Nickel complexes of the different quinolone antibacterial drugs: Synthesis, structure and interaction with DNA

Inorganica Chimica Acta 383 (2012) 178–184

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Nickel complexes of the different quinolone antibacterial drugs: Synthesis, structure and interaction with DNA Jing-Quan Sha, Xin Li, Hong-Bin Qiu ⇑, Yu-Hong Zhang, Hong Yan The Provincial Key Laboratory of Biological Medicine Formulation, School of Pharmacy, Jiamusi University, Jiamusi 154007, PR China

a r t i c l e

i n f o

Article history: Received 3 July 2011 Received in revised form 25 October 2011 Accepted 2 November 2011 Available online 13 November 2011 Keywords: Norfloxacin Pipemidic acid Enoxacin Nickel Interaction with CT-DNA

a b s t r a c t Three new nickel (II) complexes of the second/third-generation quinolone antibacterial drugs have been synthesized and structurally characterized. Single-crystal X-ray diffraction analysis shows that complex 1 exhibits 1D chain structure, and 2 and 3 2D sheet structures. UV study of the interaction of the complexes with calf-thymus DNA (CT-DNA) shows that complexes 1–3 can bind to the CT-DNA and exhibit the higher binding constant to CT-DNA than their parent drugs. Additionally, their competitive study with ethidium bromide (EB) also indicates that complexes can bind to DNA for the intercalative binding sites except for 1. Note that, due to uncoil the helix structure of DNA, 1 presents a higher value for KSV and Kb than other complexes. Ó 2011 Elsevier B.V. All rights reserved.

1. Introduction Study of the interaction between drugs and transition metals is an important and active research area in bioinorganic chemistry [1–4]. It is well known that the action of many drugs is dependent on the coordination with metal ions [1] or/and the inhibition [2] on the formation of metalloenzymes. Therefore, metal ions might play vital roles during the biological process of drug utilization in the body. Quinolones, with the term quinolone carboxylic acids or 4-quinolones, are a group of synthetic antibacterial agents containing 4oxo-1,4-dihydroquinoline skeletons [5] and are extremely useful for the treatment of various infections [6]. Pipemidic acid, HPPA (Scheme 1a), a 4-quinolone product, is a second-quinolone antimicrobial drug used to treat gram-negative urinary tract infections [7] and severely damages DNA in the absence of an exogenous metabolizing system [8]. Norfloxacin, NFX (Scheme 1b), 1-ethyl-6-fluoro1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolone carboxylic acid, is a third-quinolone antimicrobial drug and fluoro-quinolone carboxylic acid. It has effectives against gram-positive and gramnegative bacteria through inhibition of their DNA gyrase [9]. Enoxacin, ENX (Scheme 1c), 1-ethyl-6-fluoro-1,4-dihydro-4-oxo7-(piperazinyl)-1,8-naphthylidine-3-carboxylic acid, is also one of the third-generation members of quinolone antibiotics fluorinated in position 6 and bearing a piperazinyl moiety in position 7. It kills

⇑ Corresponding author. Tel.: +86 454 8610678; fax: +86 451 8610678. E-mail address: [email protected] (H.-B. Qiu). 0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2011.11.005

bacteria through inhibiting cell DNA-gyrase and prohibiting DNA replication [10]. As is well known, the quinolones can act as not only antibacterial drugs, but also excellent multi-dentate ligands coordinating with metal ions by the oxygen and nitrogen atoms. In the literature, the structures of metal and rare earth ions complexes of diverse quinolones have been reported [11–16], and the results suggest that metal ion coordination might be involved in the antibacterial activity of drug molecules and improve the drugs activity. However a thorough survey of the literature has revealed that the single crystal structures of only Ag(I), Cu(II), Zn(II), Mg(II), Pd(II), VO(II), Cd(II), Fe(III), Bi(III) quinolones complexes have been characterized to date [17–23]. The role of Ni2+ as an element of biological interest is well known, while its biocoordination behavior is still relatively unexplored. For nickel ion, only several crystal structures of nickel complexes of quinolone have been explored [24–29], in which few complexes involved the study of the interaction with DNA. Additionally, the influence of the different quinolones on the structures and properties of metal complexes is no systematically studied. Therefore, it is still a challenging work to systematically study Ni(II) complexes of different quinolones. In this context, we have studied the interaction of Ni(II) with the deprotonated NFX, PPA and ENX, in an attempt to examine the binding mode and possible synergetic effects. The resultant neutral mononuclear complexes have been characterized by elemental analysis, IR spectrum and single-crystal X-ray diffraction. The results show that complex 1 exhibits 1D chain structure, and 2 and 3 2D sheet structure. The interactions of the complexes with CT-DNA have been investigated with UV and fluorescence spectra.

