chem.Commun., 2014,47:60-62

[13]Sheldrick G M.SADABS,University of Gttingen,Germany, 1996.

[14]Sheldrick G M.SHELX-97,Program for the Solution and the Refinementof Crystal Structures,University of G?ttingen, Germany,1997.

[15]Addison A W,Rao T N,Reedijk J,et al.J.Chem.Soc., Dalton Trans.,1984,1349-1356

[16]Wang Y,Wu W N,Wang Q,et al.J.Coord.Chem.,2010, 63:147-155

Syntheses,Characterizations and Antitumor Activities of Two Copper(Ⅱ)Complexes with an Acylhydrazone Ligand Bearing Pyrrole Unit

HAN Xue-Feng1CAIHong-Xin2JIA Lei＊,2WU Wei-Na＊,2ZHANG Xin3XU Jun2
ZHANG Zhao-Po2WANG Yuan2
(1Department of Personnel,Henan Polytechnic University,Jiaozuo,Henan 454000,China)
(2Department of Physics and Chemistry,Henan Polytechnic University,Jiaozuo,Henan 454000,China)
(3College of Agricultural and Biotechnology,China Agriculture University,Beijing 100083,China)

Two interesting copper(Ⅱ)complexes,[Cu(H2L)2(THF)](1)and[Cu2(L)Cl(CH3OH)]·H2O(2)based on H3L {ethyl 5-[(2-hydroxyl-4-methylbenzoyl)amino-iminomethyl]-3,4-dimethyl-pyrrole-2-carboxylate}were synthesized and characterized by X-ray diffraction analyses.The results show that in complex 1,the copper(Ⅱ)ion is surrounded by two mono-deprotonated acylhydrazone ligands with NO donor sets and one THF molecule,and thus possesses a distorted square pyramidal geometry.However,in binuclear complex 2,the acylhydrazone ligand is tri-deprotonated and bridges two copper(Ⅱ)ions with square-planar coordination geometry through NO and N2O2 atom sets,respectively.Both complexes have excellent antitumor activities towards A549,ECA109 and SGC7901 cancer cells.CCDC:1040334,H3L·H2O·CH3CH2OH;1040335,1;1040336,2.

acylhydrazone;Cu(Ⅱ)complex;pyrrole;antitumor activity

O614.121

A

1001-4861(2015)07-1453-07

10.11862/CJIC.2015.188

2015-04-01。收修改稿日期：2015-05-12。

國家自然科學(xué)基金(No.21404033,21401046,21001040),河南省教育廳自然科學(xué)基金(No.12B150011,14B150029)，河南理工大學(xué)博士基金(No.72515/086,61307/003)和江蘇省自然科學(xué)基金(No.BK20141122)資助項(xiàng)目。

＊通訊聯(lián)系人。E-mail：jlxj@hpu.edu.cn;wuwn08@hpu.edu.cn；會員登記號：S06N4036M1112。