towards polynuclear metal complexes with enhanced bioactivities: synthesis, crystal structures and...

Inorganica Chimica Acta xxx (2013) xxx–xxx

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Inorganica Chimica Acta

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Towards polynuclear metal complexes with enhanced bioactivities: Synthesis,crystal structures and DNA cleaving activities of CuII, NiII, ZnII, CoII and MnII

complexes derived from 4-carboxy-1-(4-carboxybenzyl) pyridinium bromide

Ming Chen a, Ming-Zhen Chen a, Chun-Qiong Zhou a, Wei-Er Lin a, Jin-Xiang Chen a,⇑, Wen-Hua Chen a,⇑,Zhi-Hong Jiang a,b

a School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR Chinab Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau

a r t i c l e i n f o a b s t r a c t

Article history:Received 12 November 2012Received in revised form 7 February 2013Accepted 8 February 2013Available online xxxx

Keywords:Dicarboxylic ligandTransition metal complexesCrystal structuresDNA cleavage

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⇑ Corresponding authors. Fax: +86 20 61648533.E-mail addresses: [email protected] (J.-X. Chen)

Chen).

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Six transition metal complexes, that is, {[Cu(Ccbp)2]�4H2O}n (1), [Ni(H2O)6](Ccbp)2�4H2O (2), [M(Ccbp)2-(H2O)4]�2H2O�2MeOH (M = ZnII (3), CoII (4), MnII (5)), and [Cu(Cbp)2(H2O)2](NO3)2�4H2O (6) weresynthesized from the reaction of 4-carboxy-1-(4-carboxybenzyl)pyridinium bromide (H2CcbpBr) andN-(4-carboxybenzyl)pyridinium bromide (HCbpBr) with the corresponding metal salts in the presenceof NaOH, respectively. All these metal complexes were characterized by IR, elemental analyses and singlecrystal X-ray crystallography. In complex 1, every two Ccbp� ions bridge two Cu2+ ions through four ter-minal carboxylate ions in a monodentate coordination mode, thus forming a one-dimensional polymerstructure. Complex 2 is an ionic metal complex consisting of isolated [M(H2O)6]2+ dications and Ccbp�

anions. Complexes 3–5 have similar structures, in which the central metal atom in [M(Ccbp)2(H2O)4] unitadopts a slightly distorted octahedral geometry. In complex 6, the central Cu atom adopts a distorted tet-rahedral coordination geometry that is formed from two unidentate Cbp ligands and two H2O molecules.Agarose gel electrophoresis studies on the cleavage of plasmid pBR322 DNA by complexes 1–6 indicatedthat only complex 1 was capable of efficiently cleaving DNA, most probably via an oxidative mechanism.Kinetic assay of complex 1 afforded the maximal catalytic rate constant kmax of 0.50 h�1 and Michaelisconstant KM of 0.60 mM, respectively. Ethidium bromide displacement experiments indicated that com-plex 1 had a binding affinity of (3.10 ± 0.90) � 105 M�1 toward calf-thymus DNA, 10- to 55-fold higherthan those shown by H2CcbpBr and complexes 2–5. The high cleaving efficacy of complex 1 is thoughtto be due to its polynuclear structure.

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1. Introduction

During the past decades, construction of coordination polymers(CPs) that are composed of infinite arrays of metal ions connectedby functionalized organic linkers, has been attracting considerableinterest because of their wide applications, for example, in gasstorage [1], separation [2], catalysis [3] and luminescence [4]. Link-ers that are frequently used in building of CPs are diverse, rangingfrom polycarboxylates [5–10], phosphonates [11,12], sulfonates[13,14], imidazolates [15], amines [16,17], pyridyl derivatives[18–20] to phenolates [21,22]. Of particular interest among theselinkers are aromatic polycarboxylates. This is because carboxylicgroups have multiple coordination modes and strong metal-com-plexing abilities [1,5–10]. However, most of the studies on CPs to

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date are largely confined to structural characterization and appli-cations in functional materials, and their bioactivities have beenrarely reported [23–26].

In an earlier study, we have reported the water-soluble zinccomplexes of three zwitterionic carboxylates having quaternaryammonium groups, 1-(4-carboxybenzyl)-4,40-bipyridinium bro-mide, N-(4-carboxybenzyl)pyridinium bromide (HCbpBr) and1,10-bis(4-carboxybenzyl)-4,40-bipyridinium bromide (H2BpybcBr2)(Chart 1). We found that the zinc complex of H2BpybcBr2 exhibitedpotent DNA-cleaving activity toward pBR322 DNA and moderatecytotoxicities toward lung adenocarcinoma A549 and mouse sar-coma S-180 cells [26]. Our working hypothesis was that these activ-ities were due to the polynuclear structure of this zinc complex. Thisfinding, in combination with the results reported to date [27],inspires us to reason that a metal complex having polynuclear struc-tures generally exhibits promising bioactivity. To test this, herein wedescribe the synthesis of a simple ligand having two carboxylicgroups, i.e. 4-carboxy-1-(4-carboxybenzyl)pyridinium bromide

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N

COOHN

HOOC

Br

Br

H2BpybcBr2

N

COOH

Br

HOOC

H2CcbpBrHCbpBr

N

COOH

Br

Chart 1. Structures of HCbpBr, H2BpybcBr2 and H2CcbpBr.

