DNA-binding and anti-oxidation properties of binuclear lanthanide(III) complexes of 8-hydroxyquinoline-7-carbaldehyde-(isonicotinyl)hydrazone

Article abstract of DOI:10.1080/00958972.2012.683485

Binuclear complexes [LnL(NO₃)(H₂O)₂] ₂ were prepared from the Schiff base 8-hydroxyquino-line-7- carbaldehyde-(isonicotinyl)hydrazone (H₂L) and equivalent molar amounts of Ln(NO₃)₃ · 6H₂O (Ln = La ³⁺, Nd³⁺, Sm³⁺, Eu³⁺, Gd ³⁺, Dy³⁺, Ho³⁺, Er³⁺, Yb ³⁺), respectively. The ligand is dibasic tetradentate and the dimerization occurs through the phenolate oxygen atoms leading to a central four-membered (LnO)₂-ring. The ligand and all the Ln(III) complexes can bind to calf thymus DNA through intercalation with binding constants of 10⁵-10⁶ (molL^-1)^-1, and they show strong scavenging abilities on hydroxyl radicals and superoxide radicals. The values of SC₅₀ of Ln(III) complexes for HO^? and O₂^-. are 2.344-13.33 and 4.459-28.48 μmolL ^-1, respectively. Ln(III) complexes present stronger binding abilities to DNA and stronger anti-oxidation properties than ligand. Complex containing hydroxyl unit shows stronger scavenging abilities on hydroxyl radical, while complex containing N-heteroaromatic substituent shows stronger scavenging abilities on superoxide radicals. Furthermore, earlier rare metal complexes show stronger scavenging abilities on both hydroxyl radicals and superoxide radicals.

Full text of DOI:10.1080/00958972.2012.683485

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DNA-binding and anti-oxidation
properties of binuclear lanthanide(III)
complexes of 8-hydroxyquinoline-7-
carbaldehyde-(isonicotinyl)hydrazone
Yongchun Liu a , Kejun Zhang a , Ruixia Lei a , Jianning Liu a ,
Tianlin Zhou a & Zheng-Yin Yang b
a Key Laboratory of Longdong Biological Resources in Gansu
Province, College of Chemistry and Chemical Engineering,
Longdong University, Gansu 745000, Qingyang, P.R. China
b State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P.R. China
Version of record first published: 22 May 2012.
To cite this article: Yongchun Liu, Kejun Zhang, Ruixia Lei, Jianning Liu, Tianlin Zhou & Zheng-Yin
Yang (2012): DNA-binding and anti-oxidation properties of binuclear lanthanide(III) complexes of
8-hydroxyquinoline-7-carbaldehyde-(isonicotinyl)hydrazone, Journal of Coordination Chemistry,
65:12, 2041-2054
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Journal of Coordination Chemistry
Vol. 65, No. 12, 20 June 2012, 2041–2054
DNA-binding and anti-oxidation properties of binuclear
lanthanide(III) complexes of 8-hydroxyquinoline-7-carbal-
dehyde-(isonicotinyl)hydrazone
YONGCHUN LIU*y, KEJUN ZHANGy, RUIXIA LEIy, JIANNING LIUy,
TIANLIN ZHOUy and ZHENG-YIN YANGz
yKey Laboratory of Longdong Biological Resources in Gansu Province, College of
Chemistry and Chemical Engineering, Longdong University, Gansu 745000,
Qingyang, P.R. China
zState Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, P.R. China
(Received 27 December 2011; in final form 7 March 2012)
Binuclear complexes [LnL(NO3)(H2O)2]2 were prepared from the Schiff base 8-hydroxyquino-
line-7-carbaldehyde-(isonicotinyl)hydrazone (H2L) and equivalent molar amounts of
Ln(NO3)3 ꢀ 6H2O (Ln ¼ La3þ, Nd3þ, Sm3þ, Eu3þ, Gd3þ, Dy3þ, Ho3þ, Er3þ, Yb3þ), respectively.