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a

b

c

Scheme 1. Scheme of NFX (a); HPPA (b); ENX (c).

47.88; H, 5.52; N, 10.47%. IR (solid KBr pellet/cm1): 3429(s), 1633(s), 1568(w), 1493(m), 1383(s), 1271(m), 1085(s), 945(s), 901(m), 765(s), 524(m).

2. Experimental 2.1. Materials and methods All reagents were purchased commercially and used without further purification. DNA stock solution was prepared by the dilution of CT-DNA to buffer solution (50 mL 0.1 mol/L tris solution and 42 mL 0.1 mol/L hydrochloric acid, diluted to 100 mL) followed by exhaustive stirring at 4 °C for 3 days, and kept at 4 °C for no longer than a week. The stock solution of CT-DNA gave a ratio of UV absorbance at 260 and 280 nm (A260/A280) of 1.90, indicating that the DNA was sufficiently free of protein contamination. The DNA concentration was determined by the UV absorbance at 260 nm after 1:20 dilution using e = 6600 M1 cm1. C, H and N elemental analyses were performed on a Perkin-Elmer 2400 Elemental Analyzer. The IR spectra were obtained on an Alpha Centaurt FT/IR spectrometer with KBr pellet in the 400–4000 cm1 region. UV– Visible (UV–Vis) spectra were recorded in UV-2550. Fluorescence spectra were recorded in solution on 970CRT spectrofluorescence.

2.2.2. Synthesis of Ni(PPA)21.5H2O (2) Complex 2 was prepared in a manner similar to that described for 1, except the HPPA replaced NFX. Green block crystals were obtained. Anal. Calc. for C28H35NiN10O7.5 (700): C, 48.00; H, 5.00; N, 20.00. Found: C, 48.02; H, 5.11; N, 19.98%. IR (solid KBr pellet/ cm1): 3437(s), 2854(m), 1623(s), 1515(w), 1433(w), 1275(w). 2.2.3. Synthesis of Ni(ENX)22.5H2O (3) Complex 3 was prepared in a manner similar to that described for 1, except the ENX replaced NFX. Green block crystals were obtained. Anal. Calc. for C30H37F2NiN8O8.5 (742.36): C, 48.49; H, 4.98; N, 15.08. Found: C, 48.47; H, 5.02; N, 15.07%. IR (solid KBr pellet/ cm1): 3409(w), 1631(s), 1555(m), 1443(s), 1368(m), 1274(s). 2.3. X-ray crystallographic study

2.2. Syntheses 2.2.1. Synthesis of Ni(NFX)26H2O (1) A mixture of Ni(CH3COO)24H2O (64 mg), NFX(80 mg), NaHCO3 (20 mg) and H2O (10 mL) was stirred for 1 h in air. The pH was then adjusted to 5.1 with 1 M CH3COOH, and the mixture was transferred to an 18 ml Teflon-lined reactor. After 6 days’ heating at 155 °C, the reactor was slowly cooled to room temperature over a period of 16 h. Green block crystals of 1 were filtered, washed with water, and dried at room temperature. Anal. Calc. for C32H44F2NiN6O12 (801.42): C, 47.91; H, 5.49; N, 10.48. Found: C,

Crystal data for the complexes 1–3 were collected on a Bruker SMART-CCD diffractometer with Mo Ka monochromatic radiation (k = 0.71069 Å) at 293 K. All structures were solved by the directed methods and refined by full matrix least-squares on F2 using the SHELXTL crystallographic software package [30]. All the non-hydrogen atoms were refined anisotropically. The positions of hydrogen atoms on carbon atoms were calculated theoretically. The crystal data and structure refinements of complexes 1–3 are summarized in Table 1. Bond lengths and angles for complexes 1–3 are listed in Tables 2 and 3.