2 M. Chen et al. / Inorganica Chimica Acta xxx (2013) xxx–xxx

(H2CcbpBr) (Chart 1) and its five metal complexes, {[Cu(Ccbp)2]�4H2-

O}n (1), [Ni(H2O)6](Ccbp)2�4H2O (2), [M(Ccbp)2(H2O)4]�2H2O�2CH3OH (M = ZnII (3), CoII (4), MnII (5)). A mononuclear copper com-plex, [Cu(Cbp)2(H2O)2](NO3)2�4H2O (6) that was synthesized fromHCbpBr was used as a control. The cleaving activities of complexes1–6 toward plasmid pBR322 DNA were studied.

2. Experimental

2.1. General

1H NMR spectrum was recorded in D2O using a Varian Mercury400 spectrometer, and water at 4.8 ppm as a reference. ESI MS andHR-ESI-MS spectra were measured on Waters UPLC/Quattro PremierXE and an Agilent 6460 Triple Quadrupole mass spectrometers,respectively. IR spectra were recorded on a Nicolet MagNa-IR 550.Elemental analyses for C, H, and N were performed on an EA1110CHNS elemental analyzer. Agarose gel electrophoresis (GE) was con-ducted on DYY-8C electrophoresis apparatus and DYCP-31DN elec-trophoresis chamber, and detected on Alpha Hp 3400 fluorescenceand visible light digital image analyzer. UV–Vis and fluorescencespectra were measured on a TU-1901 spectrophotometer and a HIT-ACHI F-2500 spectrofluorimeter, respectively.

Calf-thymus (CT) DNA and plasmid pBR322 DNA were pur-chased from Sigma–Aldrich and Takara Chemical Co., respectively.The solution of CT DNA was prepared in 5 mM Tris–HCl buffer(5 mM NaCl, pH 7.0) and its concentration was determined spec-trophotometrically using the molar extinction coefficient of13200 M�1 cm�1 per base pair (bp) at 260 nm [28]. HCbpBr wasprepared according to the reported protocols [29]. All the otherchemicals and reagents were obtained from commercial sourcesand used without further purification. Buffer solutions were pre-pared in triply distilled deionized water.

2.2. Synthesis of H2CcbpBr and complexes 1–6

2.2.1. Synthesis of H2CcbpBrTo a solution of 4-(bromomethyl)benzoic acid (2.15 g, 10 mmol)

in DMF (10 mL) was added drop wise a solution of isonicotinic acid(1.23 g, 10 mmol) in DMF (80 mL). The resulting mixture was stirredat 70 �C for 6 h. The white precipitates formed were collected by fil-tration and washed with DMF (5 mL) and ether (5 mL) to afford H2-

CcbpBr (3.14 g, 93%) having 1H NMR (400 MHz, D2O, Fig. S1) d 8.85(d, J = 6.4 Hz, H4, H5, 2H), 8.15 (d, J = 6.4 Hz, H3, H6, 2H), 7.78 (d,J = 8.0 Hz, H10, H12, 2H), 7.37 (d, J = 8.0 Hz, H9, H13, 2H), 5.76 (s,H7, 2H); ESI-MS m/z: 258.08 ([M�Br]+; HR-ESI-MS for C14H12NO4

([M�Br]+) Calc.: 258.0766, Found: 258.0807; Anal. Calc. for C14H12-

NO4Br: C, 49.72; H, 3.58; N, 4.14. Found: C, 49.76; H, 3.27; N, 4.36%and main IR bands (KBr disc, cm�1) m 3448 (s), 3050 (m), 1675 (s),1634 (s), 1563 (m), 1376 (m), 759 (m), 542 (m).

2.2.2. Synthesis of complexes 1–5General procedures: H2CcbpBr (338 mg, 1.0 mmol) was dissolved

in MeOH (4 mL), and its pH was adjusted to 7.0 with 0.1 M NaOH

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solution. Then a solution of MCl2�xH2O (M = CuII, NiII, ZnII, CoII, MnII,0.5 mmol) in MeOH (5 mL) was added. The resulting mixture wasstirred for 1 h. The formed precipitates were collected by filtration,re-dissolved in H2O (25 mL) and allowed to stand at ambient tem-perature for about one month to produce the crystals of complexes1–5.

{[Cu(Ccbp)2]�4H2O}n (1): blue crystals, 160 mg (49%) fromCuCl2�2H2O (85 mg). Anal. Calc. for C28H28N2O12Cu: C, 51.89; H,4.35; N, 4.32. Found: C, 51.55; H, 4.62; N, 4.54%. Main IR bands(KBr disc, cm�1) m 3446 (s), 3057 (m), 1641 (s), 1565 (m), 1379(s), 771 (m).

[Ni(H2O)6](Ccbp)2�4H2O (2): green crystals, 186 mg (50%) fromNiCl2�6H2O (119 mg). Anal. Calc. for C28H40N2O18Ni: C, 44.76; H,5.37; N 3.73. Found: C, 44.92; H, 5.75; N, 3.45%. Main IR bands(KBr disc, cm�1) m 3400 (s), 3054 (m), 1623 (s), 1560 (m), 1379(s), 766 (m).

[Zn(Ccbp)2(H2O)4]�2H2O�2MeOH (3): colorless crystals, 154 mg(41%) from ZnCl2 (70 mg). Anal. Calc. for C30H40N2O16Zn: C,48.04; H, 5.38; N, 3.74. Found: C, 48.41; H, 5.59; N, 3.91%. MainIR bands (KBr disc, cm�1) m 3447 (s), 3052 (m), 1632 (s), 1564(m), 1375 (s), 767 (m).