The ligand is dibasic tetradentate and the dimerization occurs through the phenolate oxygen
atoms leading to a central four-membered (LnO)2-ring. The ligand and all the Ln(III)
complexes can bind to calf thymus DNA through intercalation with binding constants of 105–
106 (mol Lꢁ1 ꢁ1, and they show strong scavenging abilities on hydroxyl radicals and superoxide
)
.
radicals. The values of SC50 of Ln(III) complexes for HOꢂ and O2ꢁ are 2.344ꢁ13.33 and
4.459ꢁ28.48 mmol Lꢁ1, respectively. Ln(III) complexes present stronger binding abilities to
DNA and stronger anti-oxidation properties than ligand. Complex containing hydroxyl unit
shows stronger scavenging abilities on hydroxyl radical, while complex containing N-
heteroaromatic substituent shows stronger scavenging abilities on superoxide radicals.
Furthermore, earlier rare metal complexes show stronger scavenging abilities on both hydroxyl
radicals and superoxide radicals.
Keywords: 8-Hydroxyquinoline-7-carbaldehyde; Schiff-base ligand; Lanthanide(III) com-
plexes; Calf thymus DNA; Intercalation; Anti-oxidation properties
1. Introduction
DNA is an important cellular receptor, many chemicals exert their antitumor effects
through binding to DNA thereby changing the replication of DNA and inhibiting the
growth of tumor cells, which is the basis for designing more efficient antitumor drugs;
their effectiveness depends on the mode and affinity of the binding [1–3]. A number of
metal chelates, as agents for mediation of strand scission of duplex DNA and as
chemotherapeutic agents, have been used as probes of DNA structure in solution [4–6].
Apart from magnetic and photophysical properties, the bioactivities of lanthanides such
*Corresponding author. Email: ychliu001@163.com
Journal of Coordination Chemistry
ISSN 0095-8972 print/ISSN 1029-0389 online ß 2012 Taylor & Francis
http://dx.doi.org/10.1080/00958972.2012.683485

2042
Y. Liu et al.
as antimicrobial, antitumor, antivirus, anticoagulant action, enhancing NK and
macrophage cell activities, and prevention from arteriosclerosis have been explored
.
[7–10]. An excess of activated oxygen species, superoxide anion (Oꢁ2 ), and hydroxyl
radical (OH. ), generated by normal metabolic processes, may cause various diseases
such as carcinogenesis, drug-associated toxicity, inflammation, atherogenesis, and aging
in aerobic organisms [11–13]. Some minor groove binders for DNA are effective
inhibitors of formation of a DNA/TBP complex or topoisomerases. Adding a reactive
entity endowed with oxidative properties should improve the efficiency of inhibitors
[14–16]. Well-designed organic ligands enable fine tuning of properties of the metal
ions. Quinoline and its derivatives have attracted special interest due to their
therapeutic properties. Quinoline sulphonamides have been used in the treatment of
cancer, tuberculosis, diabetes, malaria, and convulsion for decades [17, 18].
Previously, we investigated biological properties of lanthanide(III) complexes of
Schiff bases derived from 8-hydroxyquinoline-2-carbaldehyde with some aroylhydra-
zines and 8-hydroxyquinoline-7-carbaldehyde with benzoylhydrazine. All these ligands
and rare-earth metal complexes showed strong anti-oxidation and DNA-binding
properties, useful as potential anticancer drugs [19–24]. In this article, the Schiff base
derived from 8-hydroxyquinoline-7-carbaldehyde with isonicotinylhydrazine and its
lanthanide(III) complexes are prepared to investigate their anti-oxidation and DNA-
binding properties.
2. Experimental
2.1. Materials
Calf thymus DNA (ct-DNA) and ethidium bromide (EB) were obtained from Sigma-
Aldrich Biotech. Co., Ltd. Stock solution (1.0 mmol Lꢁ1) of the investigated compound
was prepared by dissolving the powdered material into appropriate amounts of DMF.