Table 1 Crystal data and structure refinement for complexes 1–3.a,b Empirical formula CCDC Formula weight T (K) Wavelength (nm) Crystal system Space group a (Å) b (Å) c (Å) b (°) V (Å3) Z Calculated density (mg/m3) Absorption coefficient (mm1) F(0 0 0) Goodness-of-fit (GOF) on F2 Reflections Collected/unique Final R indices [I > 2r(I)] a

P ||Fo|  |Fc||/ |Fo|. P P 2 wR2 = { [w(Fo  Fc2)2]/ [w(Fo2)2]}1/2.

R1 =

b

P

C32H44F2NiN6O12 823600 801.42 293(2) 0.71069 monoclinic  P1 10.404(5) 11.538(5) 14.565(5) 94.557(5) 1742.9(13) 2 2.531 5.915 1298 0.908 8843/6060 [R(int) = 0.0755] R1 = 0.0818 wR2 = 0.1880

C28H35NiN10O7.5 823601 700.32 296(2) 0.71073 monoclinic P21/c 6.1608(7) 21.226(2) 12.5094(14) 101.6180(1) 1602.4(3) 2 2.109 5.784 1000 0.890 8500/3065 [R(int) = 0.0329] R1 = 0.0606 wR2 = 0.1976

C30H37F2NiN8O8.5 823602 742.36 296(2) 0.71073 monoclinic P21/c 6.0415(8) 20.590(3) 14.205(2) 98.801(2) 1746.2(4) 2 2.182 5.098 1121 0.917 9247/3318 [R(int) = 0.0698] R1 = 0.0646 wR2 = 0.1923

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Table 2 Selected bond length (Å) for complexes 1–3. Bond (Å) for 1

Bond (Å) for 2

Ni(1)–O(12) Ni(1)–O(01) Ni(1)–O(7) Ni(1)–O(5) Ni(1)–N(3) Ni(1)–N(1)

2.024(5) 2.032(6) 2.130(5) 2.133(5) 2.181(6) 2.191(6)

Ni(1)–O(3) Ni(1)–O(3)#1 Ni(1)–O(1) Ni(1)–O(7) Ni(1)–O(8) Ni(1)–O(8)#1

Bond (Å) for 3 2.023(3) 2.023(3) 2.041(3) 2.010(3) 2.047(2) 2.047(2)

Ni(1)–O(3) Ni(1)–O(3)#1 Ni(1)–O(1) Ni(1)–O(1)#1 Ni(1)–N(5)#1 Ni(1)–N(5)

2.023(3) 2.023(3) 2.041(3) 2.041(3) 2.199(4) 2.199(4)

Symmetry transformations used to generate equivalent atoms: #1 x + 1,y + 1,z + 2; #2 x,y1/2,z + 3/2; #3 x,y + 1/2,z + 3/2.

Table 3 Selected bond angle (°) for complexes 1–3. Bond angle (°) for 1 O(12)–Ni(1)–O(01) O(12)–Ni(1)–O(7) O(01)–Ni(1)–O(7) O(12)–Ni(1)–O(5) O(01)–Ni(1)–O(5) O(7)–Ni(1)–O(5) O(01)–Ni(1)–N(3) Bond angle (°) for 2 O(7)–Ni(1)–O(8) O(7)#1–Ni(1)–N(1) O(8)#1–Ni(1)–N(1) O(7)–Ni(1)–O(8)#1 Bond angle (°) for 3 O(3)–Ni(1)–O(1) O(3)#1–Ni(1)–O(1) O(3)–Ni(1)–N(5)#1 O(1)–Ni(1)–N(5) O(3)#1–Ni(1)–O(1)#1

176.5(2) 84.8(2) 92.2(2) 92.1(2) 85.5(2) 82.2(2) 84.8(2)

O(5)–Ni(1)–N(3) O(12)–Ni(1)–N(1) O(01)–Ni(1)–N(1) O(7)–Ni(1)–N(1) O(5)–Ni(1)–N(1) N(3)–Ni(1)–N(1) O(7)–Ni(1)–N(3)