[Co(Ccbp)2(H2O)4]�2H2O�2MeOH (4): purple-red crystals,140 mg (38%) from CoCl2�6H2O (120 mg). Anal. Calc. for C30H40N2-

O16Co: C, 48.46; H, 5.42; N, 3.77. Found: C, 48.69; H, 5.62; N,4.03%. Main IR bands (KBr disc, cm�1) m 3371 (s), 3042 (m), 1628(s), 1563 (m), 1392 (s), 765 (m).

[Mn(Ccbp)2(H2O)4]�2H2O�2MeOH (5): light yellow crystals,172 mg (47%) from MnCl2 (63 mg). Anal. Calc. for C30H40N2O16Mn:C, 48.72; H, 5.45; N, 3.79. Found: C, 49.03; H, 5.81; N, 4.08%. MainIR bands (KBr disc, cm�1) m 3416 (s), 3051 (m), 1633 (s), 1559 (m),1381 (s), 763 (m).

2.2.3. Synthesis of complex 6HCbpBr (293 mg, 1 mmol) was dissolved in H2O (5 mL), and the

pH was adjusted to 7 with 0.1 M NaOH solution. Then, a solution ofCu(NO3)2�3H2O (122 mg, 0.5 mmol) in H2O (5 mL) was added. Theresulting mixture was stirred for 30 min to give a clear solution,and then allowed to stand for several days to produce blue blocks.Washing with Et2O and subsequent drying under vacuum yielded 6(173 mg, 48% based on HCbpBr). Anal. Calc. for C26H34CuN4O16: C,43.25; H, 4.75; N, 7.76. Found: C, 43.51; H, 4.56; N, 7.52%. MainIR bands (KBr disc, cm�1) m 3413 (s), 3056 (m), 1630 (s), 1560(m), 1385 (s), 861 (m).

2.3. X-ray structures of complexes 1–6

All the measurements were made on a Rigaku Mercury CCDX-ray diffractometer by using graphite monochromated Mo Ka(k = 0.71070 Å). The crystals of complexes 1–6 were mounted atthe top of a glass fiber with grease. Cell parameters were refinedby using the program CrystalClear (Rigaku and MSC, Ver. 1.3,2001). The collected data were reduced by using the program Crys-talStructure (Rigaku and MSC, Ver. 3.60, 2004) while an absorptioncorrection (multiscan) was applied. A summary of the key crystal-lographic information for complexes 1–6 was tabulated in Table 1.

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Table 1Crystallographic data for complexes 1–6.

Complex 1 2 3

Molecular formula C28H28N2O12Cu C28H40N2O18Ni C30H40N2O16ZnFormula weight 648.07 751.33 750.01Crystal system monoclinic monoclinic triclinicSpace group C2/c Cc P�1Size 0.3 � 0.25 � 0.25 0.40 � 0.10 � 0.10 0.40 � 0.32 � 0.30a (Å) 19.848(4) 16.445(3) 8.0389(16)b (Å) 13.247(3) 21.286(4) 8.9235(18)c (Å) 12.243(2) 11.638(2) 12.148(2)a (�) 90 90 96.03(3)b (�) 119.36(3) 124.55(3) 98.16(3)c (�) 90 90 97.48(3)V (Å3) 2805.5(10) 3355.4(12) 848.5(3)Z 4 4 1T (K) 293(2) 293(2) 291(2)Dcalc (g cm�3) 1.534 1.487 1.468k (Mo Ka) (Å) 0.71073 0.71073 0.71073l (cm�1) 8.480 6.610 8.0002hmax (�) 55.0 55.0 55.0Total reflections 14196 17160 8983Unique reflections (Rint) 3217 (0.0693) 7590 (0.0905) 3893 (0.0484)No. observations [I > 2.00r(I)] 2430 5027 3002No. parameters 195 425 218Ra 0.0796 0.0801 0.0509wRb 0.1141 0.1367 0.1116GOFc 1.143 1.037 1.051Dqmax (e Å�3) 0.661 0.792 0.498Dqmin (e Å�3) �0.786 �0.379 �0.380

Complex 4 5 6

Molecular formula C30H40N2O16Co C30H40N2O16Mn C26H34CuN4O16

Formula weight 743.57 739.58 722.11Crystal system triclinic triclinic triclinicSpace group P�1 P�1 P�1Size 0.30 � 0.20 � 0.20 0.34 � 0.28 � 0.22 0.40 � 0.30 � 0.28a (Å) 8.0488(16) 8.0526(16) 8.0571(16)b (Å) 8.9351(18) 8.9534(18) 9.899(2)c (Å) 12.149(2) 12.222(2) 11.020(2)a (�) 96.16(3) 95.97(3) 104.06(3)b (�) 98.30(3) 98.23(3) 90.01(3)c (�) 97.50(3) 97.22(3) 110.88(3)V (Å3) 850.1(6) 858.5(3) 792.9(3)Z 1 1 1T/K 291(2) 291(2) 291(2)Dcalc (g cm�3) 1.453 1.431 1.512k (Mo Ka) (Å) 0.71073 0.71073 0.71073l (cm�1) 5.81 4.60 7.692hmax (�) 55.0 55.0 55.0Total reflections 8846 8982 8339Unique reflections (Rint) 3895 (0.0348) 3930 (0.0365) 3633 (0.0351)No. observations [I > 2.00r(I)] 3211 2844 2844No. parameters 218 227 205Ra 0.0614 0.0509 0.0629wRb 0.1628 0.1175 0.1511GOFc 1.115 1.034 1.048Dqmax (e Å�3) 0.684 0.424 0.748Dqmin (e Å�3) �0.496 �0.235 �0.472

a R = R||Fc| � |Fc|/R|Fo|.b wR = {Rw(Fo

2 � Fc2)2/Rw(Fo

2)2}1/2.c Goodness-of-fit = {Rw((Fo

2 � Fc2)2)/(n � p)}1/2, where n, number of reflections and p, total numbers of parameters refined.