Deionized double distilled water and analytical grade reagents were used throughout.
ct-DNA stock solution was prepared by dissolving the solid material in 5 mmol Lꢁ1
Tris-HCl buffer (pH 7.20) containing 50 mmolLꢁ1 NaCl. The ct-DNA concentration in
terms of base pair Lꢁ1 was determined spectrophotometrically by employing an
extinction coefficient of ꢀ ¼ 13,200 (mol L
)
ꢁ1 ꢁ1 cmꢁ1 (base pair)ꢁ1 at 260 nm and the
concentration in terms of nucleotide Lꢁ1 was also determined spectrophotometrically
by employing an extinction coefficient of 6600 (mol L
)
ꢁ1 ꢁ1 cmꢁ1 (nucleotide)ꢁ1 at
260 nm [25]. The stock solution was stored at ꢁ20ꢃC until it was used. EB was dissolved
in 5 mmol Lꢁ1 Tris-HCl buffer (pH 7.20) containing 50 mmol Lꢁ1 NaCl and its
concentration was determined assuming
5600 L molꢁ1 cmꢁ1 at 480 nm [26].
a
molar extinction coefficient of
2.2. Methods
Melting points of the compounds were determined on an XT4-100X microscopic
melting point apparatus (Beijing). Elemental analyses of C, N, and H were carried out
on an Elemental Vario EL analyzer. The metal ion content was determined by
complexometric titration with EDTA after destruction of the complex in the

Lanthanide hydrazone
2043
conventional manner. Infrared (IR) spectra were recorded on a Nicolet Nexus 670 FT-
1
IR spectrometer using KBr discs from 4000 cmꢁ1 to 400 cmꢁ1. H NMR spectra were
recorded on a Bruker Advance DRX 200-MHz spectrometer with tetramethylsilane
(TMS) as an internal standard. ESI-MS (ESI-Trap/Mass) spectra were recorded on a
Bruker Esquire6000 Mass spectrophotometer and formic acid was used as the proton
source.
Viscosity titration experiments were carried on an Ubbelohde viscometer in a
thermostated water-bath maintained at 25.00 ꢄ 0.01ꢃC. Data were presented as (ꢁ/ꢁo)1/3
versus the ratio of the compound to DNA, where ꢁ is the viscosity of DNA in the
presence of the compound corrected from the solvent effect and ꢁo is the viscosity of
DNA alone [26, 27].
Ultraviolet-Visible (UV-Vis) spectra were obtained using a Perkin Elmer Lambda
UV-Vis spectrophotometer. The binding constant (Kb) was determined by the following
equation [28, 29]:
½DNAꢅ ½DNAꢅ
1
¼
þ
,
ð1Þ
ꢁ1 ꢁ1 cmꢁ1
)
"f ꢁ "a
"f ꢁ "b Kbð"f ꢁ "bÞ
where [DNA] is the molar concentration of DNA in base pairs, ꢀa ((mol L
)
corresponds to the extinction coefficient observed, ꢀf ((mol L
the extinction coefficient of the free compound, ꢀb ((mol L
)
ꢁ1 ꢁ1 cmꢁ1) corresponds to
ꢁ1 ꢁ1 cmꢁ1) is the extinction
)
coefficient of the compound when fully bound to DNA, and Kb is the intrinsic binding
constant. The ratio of slope to intercept in the plot of [DNA]/(ꢀf ꢁ ꢀa) versus [DNA]
gives the value of Kb.