166.7(2) 85.6(2) 97.0(2) 166.3(2) 88.4(2) 101.7(2) 89.2(2)

91.65(10) 89.61(11) 91.35(10) 88.35(10)

O(7)–Ni(1)–N(1)#1 O(8)–Ni(1)–N(1) O(7)#1–Ni(1)–O(8) O(7)–Ni(1)–N(1)

89.61(11) 88.65(10) 88.35(10) 90.39(11)

91.12(12) 88.88(11) 91.60(13) 88.33(13) 91.12(12)

O(3)#1–Ni(1)–N(5)#1 O(1)–Ni(1)–N(5)#1 O(1)#1–Ni(1)–N(5) O(3)–Ni(1)–N(5) O(3)#1–Ni(1)–N(5)

88.40(13) 91.67(13) 91.67(13) 88.40(13) 91.60(13)

Symmetry transformations used to generate equivalent atoms: #1 x + 1,y + 1,z + 2; #2 x,y1/2,z + 3/2; #3 x,y + 1/2,z + 3/2.

2.4. DNA binding studies Study of the interaction of complexes with DNA is of great importance since their activities as antibacterial drugs are focused on the inhibition of DNA replication [31]. DNA can provide three distinctive binding sites for quinolone metal complexes (groove binding, electrostatic binding to phosphate group and intercalation) [32]. The interaction can be studied with UV spectroscopy in order to investigate the possible binding modes to CT-DNA .The changes observed in the UV spectra upon titration may give the evidence of the existing interaction mode, since a hypochromism, due to p–p⁄ stacking interactions, may appear in the case of the intercalative binding mode, while red-shift (bathochromism) may be observed when the DNA duplex is stabilized. In UV titration experiments, the spectra of CT-DNA in the presence of each complex have been recorded for a constant CT-DNA concentration in diverse [complex]/[CT-DNA] mixing ratios (r). The ability of the complexes to displace EB from its EB–DNA compound can be examined through a competitive EB binding

study with fluorescence experiments [33]. EB is an embedded fluorescent dye and typical indicator of intercalation, forming soluble complexes with nucleic acids and emitting intense fluorescence in the presence of CT-DNA due to the intercalation of the planar phenanthridinium ring between adjacent base pairs on the double helix. The changes observed in the spectra of EB on its binding to CT-DNA are often used for the interaction study between DNA and other complexes, such as metal complexes. The CT-DNA–EB complex was prepared by adding 20 lM EB and 25 lM CT-DNA in buffer solution. The intercalating effect of the NFX, HPPA, ENX and complexes 1–3 with the DNA–EB complex was studied by adding a certain amount of the solution of the complexes step by step into the solution of the DNA–EB. The influence has been obtained by recording the variation of the fluorescence emission spectra.

3. Results and discussion 3.1. Description of the structures of complexes 1–3 Single-crystal X-ray diffraction analysis reveals that complex 1 is constructed by one Ni center, two NFX drug molecules and six water molecules (shown in Fig. 1 left). There are two crystallographically unique NFX molecules and one crystallographically unique nickel ion, in which NFX as bridging tri-dentate organic ligand coordinates with two nickel ions, resulting in hexad-coordinated octahedral geometries of nickel atoms achieved by four O atoms (O7, O25, O42 and O01) and two N atoms (N1 and N3). Due to the bridging of NFX, 1D chain structure is formed shown in Fig. 1 right. Single-crystal X-ray diffraction analysis reveals that complexes 2 and 3 are constructed by one Ni center, two PPA molecules for 2 and two ENX for 3, and water molecules (shown in Fig. 2). Complexes 2 and 3 are isostructural and both crystallize in the space group P21/c, therefore we only discuss the structure of 2 herein. Different from 1, there are one crystallographically unique PPA drug molecules and one crystallographically unique nickel ion, which forms 2D sheet structure. In the 2D sheet, PPA as bridging tri-dentate organic ligands coordinates with two nickel ions, resulting in hexad-coordinated octahedral geometries of nickel atoms achieved by four O atoms (O7, O8, O7 and O8) and two N

Fig. 1. The fundamental building block of complex 1. Only part atoms are labeled, and water molecules and all hydrogen atoms are omitted for clarity (left); Organic– inorganic hybrid 1D chain structure (right).