M. Chen et al. / Inorganica Chimica Acta xxx (2013) xxx–xxx 3

2.4. DNA cleavage experiments

The cleavage experiments were conducted by using the meth-ods similar to those described previously [30–32]. Specifically, amixture of pBR322 DNA (0.5 g/L, 0.7 lL) and each of complexes1–6 was diluted with 5 mM Tris–HCl buffer (5 mM NaCl, pH 7.0)to 16 lL and incubated at 50 �C for 5 h. The reaction was quenchedby adding loading buffer containing 0.035% bromophenol blue, 36%glycerol, 30 mM EDTA and 0.05% xylene cyanol FF. The solutionwas then loaded on 1% agarose gel containing ethidium bromide(EB) (1.0 mg/L), and analyzed with electrophoresis in Tris–ace-tate–EDTA (TAE) buffer (pH 8.0) at 90 V. Bands were visualized


by UV light and photographed for analysis. The extent of cleavageof the supercoiled DNA was determined by measuring the intensi-ties of the bands using the Alpha Innotech gel documentation sys-tem (Alpha Hp3400).

The kinetics for the DNA cleavage was investigated at 50 �C fordifferent intervals of time, by varying the concentrations of com-plex 1 from 0 to 1.5 mM and at the concentrations of 1.0 mM forcomplexes 2–5 in 5 mM Tris–HCl buffer (5 mM NaCl, pH 7.0).The percentage of the supercoiled DNA was plotted against timefor each concentration of complexes 1–5. The data were fitted witha single-exponential curve (pseudo first-order kinetics) to give thekobs values. The kobs values of complex 1 were then plotted against

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its concentrations (Eq. (1)), allowing a pseudo Michaelis–Mentenanalysis and the determination of the corresponding maximalfirst-order rate constant kmax and Michaelis constant KM.

kobs ¼ kmax½complex 1�=ðKM þ ½complex 1�Þ ð1Þ

For mechanistic investigations, experiments were carried out ina similar way, except under both the aerobic and anaerobic condi-tions and in the presence of DMSO (1.0 M), MeOH (1.0 M), NaN3

(0.1 M), KI (0.1 M) and EDTA (0.1 M), followed by the addition ofcomplex 1.

2.5. DNA binding experiments

EB displacement experiments of H2CcbpBr and complexes 1–5were performed by keeping the concentrations of CT DNA and EBconstant, while gradually increasing the concentration of H2CcbpBror each of the metal complexes. Specifically, to a solution of CTDNA (2.40 lM) and EB (3.03 lM) in 5 mM Tris–HCl (5 mM NaCl,pH 7.0) were added aliquots of a solution of each complex contain-ing CT DNA (2.40 lM) and EB (3.03 lM) in the same buffer. Thecorresponding fluorescence spectra were measured (kex = 510 nm)until saturation was observed. The apparent binding constant (Ka)was obtained by analyzing the relative fluorescence intensity (I/I0,kem = 590 nm) as a function of the concentrations of each complex[33].

N

COOH

Br

HOOCN

COOH

+

COOH

Br

DMF

H2CcbpBr

M

H2O

H2O

H2O

HO

Cu

CuCl2.2H2O

NiCl2.6H2

1

MCl2

M = ZnII (3), CoII (4), MnII (5)

O

ON

O

O O

O

N

O

O

N

O

O

N

O

O O

O

N

O

O O

O

N

COOH

Br

HCbpBr

Cu(NO3)2.3H2O

NO

O

Scheme 1. Synthesis of H2Ccb


3. Results and discussion

3.1. Synthesis and characterization of H2CcbpBr and complexes 1–6

The synthetic route of H2CcbpBr and complexes 1–6 is shown inScheme 1. Thus, reaction of 4-(bromomethyl)benzoic acid withisonicotinic acid in DMF afforded H2CcbpBr in 93% yield. Treatmentof H2CcbpBr and HCbpBr with 1/2 equiv. of the corresponding me-tal salts gave complexes 1–5 in 38–50% yields and complex 6 in48% yield, respectively.

H2CcbpBr was characterized by 1H NMR, ESI MS, HR-ESI-MS, IRand elemental analyses, whereas complexes 1–6 were character-ized by IR, elemental analyses and X-ray crystallography. H2CcbpBrgave a mass spectrum with the m/z value corresponding to[M�Br]+, and its 1H NMR was also in full agreement with the givenstructure. The elemental analyses of H2CcbpBr and complexes 1–6were consistent with their chemical formula. Complexes 1–6 werefurther characterized by single-crystal X-ray crystallography.

The deprotonation and metal ion-coordinating modes of thecarboxylic groups in H2CcbpBr and HCbpBr were confirmed by IRspectrometry. In the IR spectrum of H2CcbpBr, the bands at1675 cm�1 and around 1376 cm�1 are assigned to the asymmetricand symmetric stretching vibrations of mC@O in carboxylic groups,respectively. In complexes 1–5, the absence of strong bands around1675 cm�1 suggested that the carboxylic groups of H2CcbpBr weredeprotonated. In addition, the asymmetric and symmetric

[Ni(H2O)6]2+

2-N

O

O O

O

n

O

2

NO

O

O

O

O

O

. 2MeOH.

.

Cu

H2O

H2O

N

O

O

6

[NO3)2 .

2H2O

4H2O

4H2O

pBr and complexes 1–6.