Fluorescence spectra were recorded using an RF-5301PC spectrofluorophotometer
(Shimadzu, Japan) with a 1 cm quartz cell. Both excitation and emission band widths
were 10 nm. DNA-EB quenching assay was performed according to literature
procedure [19, 20]. DNA (4.0 mmol Lꢁ1, nucleotides) solution was added incrementally
to 0.32 mmol Lꢁ1 EB solution, then small aliquots of concentrated solutions
(1.0 mmolLꢁ1) were added till the drop in fluorescence intensity (ꢂex ¼ 525 nm,
ꢂem ¼ 587 nm) reached a constant value. Measurements were made after 5 min at
298 K. The Stern–Volmer equation was used to determine the fluorescence quenching
mechanism [30]:
Fo=F ¼ 1 þ KSV½Qꢅ,
ð2Þ
where Fo and F are the fluorescence intensity in the absence and presence of a
compound at [Q], respectively; KSV is the Stern–Volmer dynamic quenching constant.
Hydroxyl radicals (OH. ) in aqueous media were generated through the Fenton-type
reaction [31, 32]. The 5 mL reaction mixtures contained 2.0 mL of 100 mmolLꢁ1
phosphate buffer (pH ¼ 7.4), 1.0 mL of 0.10 mmolLꢁ1 aqueous safranin, 1 mL of
1.0 mmolLꢁ1 aqueous EDTA-Fe(II), 1 mL of 3% aqueous H2O2, and a series of
quantitatively microadding solutions of the tested compound. The reaction mixtures
were incubated at 37ꢃC for 60 min in a water-bath. Absorbance at 520 nm was measured
and the solvent effect was corrected throughout. The scavenging effect for OH. was
calculated from the following expression [33, 34]:
Asample ꢁ Ablank
Scavenging effect ð%Þ ¼
ꢆ 100,
ð3Þ
Acontrol ꢁ Ablank

2044
Y. Liu et al.
where Asample is the absorbance of the sample in the presence of the tested compound,
Ablank is the absorbance of the blank in the absence of the tested compound, and Acontrol
is the absorbance in the absence of the tested compound and EDTA-Fe(II).
.
Superoxide radicals (Oꢁ2 ) were produced by the MET-VitB2-NBT system [33, 34].
The 5 mL reaction mixtures contained 2.5 mL of 100 mmol Lꢁ1 phosphate buffer (pH
7.8), 1.0 mL of 50 mmol Lꢁ1 MET (methionine), 1.0 ml of 0.23 mmol Lꢁ1 NBT
(nitroblue tetrazolium), 0.50 ml of 33 mmol Lꢁ1 VitB2 (vitamin B2), and a series of
quantitatively microadding solutions of the tested compound in the absence of light.
After incubation at 30ꢃC for 10 min in a water-bath and then illumination with a
fluorescent lamp (4000 Lux), the absorbance of the sample was measured at 560 nm and
.
the solvent effect was corrected throughout. The scavenging effect for Oꢁ2 was
calculated from the following expression:
Ao ꢁ Ai
Scavenging effect ð%Þ ¼
ꢆ 100,
ð4Þ
Ao
where Ai is the absorbance in the presence of the tested compound and Ao is the
absorbance in the absence of the tested compound.
Data for anti-oxidation are presented as means ꢄSD of three determinations and
followed by Student’s t-test. Differences were considered to be statistically significant if
p 5 0.05. SC50 value, calculated from the regression line of the log of the tested
compound concentration versus the scavenging effect (%) of the compound, is
introduced to denote the molar concentration of the tested compound which causes a
50% scavenging effect on hydroxyl radicals or superoxide radicals.
2.3. Synthesis of 8-hydroxyquinoline-7-carbaldehyde
8-Hydroxyquinoline-7-carbaldehyde was prepared as previously reported [35–37].
Chloropicrin (32 mL, 0.4 mol) was dropped into ethanol solution of 14.5 g (0.1 mol)
8-hydroxyquinoline and 40% NaOH (1 mol) aqueous solution. Refluxing the mixture at
65–70ꢃC for 4 h, the crude product was obtained after acidification at pH 5.0ꢁ5.5 by
0.1 mol Lꢁ1 HCl. A salmon pink crystal was separated, obtained by chromatographic
column (eluent, Vpetroleum : Vethyl acetate ¼ 40 : 1). Then, recrystallization by chloropicrin
and ethanol gave 3.1 g pale-orange needle-like crystals after drying by vacuum, yield
18%, m.p. 178ꢃC.