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Fig. 2. The fundamental building block of 2 (left) and 3 (right). Only part atoms are labeled, and water molecules and all hydrogen atoms are omitted for clarity.

atoms (N1 and N1). It is interesting that PPA ligands and Ni ions are alternatively arranged to generate big vacancies (ca. 21.226  15.6916 Å). For the sake of clarity, we draw the 2D diagram of complex 2. An important feature of the structure is that the 2D sheets array parallelly in the direction perpendicular to the sheet, and form a 3D structure with the 1D channels, in which are occupied by 1D supramolecular water columns shown in Fig. 3. Note that guest water molecules as linkers play important roles in stabilizing the 3D structure, namely, water molecules link with PPA molecules in the same sheet, and link with itself in the adjacent sheets via extensive hydrogen bonds. 3.2. Interaction with DNA The UV spectra of CT-DNA in the presence of the NFX, HPPA and ENX as well as complexes 1–3 have been recorded for diverse [complex]/[DNA] mixing ratios (r) shown in Fig. 4. The changes observed in the absorption spectra, namely, the increase of the intensity at kmax = 258 nm is accompanied with a red-shift of the kmax up to 261 nm for NFX, 260 nm for PPA, 263 nm for 1 and 261 nm for 2, after mixing with each complex, indicate that the interaction with CT-DNA results in the direct formation of a new compound with double-helical CT-DNA [34]. The absorption intensity at 258 nm is increased due to the fact that the purine and pyrimidine DNAbases are exposed because of the binding of the complexes to DNA. These characteristics can be attributed to an interaction having caused the changes of the conformation of DNA [35]. In Fig. 5, the changes occurred in the spectra of a 105 M solution of NFX, HPPA, ENX and complexes 1–3 during the titration upon addition of CT-DNA in diverse r values are presented. In the UV region, the intense absorption bands observed in the spectra of the quinolones and the complexes are attributed to the intraligand p–p⁄ transition of the coordinated groups [36]. Any

interaction between each complex and CT-DNA could perturb the intra-ligand centred spectral transition bands of the complexes. As shown in Fig. 5, the bands centred at 348 and 360 nm exhibit a hypochromism for NFX in the presence of increasing amounts of CT-DNA (Fig. 5a); at 355 nm a hypochromism for PPA (Fig. 5b); at 335 and 347 nm a hypochromism for ENX (Fig. 5c); at 357 and 370 nm a hyperchromism for 1 (Fig. 5d); at 329 nm a hypochromism for 2 (Fig. 5e), and at 335 and 347 nm a hypochromism for 3 (Fig. 5f). The observed hyperchromic effect suggests that the binding to CT-DNA maybe attribute either to external contact (electrostatic or groove binding) or to the fact that complex could uncoil the helix structure of DNA resulting in the destabilization of the DNA duplex [37]. The resultant hypochromism suggests the tight binding of complex to CT-DNA probably by the intercalative mode. So the above discussed results suggest that all complexes can bind to CT-DNA and stabilize DNA duplex except for 1. Because of the observed hyperchromic effect, the possible binding mode of 1 with CT-DNA needs further experiments to do. Additionally, as a tool investigating the magnitude of the binding strength with CT-DNA, the intrinsic binding constant Kb can be obtained by monitoring the changes in the absorbance at the corresponding kmax with increasing concentrations of CT-DNA from plots ð½DNA ea ef Þ versus [DNA] (Inset of Fig. 5) and is given by the ratio of slope to the y intercept, according to the following equation [38]:

½DNA ½DNA 1 ¼ þ ðea  ef Þ ðeb  ef Þ K b ðeb  ef Þ

ð1Þ

where ea = Aobsd/[(complex)], ef = extinction coefficient for the free complex and eb = extinction coefficient for the complex in the fully bound form. The calculated Kb values for NFX, HPPA, ENX and complexes 1–3 are cited in Table 4. As shown in Table 4, the Kb values of all com-

Fig. 3. The 2D structure (a) and diagram (b) of complex 2, and the coordination mode of nickel ions (c) and the packing 3D structure of 2D sheets with 1D channels (d).