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Fig. 1. One dimensional polymer structure in complex 1. All the hydrogen atoms were omitted for clarity. Symmetry transformations were used to generate equivalentatoms: (A) �x + 1, y, 0.5 �z; (B) �x + 1, y, 0.5 �z; (AA) x, y + 1, z.

Table 2Selected bond distances (Å) and angles (�) for complex 1.

Cu(1)–O(2) 1.9568(12) Cu(1)–O(2A) 1.9568(12)Cu(1)–O(4B) 1.9872(13) Cu(1)–O(4AA) 1.9872(13)

O(2)–Cu(1)–O(2A) 92.81(7) O(2)–Cu(1)–O(4B) 89.49(5)O(2A)–Cu(1)–O(4B) 166.83(3) O(2)–Cu(1)–O(4AA) 166.83(3)O(2A)–Cu(1)–O(4AA) 89.49(5) O(4B)–Cu(1)–O(4AA) 91.22(8)

Fig. 2. The molecular structure of [Ni(H2O)6](Ccbp)2 in complex 2. All the hydrogenatoms were omitted for clarity.


stretching vibrations of mC@O of the carboxylate ions wereobserved at 1641 and 1379 cm�1 for complex 1, 1632 and1375 cm�1 for complex 3, 1628 and 1392 cm�1 for complex 4,1633 and 1381 cm�1 for complex 5, and 1630 and 1385 cm�1 forcomplex 6, respectively. Their difference (Dm = mas(COO) � ms(COO))

Fig. 3. Two-dimensional network structure formed by hydrogen bonds in complex 2. Sy�y, �1/2 + z; (B) x, 1 � y, 1/2 + z; (C) 1/2 + x, 1/2 � y, 1/2 + z.


was 262 cm�1 for complex 1, 257 cm�1 for complex 3, 236 cm�1

for complex 4, 252 cm�1 for complex 5 and 245 cm�1 for complex6, respectively, suggesting that the carboxylate ions coordinated tothe metal ions only in a monodentate bridging mode. Comparedwith complexes 1 and 3–6, complex 2 exhibited stretching vibra-tions of the carboxylate ions at lower frequencies, that is, at 1623and 1379 cm�1, suggesting that its carboxylate ions were not coor-dinated to the nickel ion [34].

3.2. Crystal structures of complexes 1–6

3.2.1. Complex 1It crystallizes in the monoclinic space group C2/c and the asym-

metric unit consists of half a [Cu(Ccbp)2] molecule and two sol-vated H2O molecules. As shown in Fig. 1, there is a twofold axislocated on the central Cu atom that is coordinated by four oxygenatoms from four Ccbp ligands, thereby forming a distorted tetrahe-dron coordination geometry. In complex 1, every two trans-Ccbp li-gands bridge two Cu2+ ions through four terminal carboxylate ionsin a monodentate cis-coordination mode, thereby forming a one-dimensional polymer structure, or so-called double-strandedchains (Fig. 1). In this double-stranded chain, there is a macrocyclic[Cu2(Ccbp)2] ring that looks like a hexagonal window with theadjacent Cu� � �Cu contact of 7.58(2) Å, which excludes any metal–metal interaction. Because the methylene group is used as a knotto link the isonicotinicate with the benzoate, the whole Ccbp ligandis not linear but exhibits a zigzag conformation. There is a dihedralangle of 73.5(1)� between the pyridyl ring of the isonicotinicateand the phenyl ring of the benzoate. The selected bond distancesand angles for complex 1 are shown in Table 2.

3.2.2. Complex 2It crystallizes in the monoclinic space group Cc and each asym-

metric unit comprises an Ni atom that lies on an inversion centerand has six coordinated water molecules, two Ccbp� anions andfour solvated H2O molecules. The perspective view structure of

mmetry transformations were used to generate equivalent atoms: (A) �1/2 + x, 1/2

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Fig. 4. The molecular structure of [Zn(Ccbp)2(H2O)4] in complex 3. All the hydrogen atoms were omitted for clarity. Symmetry transformation was used to generateequivalent atoms: (A) �x + 1, �y, �z.

Fig. 5. The double-stranded chains formed via hydrogen bonds in complex 3. Symmetry transformations were used to generate equivalent atoms: (A) �x + 1, �y, �z; (B)�1 + x, y, 1 + z; (C) �x + 2, �y, �z.

Table 3Selected bond distances (Å) and angles (�) for complexes 3–5.

Complex 3

Zn(1)–O(1) 2.061(2) Zn(1)–O(1A) 2.061(2)Zn(1)–O(1W) 2.1305(13) Zn(1)–O(1WA) 2.1305(13)Zn(1)–O(2W) 2.1073(12) Zn(1)–O(2WA) 2.1073(12)

O(1)–Zn(1)–O(1A) 180.00(7) O(1A)–Zn(1)–O(1W) 88.90(8)O(1)–Zn(1)–O(1WA) 88.90(8) O(1A)–Zn(1)–O(2W) 86.91(7)O(1)–Zn(1)–O(1W) 91.10(8) O(1A)–Zn(1)–O(1WA) 91.10(8)O(1)–Zn(1)–O(2W) 93.09(7) O(1A)–Zn(1)–O(2WA) 93.09(7)O(1)–Zn(1)–O(2WA) 86.91(7) O(1WA)–Zn(1)–O(1W) 180.00(6)O(2W)–Zn(1)–O(1WA) 86.70(1) O(2WA)–Zn(1)–O(1W) 86.70(2)O(2W)–Zn(1)–O(2WA) 180.00(6) O(1WA)–Zn(1)–O(2WA) 93.30(2)O(2W)–Zn(1)–O(1W) 93.30(1)