2.4. Synthesis of 8-hydroxyquinoline-7-carbaldehyde-(isonicotinyl)hydrazone (1)
Ligand 1 (H2L) was prepared by refluxing and stirring a mixture of 10 mL ethanol
solution of 8-hydroxyquinoline-7-carbaldehyde (0.519 g, 3 mmol) and a 10 mL 90%
ethanol aqueous solution of isonicotinylhydrazine (0.411 g, 3 mmol) for 8 h. After
cooling to room temperature, the precipitate was filtered, recrystallized from 80%
methanol aqueous solution, and dried in vacuum over 48 h to give a pale yellow
powder, yield 72.3% (0.633 g); m.p. 251ꢁ252ꢃC. UV-Vis (ꢂmax nm, ꢀ ꢆ 104
(mol L )
ꢁ1 ꢁ1 cmꢁ1): 246 (2.17), 353 (1.57). IR (KBr): 3335, 3190, 1642, 1592, 1568,
1551, 1231. Anal. Calcd for C16H12N4O2 (%): C, 65.75; H, 4.14; N, 19.17. Found:
C, 65.67; H, 4.12; N, 19.22. MS (ESI-TOF) m/z: 293.1 [M þ H]þ. 1H NMR (DMSO-d6,

Lanthanide hydrazone
2045
200 MHz, TMS) ꢃ: 12.032 (1H, s, 13-NH), 9.619ꢁ9.586 (1H, dd, J23 ¼ 8.7 Hz,
J24 ¼ 1.2 Hz, 2-CH), 8.964ꢁ8.947 (1H, s, 11-CH¼N), 8.830ꢁ8.800 (3H, m, 4-CH, 17-
CH, 19-CH), 7.872ꢁ7.853 (2H, d, J ¼ 5.7 Hz, 16-CH, 20-CH), 7.825ꢁ7.800 (1 H, d,
J ¼ 7.5 Hz, 6-CH), 7.778ꢁ7.735 (1H, m, 3-CH), 7.194ꢁ7.169 (1H, d, J ¼ 7.5 Hz, 5-CH).
2.5. Synthesis of metal complexes (2–10)
Each Ln(III) complex was prepared by refluxing and stirring a mixture of a 40 mL
methanol solution of 1 (0.058 g, 0.2 mmol) and an equivalent molar amount of
Ln(NO3)3 ꢀ 6H2O (Ln ¼ La3þ, Nd3þ, Sm3þ, Eu3þ, Gd3þ, Dy3þ, Ho3þ, Er3þ, Yb3þ) on a
water-bath, respectively. After refluxing for 30 min, triethylamine (0.020 g, 0.2 mmol)
was added dropwise to deprotonate the phenolic hydroxyl substituent of 8-hydro-
xyquinolinate. Then, the mixture was refluxed and stirred continuously for 8 h. Cooling
to room temperature, the precipitate was centrifuged, washed with methanol, and dried
in vacuum over 48 h to give a powder. All the Ln(III) complexes are yellow powders and
their melting points exceed 300ꢃC.
Complex 2: Yield 89.7% (0.095 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 248
(4.63), 356 (3.26). IR (KBr): 3390, 3206, 1654, 1591, 1555, 1096, 1465, 1319, 1034, 965,
839, 721, 634, 533, 436. MS (ESI-TOP, DMF) m/z: 293.1, 636.5, 637.4, 638.1, 638.6,
639.3, 1273.0, 1275.1, 1277.3. Anal. Calcd for C32H28N10O14La2 (%): C, 36.45; H, 2.68;
N, 13.28; La, 26.35. Found: C, 36.72; H, 2.65; N, 13.19; La, 26.44. ꢀm (cm2 ꢁꢁ1 molꢁ1
,
DMF): 51.1.