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Fig. 4. UV spectra of CT-DNA in buffer solution in the absence or presence of (a) NFX, (b) HPPA, (c) ENX, (d) Ni(NFX)26H2O 1, (e) Ni(PPA)21.5H2O 2, (f) Ni(ENX)22.5H2O 3. The arrows show the changes upon increasing amounts of complex.

Fig. 5. UV spectra of (a) NFX, (b) HPPA, (c) ENX, (d) Ni(NFX)26H2O 1, (e) Ni(PPA)21.5H2O 2 and (f) Ni(ENX)22.5H2O 3, in DMSO ([complex] = 10 lM) solution in the presence of CT-DNA at increasing amounts. The arrows show the changes upon increasing amounts of CT-DNA. Insets: plot of ðe½DNA vs. [DNA]. a e Þ f

plexes are in the range of 1.33(±0.02)  103 to 5.88(±0.03)  104 M1, which suggest a relatively moderate binding of each complex to CT-DNA. Note that the Kb values of complexes 1–3 are much higher than their parent drugs, respectively, which can be explained that the coordinated nickel ions can change the configuration of drugs, and the resulted complexes are favor of the interactions with CT-DNA. Complexes 1–3 do not show any fluorescence at room temperature in solution or in the presence of CT-DNA, so that the binding to DNA cannot be directly predicted through the emission spec-

Table 4 The DNA binding constants (Kb) and the Stern–Volmer constants (KSV) of the quinolones NFX, HPPA, ENX and complexes 1–3. Complexes NFX HPPA ENX Ni(NFX)26H2O 1 Ni(PPA)21.5H2O 2 Ni(ENX)22.5H2O 3

Kb (M1)

KSV (M1) 3

3.91(±0.01)  10 1.88(±0.02)  103 1.33(±0.02)  103 5.88(±0.03)  104 4.79(±0.07)  104 4.12(±0.02)  104

3.00(±0.11)  104 1.69(±0.06)  104 3.20(±0.02)  104 6.04(±0.04)  104 3.55(±0.06)  104 5.34(±0.04)  104

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Fig. 6. (a) Plot of % EB relative fluorescence intensity at kem = 669 nm (%) vs. r (r = [complex]/[DNA]) for NFX, HPPA, ENX and complexes 1–3 in buffer solution. (b) Stern– Volmer plot for NFX, HPPA, ENX and complexes 1–3. [EB] = 20 lM, [DNA] = 25 lM.

trum. Hence, a competitive EB binding study has been undertaken with fluorescence titration. EB does not show any appreciable emission in buffer solution due to fluorescence quenching of the free EB by the solvent molecules. On addition of CT-DNA, its fluorescence intensity is highly enhanced due to its strong intercalation between the adjacent DNA base pairs. Addition of another molecule binding to DNA more strongly than EB can decrease the DNA-induced EB emission. In the absence and presence of NFX, HPPA, ENX and complexes 1–3, respectively, the emission spectra of EB bound to CT-DNA (Fig. 6a) have been recorded for [EB] = 2  105 M, [DNA] = 2.5  105 M for increasing amounts of the each complex. The addition of each complex results in a decrease of the intensity of the emission band at 669 nm of the DNA–EB system upon addition of each complex at diverse r values (Fig. 6a) (up to 46.1% of the initial EB– DNA fluorescence intensity for NFX, 54.5% for HPPA, 49.5% for ENX, 37.7% for 1, 46.9% for 2 and 40.9% for 3) indicating the competition of the complexes with EB in binding to DNA. The observed quenching of DNA–EB fluorescence for NFX, HPPA, ENX and complexes 1– 3 may suggest that they can displace EB from the DNA–EB complex interacting with CT-DNA probably by the intercalative mode [39] or uncoil the helix structure of DNA. The quenching efficiency for each complex is evaluated by the Stern–Volmer constant KSV, which varies with the experimental conditions [40]:

separate and rationalize them. In summary, comparing the affinity of NFX, HPPA, ENX and complexes 1–3 with CT-DNA, it is evident that complexes 1–3 show much higher affinity and binding constants than their respective free drugs, and 1 changes the binding mode to CT-DNA of drug molecules, namely, intercalative binding mode for parent drug NFX and binding with uncoiling the DNA for 1, sulting in its high affinity to CT-DNA.