Complex 4Co(1)–O(1) 2.066(2) Co(1)–O(1A) 2.066(2)Co(1)–O(1W) 2.097(2) Co(1)–O(1WA) 2.097(2)Co(1)–O(2W) 2.113(2) Co(1)–O(2WA) 2.113(2)

O(1)–Co(1)–O(1A) 180.00(15) O(1A)–Co(1)–O(1W) 87.08(9)O(1)–Co(1)–O(1WA) 87.08(9) O(1A)–Co(1)–O(2W) 88.69(10)O(1)–Co(1)–O(1W) 92.92(9) O(1A)–Co(1)–O(1WA) 92.92(9)O(1)–Co(1)–O(2W) 91.31(10) O(1A)–Co(1)–O(2WA) 91.31(10)O(1)–Co(1)–O(2WA) 88.69(10) O(1WA)–Co(1)–O(1W) 180.00(1)O(2W)–Co(1)–O(1WA) 86.93(9) O(2WA)–Co(1)–O(1W) 86.93(9)O(2W)–Co(1)–O(2WA) 180.00(19) O(1WA)–Co(1)–O(2WA) 93.07(9)O(1W)–Co(1)–O(2W) 93.07(9)

Complex 5Mn(1)–O(1) 2.1292(19) Mn(1)–O(1A) 2.1292(19)Mn(1)–O(1W) 2.1930(14) Mn(1)–O(1WA) 2.1930(14)Mn(1)–O(2W) 2.200(2) Mn(1)–O(2WA) 2.200(2)O(1)–Mn(1)–O(1A) 180.00(1) O(1A)–Mn(1)–O(1W) 88.64(7)O(1)–Mn(1)–O(1WA) 88.64(7) O(1A)–Mn(1)–O(2W) 89.16(9)O(1)–Mn(1)–O(1W) 91.36(7) O(1A)–Mn(1)–O(1WA) 91.36(7)O(1)–Mn(1)–O(2W) 90.84(9) O(1A)–Mn(1)–O(2WA) 90.84(9)O(1)–Mn(1)–O(2WA) 89.16(9) O(1WA)–Mn(1)–O(1W) 180.00(1)O(2W)–Mn(1)–

O(1WA)87.71(7) O(1W)–Mn(1)–O(2WA) 87.71(7)

O(2W)–Mn(1)–O(2WA)

180.00(1) O(1WA)–Mn(1)–O(2WA)

92.29(7)

O(1W)–Mn(1)–O(2W) 92.29(7)



[Ni(H2O)6](Ccbp)2 in 2 is depicted in Fig. 2. The NiII atom in hexa-aquanickel(II) cation is six-coordinated in a distorted octahedralenvironment with bond angles in the range of 86.55(18)–176.92(19)�. The Ccbp� anion contains two carboxylate anion cen-ters and an ammonium cation center. The carboxylate ions O1/C1/O2, O3/C14/O4, O5/C15/O6 and O7/C28/O8 lie on the equatorialsite of C2 (C14 or C15 or C28) atom of the benzene ring, and thetwo C–O bonds are nearly equivalent. For the isolated cationsand anions, there is no interaction between the oxygen atoms ofcarboxylate ions in Ccbp� and the metal center in [Ni(H2O)4]2+ insolid state.

On the other hand, the uncoordinated carboxylate ions of thetwo Ccbp� ligands in the complex form strong hydrogenbonds with the water molecules coordinated on the adjacent[Ni(H2O)6]2+ units, thus generating two-dimensional networkstructure as shown in Fig. 3. Between the pyridyl rings of theisonicotinicate and the phenyl rings of the benzoate, the dihedralangles are 108.9(1) and 107.1(2)� in two Ccbp� anions,respectively.

3.2.3. Complexes 3–5An X-ray analysis revealed that complexes 3–5 all crystallize in

the triclinic space group P�1 and the asymmetric unit is composedof half a [M(Ccbp)2(H2O)4] molecule (M = Zn (3), Co (4), Mn (5)),one solvated H2O and one MeOH molecule. Because complexes3–5 have similar molecular structures, only complex 3 is depictedin Fig. 4. The molecular structures of complexes 4 and 5 are shownin Figs. S2 and S4.

It can be seen that in each molecular unit, the central metal ionis strongly coordinated by four water molecules and two O atomsof carboxylate ion from two mono-unidentate Ccbp� ligands,thereby forming a slightly distorted octahedral geometry. The pyr-idyl rings of the isonicotinate and the phenyl rings of the benzoatehave dihedral angles of 69.2(2)� in both Ccbp� ligands for com-plexes 3–5.

On the other hand, the uncoordinated carboxylate ions of thetwo Ccbp� ligands in complexes 3–5 form strong hydrogen bonds

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Fig. 6. The perspective view structure of [Cu(Cbp)2(H2O)2]2+ dication in complex 6. All the hydrogen atoms were omitted for clarity. Symmetry transformation was used togenerate equivalent atoms: (A) �x + 1, �y + 1, �z + 1.

Fig. 7. Agarose GE patterns for the cleavage of pBR322 DNA by complexes 1–5 at pH7.0 and 50 �C for 5 h. Lane 1, DNA alone; Lane 2, DNA + H2CcbpBr (2.0 mM); Lanes3–7, DNA in the presence of complexes 1–5 (1.0 mM), respectively.

Table 4Pseudo-first-order rate constants (kobs, h�1) of pBR322 DNA degradation by H2CcbpBrand complexes 1–5, and their binding constants (Ka’s, M�1) with CT DNA.