Complex 3: Yield 87.8% (0.094 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 248
(4.68), 356 (3.52). IR (KBr): 3369, 3215, 1655, 1590, 1557, 1095, 1465, 1318, 1046, 965,
839, 725, 631, 534, 442. MS (ESI-TOP, DMF) m/z: 293.2, 640.1, 640.4, 640.9, 641.3,
643.3, 643.6, 644.0, 644.3, 644.7, 646.1, 647.0, 647.6, 648.0, 648.8, 649.5, 650.2, 1280.5,
1281.2, 1281.8, 1282.7, 1283.3, 1284.8, 1285.6, 1286.3, 1287.5, 1288.4, 1289.9, 1290.4,
1291.3, 1291.7, 1293.3, 1294.0, 1294.9, 1295.4, 1296.1, 1296.5, 1297.7, 1299.0, 1299.8.
Anal. Calcd C32H28N10O14Nd2 (%): C, 36.08; H, 2.65; N, 13.13; Nd, 27.08. Found:
C, 36.13; H, 2.65; N, 13.24; Nd, 27.01. ꢀm (cm2 ꢁꢁ1 molꢁ1, DMF): 45.3.
Complex 4: Yield 87.2% (0.094 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 262
(4.01), 365 (2.40), 393 (2.38). IR (KBr): 3376, 3216, 1655, 1591, 1558, 1097, 1467, 1323,
1031, 965, 840, 726, 634, 535, 442. MS (ESI-TOP, DMF) m/z: 293.1, 642.1, 643.1, 644.4,
645.1, 646.0, 647.2, 647.6, 648.1, 648.6, 649.2, 650.2, 650.8, 651.3, 651.8, 653.6, 654.1,
1284.9, 1288.4, 1289.1, 1291.1, 1293.4, 1294.7, 1297.7, 1300.3, 1301.0, 1304.3, 1305.1,
1306.2. Anal. Calcd for C32H28N10O14Sm2 (%): C, 37.97; H, 2.81; N, 10.42; Sm, 27.96.
Found: C, 38.13; H, 2.80; N, 10.37; Sm, 27.81. ꢀm (cm2 ꢁꢁ1 molꢁ1, DMF): 45.5.
Complex 5: Yield 81.4% (0.088 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 260
(3.86), 377 (2.34). IR (KBr): 3403, 3206, 1655, 1591, 1558, 1098, 1468, 1328, 1022, 964,
839, 724, 643, 533, 451. MS (ESI-TOP, DMF) m/z: 293.2, 649.9, 651.3, 652.0, 652.9,
1298.1, 1299.7, 1300.6, 1302.1, 1302.6, 1304.2, 1305.3. Anal. Calcd for
C32H28N10O14Eu2 (%): C, 35.57; H, 2.61; N, 12.96; Eu, 28.13. Found: C, 35.66; H,
2.60; N, 12.84; Eu, 28.28. ꢀm (cm2 ꢁꢁ1 molꢁ1, DMF): 49.0.
Complex 6: Yield 84.9% (0.093 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol Lꢁ1 ꢁ1 cmꢁ1): 261
)
(5.13), 363 (3.23), 399 (3.18). IR (KBr): 3383, 3212, 1655, 1591, 1559, 1098, 1467, 1323,

2046
Y. Liu et al.
1034, 964, 839, 727, 633, 535, 447. MS (ESI-TOP, DMF) m/z: 293.1, 651.1, 652.1, 653.2,
654.1, 655.5, 656.6, 657.8, 658.6, 659.1, 1300.0, 1301.4, 1302.5, 1303.7, 1305.4, 1306.9,
1310.1, 1313.3, 1315.0, 1315.9, 1317.2, 1319.0. Anal. Calcd for C32H28N10O14Gd2 (%):
C, 35.22; H, 2.59; N, 12.84; Gd, 28.82. Found: C, 35.37; H, 2.57; N, 12.73; Gd, 28.99.