I0 ¼ 1 þ K SV ½Complex I

This work is financially supported by the Education Ministry Key Teachers Foundation (1155G53) of Heilongjiang Province.

ð2Þ

where I0 and I are the emission intensities in the absence and the presence of the complex, respectively. The Stern–Volmer plot of DNA–EB for NFX, HPPA, ENX and complexes 1–3 (Fig. 6b) illustrates that the quenching of EB bound to DNA by NFX, HPPA, ENX and complexes 1–3 is in good agreement with the linear Stern–Volmer equation (R = 0.98), which proves that the partial replacement of EB bound to DNA by each complex results in a decrease in the fluorescence intensity. The relatively high KSV value of the complexes (Table 4) shows that they can displace EB and bind very tightly to CTDNA [41] Note that complex 1 presents a higher value for KSV than other complexes, which is in accordance to the magnitude order observed for the Kb values. The facts indicate that 1 possesses higher affinity to CT-DNA, maybe due to uncoil the helix structure of DNA resulting in the quenching (37.7%) of EB bound to DNA. Let us recall that the 1 exhibits 1D chain structure and 2 and 3 2D sheet structures. Their different structures cause the configuration changes of drug molecules, which result in the different interaction of complexes with CT-DNA. It should be noted that many factors, such as the species and configuration of drug molecules, the metal ions and the structures of complexes, play important roles in the final properties of the complexes. Since these factors work together to affect the interaction of complexes with CT-DNA, it is difficult to

4. Conclusions By using the second/third-generation quinolone antibacterial agents and Ni ions, three new complexes were successfully obtained. UV studies of the interaction of complexes with CT-DNA show that they can bind to the CT-DNA and exhibit the higher binding constant to CT-DNA than their parent drugs. And the results of competitive binding studies with EB show all complexes bind to DNA in strong competition with EB for the intercalative binding sites for 2 and 3 and uncoil the helix structure of DNA for 1, which result in the relatively high KSV value. Due to uncoil the helix structure of DNA, 1 presents a higher value for KSV and Kb than other complexes. Acknowledgement

Appendix A. Supplementary material IR for complexes 1–3 are provided in supporting information. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ica.2011.11.005. References [1] A. Albert, The Physico-Chemical Basis of Therapy: Selective Toxicity, sixth ed., Chapman & Hall, London, 1979. [2] M.N. Hughes (Ed.), The Inorganic Chemistry of Biological Processes, second ed., Wiley, New York, 1981. [3] A. Tarushi, C.P. Raptopoulou, V. Psycharis, A. Terzis, G. Psomas, D.P. Kessissoglou, Bioorg. Med. Chem. 18 (2010) 2678. [4] M.N. Patel, P.A. Parmar, D.S. Gandhi, Bioorg. Med. Chem. 18 (2010) 1227. [5] D.C. Hooper, E. Rubinstein (Eds.), Quinolone Antimicrobial Agents, third ed., ASM Press, Washington, DC, 2003. [6] J.E.F. Reynolds (Ed.), Martindale: The Extra Pharmacopeia, 30th ed., The Pharmaceutical Press, London, 1993. p. 145. [7] K.G. Naber, J. Antimicrob. Chemother. 46 (2000) 49. [8] V. M-Sundermann, K.H. Hauff, P. Braun, W. Lu, Int. J. Oncol. 5 (1994) 849. [9] K.J. Huang, X. Liu, W.Z. Xie, H.X. Yuan, Colloids Surf., B 64 (2008) 269. [10] C.L. Tong, G.H. Xiang, J. Lumin. 126 (2007) 575. [11] D. Rehder, J. Costa Pessoa, C.F.G.C. Geraldes, T. Kabanos, T. Kiss, B. Meier, G. Micera, L. Pettersson, M. Rangel, A. Salifoglou, I. Turel, D. Wang, J. Biol. Inorg. Chem. 7 (2002) 384.

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