Complex Form I (%) Form II (%) kobsa Ka

b

None 87.7 12.3 / /H2CcbpBr 78.7 21.3 0.084 ± 0.005 (1.21 ± 0.43) � 104

1 0 100 0.319 ± 0.002 (3.10 ± 0.90) � 105

2 76.2 16.8 0.067 ± 0.002 (5.60 ± 0.90) � 103

3 84.8 15.2 0.087 ± 0.005 (6.90 ± 0.90) � 103

4 72.0 28.0 0.058 ± 0.003 (2.16 ± 0.46) � 104

5 77.6 26.4 0.089 ± 0.003 (2.81 ± 0.93) � 104

a Measured at the concentration of 1.0 mM for each complex, in 5 mM Tris–HCl(5 mM NaCl, pH 7.0) at 50 �C.

b Measured by means of EB displacement experiments, in 5 mM Tris–HCl (5 mMNaCl, pH 7.0) at room temperature.

Fig. 8. Agarose GE patterns for the cleavage of pBR322 DNA by complex 1 ofincreasing concentrations at pH 7.0 for 5 h at 50 �C. Lane 1: DNA alone and Lanes 2–7: DNA with complex 1 at the concentrations of 0.1, 0.2, 0.4, 0.6, 0.8 and 1.0 mM,respectively.

Fig. 9. (a) Time course of pBR322 DNA cleavage promoted by complex 1 (0.1 mM) at pH 71–8, reaction time was 0, 1, 2.5, 4, 5.5, 7, 8.5 and 10 h, respectively. (b) Saturation kinet



with the water molecules coordinated on the adjacent [M(Ccbp)2-(H2O)4] units, thus generating a one-dimensional, double-strandedpolymer structure for complex 3 as shown in Fig. 5. The similarstructures of complexes 4 and 5 are shown in Figs. S3 and S5.The selected bond distances and angles for complexes 3–5 arelisted in Table 3.

3.2.4. Complex 6It crystallizes in the triclinic space group P�1 and each asymmet-

ric unit comprises one half [Cu(Cbp)2(H2O)2]2+ dication, one NO3�

anion and two solvated H2O molecules. The perspective viewstructure of [Cu(Cbp)2(H2O)2]2+ dication in 6 is shown in Fig. 6. Itcan be seen that there is a C2 axis through the central Cu atom thatis strongly coordinated by two unidentate Cbp ligands and twoH2O molecules, hence forming a distorted tetrahedral coordinationgeometry.

3.3. Cleavage of pBR 322 DNA

It is known that many metal complexes are capable of catalyz-ing the cleavage of DNA [35–40]. Therefore we investigated thecleaving activities of complexes 1–5 toward supercoiled pBR322DNA by using agarose GE assay. Fig. 7 shows the GE patterns forthe cleavage of pBR322 DNA at pH 7.0 and 50 �C. It can be seen thatconversion of the supercoiled DNA form (CCC, Form I) into the opencircular form (OC, Form II) are apparent. The catalytic efficiencythat was estimated from the density ratios of Form II to Form I, de-creases in the order of complex 1 (Lane 3)� 4 (Lane 6)� 5 (Lane 7)> 2 (Lane 4) � 3 (Lane 5), which is further evidenced from theirpseudo-first-order rate constants (kobs’s) at the concentration of1.0 mM (Table 4). Of the five complexes, complex 1 was the mostactive and therefore its DNA-cleaving activity was furtherexplored.

Firstly, we carried out the concentration-dependent DNAcleavage by complex 1 (Fig. 8). It can be seen that complex 1 was

.0 and 50 �C. Inset: agarose GE patterns of the time-variable reaction products. Lanesics plot of kobs versus the concentrations of complex 1.

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Fig. 10. Agarose GE patterns for the cleavage of pBR322 DNA by complex 1 (1 mM)at pH 7.0 and 50 �C for 5 h, in the presence of DMSO (1 M, Lane 3), MeOH (1 M, Lane4), KI (0.1 M, Lane 5), NaN3 (0.1 M, Lane 6), EDTA (0.1 M, Lane 7). Lane 1, DNA aloneand Lane 2: DNA + complex 1.


capable of efficiently converting pBR322 DNA into OC form andthat the cleaving activity increased with the concentrations ofcomplex 1 (Lanes 2–7). When the concentration of complex 1was about 0.6 mM, almost all of Form I was converted to Form II.Such concentration dependence experiments lent strong supportthat complex 1 catalyzed the cleavage.

To gain further insight into the cleaving activity of complex 1,the kinetics of pBR322 DNA degradation was studied [30–32].Fig. 9a shows that the extent of supercoiled DNA cleavage intoForm II varied exponentially with the reaction time (0.1 mM),giving pseudo first-order kinetics with a rate constant of0.104 ± 0.030 h�1. The saturation kinetics profile (Fig. 9b) gavethe maximal first-order rate constant kmax of 0.503 ± 0.045 h�1

and Michaelis constant KM of (0.600 ± 0.126) mM, respectively,which represents about 1.4 � 107-fold rate acceleration overuncatalyzed cleavage of supercoiled DNA (k = 3.6 � 108 h�1 forcleavage of a phosphodiester bond in double-stranded DNA underphysiological condition) [41,42]. Interestingly, the catalytic activityof complex 1 is comparable to those of some reported metal com-plexes, such as the mononuclear copper complex of 9-O-(4-carb-oxybenzyl)berberine (kmax = 2.41 h�1) [30], the mononuclearcopper complex of 1,7-dioxa-4,10-diazacyclododecane containingdiaminoethyl double side arms (kmax = 0.596 h�1) [43] and the ter-nary mononuclear Cu(II) polypyridyl complex, [Cu(saltyr)(B)] (sal-tyr = salicylidene tyrosine, B = 2, 20-bipyridine, kmax = 2.11 h�1)[44]. In addition, it should be noted that while the cleavage activ-ities of mono- or multinuclear copper complexes of Shiff bases,polypyridyl derivatives and macrocyclic polyamines have beenwidely studied, the polynuclear copper complexes of carboxylateswere much less reported [23–26].

This catalytic efficiency is thought to be due to the polynulcearstructure of complex 1. In other words, the polynuclear structureis beneficial to enhance both the DNA-cleaving and binding activ-ities. To demonstrate this hypothesis, we firstly attempted tocharacterize the solution structures of complexes 1 and 6 bymeans of HR-ESI-MS spectrometry (Figs. S26 and S27). Complex6 gave a positive mass spectrum in which the ion peaks that wereassignable to the mono-copper complex were predominantly ob-served. However, complex 1 afforded a much more complicatedmass spectrum. In addition to the ion peak from H2CcbpBr, sev-eral other ion peaks that could not be convincingly assigned wereobserved. Therefore, in order to elucidate the role of the polynu-clear structure of complex 1 in the DNA cleavage process, westudied the DNA-cleaving activity of the mononuclear coppercomplex 6 under the similar conditions. As a result, complex 6did not exhibit any detectable DNA-cleaving activity even whenthe concentration was about 2 mM (Fig. S28). This result stronglysuggests that the catalytic efficiency of complex 1 is attributed toits polynulcear structure. Thirdly, we estimated the binding affin-ities of complexes 1–5 by means of EB displacement experiments(Table 4). The results indicate that complex 1 shows a relativebinding affinity of (3.10 ± 0.90) � 105 M�1 that is about 10- to55-fold higher than those of complexes 2–5, and comparable tothat of [Cu(CBB)2](NO3)2�2H2O (CBB = 9-O-(4-carboxybenzyl)berberine, Ka = (2.19 ± 0.10)�105 M�1) [30].


3.4. Cleaving mechanism of action

It is known that nucleic acid can be cleaved through either anoxidative or hydrolytic pathway. In general, oxidative cleavage ofplasmid DNA may lead to the formation of reactive singlet oxygen(1O2), hydrogen peroxide (H2O2) and/or hydroxyl radical (HO�) spe-cies. These species contain a photo or a redox active center, whichcauses damage to the sugar and/or base [45,46]. Therefore, to gaininsight into the probable mechanism of action of complex 1, weconducted the cleavage reactions in the presence of hydroxyl rad-ical scavengers DMSO and MeOH, singlet oxygen scavenger NaN3,hydrogen peroxide scavenger KI and metal ion-chelating agentEDTA [47] (Fig. 10). As a result, EDTA (Lane 7) efficiently inhibitedDNA cleavage, indicating that complex 1 was obligatory in DNAcleavage reaction. When DMSO (Lane 3) and MeOH (Lane 4) wereadded to the reaction mixture, no significant influence on the DNAcleavage was observed, strongly suggesting that hydroxyl radicalwas not involved in the DNA cleavage. In the presence of NaN3

(Lane 6), the DNA cleavage was significantly inhibited, suggestingthat singlet oxygen was likely to be the reactive species responsi-ble for the nuclease activity [48]. Similarly, in the presence of KI(Lane 5), the cleavage was repressed, suggesting that H2O2 mightbe the reactive species in the cleavage process. To further demon-strate this, we carried out the DNA cleavage experiments of com-plex 1 under an anaerobic condition. As a result, no obvious DNAdegradation was observed (Fig. S29). Taken together, these resultsstrongly suggest that DNA cleavage by complex 1 proceeded via anoxidative mechanism [49]. Thus, the proposed mechanism may bethat the copper centers strongly bind O2 to form reactive oxygenspecies (ROS), such as singlet oxygen and superoxide, which canfurther activate the cleavage of supercoiled DNA to form nickedDNA [50,51]. According to this, the polycopper structure of com-plex 1 may be the origin of the high DNA cleavage efficiency.

4. Conclusions

In summary, H2CcbpBr and its five metal complexes have beensynthesized and fully characterized. The efficiency of H2CcbpBr andits metal complexes in promoting the cleavage of DNA was moni-tored by use of Agarose GE. Kinetic assays indicated that complex 1was capable of efficiently cleaving plasmid pBR322 DNA, mostprobably through an oxidative mechanistic pathway. This catalyticefficiency may be attributed to the poly-nuclear structure of com-plex 1. The results presented in this study highlight the fact thatpolynuclear metal complexes generally exhibit enhanced biologi-cal activities. Efforts aimed at developing diverse polynuclear me-tal complexes are currently in progress with a view toward thedesign of new synthetic nucleases with promising bioactivities.

Acknowledgments

This work was financially supported by the National NaturalScience Foundation of China (No. 21102070), the Department ofEducation of Guangdong Province of China (C1030388 and2012KJCX0024) and the Program for Pearl River New Stars of Sci-ence and Technology in Guangzhou (No. 2011J2200071).

Appendix A. Supplementary material

CCDC 902342–902346 and 921579 contain the supplementarycrystallographic data for 1–6. These data can be obtained free ofcharge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif. Supplementary data associ-ated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ica.2013.02.008.

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http://www.ccdc.cam.ac.uk/data_request/cif





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