ꢀm (cm2 ꢁꢁ1 molꢁ1, DMF): 48.6.
Complex 7: Yield 89.1% (0.098 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 262
(4.49), 368 (2.75), 402 (2.81). IR (KBr): 3382, 3214, 1656, 1591, 1561, 1098, 1467, 1323,
1034, 965, 839, 728, 636, 535, 447. MS (ESI-TOP, DMF) m/z: 293.1, 654.9, 656.1, 657.3,
657.9, 658.7, 659.4, 660.3, 660.8, 661.3, 662.2, 663.0, 663.5, 664.2, 1315.2, 1316.9,
1317.8, 1324.4, 1325.6, 1328.6. Anal. Calcd for C32H28N10O14Dy2 (%): C, 34.89;
H, 2.56; N, 12.71; Dy, 29.50. Found: C, 34.74; H, 2.55; N, 12.62; Dy, 29.66. ꢀm (cm2
ꢁ
ꢁ1 molꢁ1, DMF): 44.3.
Complex 8: Yield 88.2% (0.098 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 262
(5.03), 363 (3.07), 405 (3.25). IR (KBr): 3376, 3214, 1655, 1591, 1561, 1098, 1467, 1321,
1037, 961, 839, 729, 634, 536, 449. MS (ESI-TOP, DMF) m/z: 293.2, 663.1, 663.8, 664.3,
664.9, 665.3, 1326.2, 1327.6, 1328.2, 1328.9, 1329.5. Anal. Calcd for C32H28N10O14Ho2
(%): C, 34.74; H, 2.55; N, 12.66; Ho, 29.81. Found: C, 34.62; H, 2.54; N, 12.78; Ho,
29.92. ꢀm (cm2 ꢁꢁ1 molꢁ1, DMF): 41.3.
Complex 9: Yield 83.9% (0.093 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 262
(4.93), 362 (2.90), 408 (3.13). IR (KBr): 3384, 3216, 1656, 1590, 1562, 1099, 1468, 1321,
1035, 963, 839, 729, 632, 535, 447. MS (ESI-TOP, DMF) m/z: 293.2, 660.1, 660.7, 661.7,
662.2, 663.1, 663.8, 664.4, 665.1, 665.9, 666.7, 667.5, 669.1, 669.9, 1320.1, 1320.7,
1321.8, 1323.4, 1324.2, 1326.5, 1327.9, 1329.0, 1329.5, 1330.2, 1331.0, 1331.8, 1334.1,
1335.0, 1336.1, 1338.3, 1339.6. Anal. Calcd for C32H28N10O14Er2 (%): C, 34.59; H,
2.54; N, 12.61; Er, 30.11. Found: C, 34.48; H, 2.55; N, 12.72; Er, 30.24. ꢀm (cm2
ꢁ
ꢁ1 molꢁ1, DMF): 37.1.
Complex 10: Yield 86.1% (0.097 g). UV-Vis (ꢂmax nm, ꢀ ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1): 262
(4.68), 363 (2.93), 406 (3.19). IR (KBr): 3400, 3213, 1656, 1591, 1562, 1100, 1469, 1324,
1034, 966, 839, 730, 635, 535, 450. MS (ESI-TOP, DMF) m/z: 293.1, 667.3, 669.2, 671.1,
671.9, 672.9, 674.3, 675.7, 1338.6, 1341.5, 1347.0, 1348.3, 1350.5, 1351.0. Anal. Calcd
for C32H28N10O14Yb2 (%): C, 34.23; H, 2.51; N, 12.48; Yb, 30.83. Found: C, 34.29; H,
2.50; N, 12.57; Yb, 30.69. ꢀm (cm2 ꢁꢁ1 molꢁ1, DMF): 39.4.
3. Results and discussion
3.1. Syntheses of compounds
8-Hydroxyquinoline-7-carbaldehyde-(isonicotinyl)hydrazone (1, H2L) was prepared
from equivalent molar amounts of 8-hydroxyquinoline-7-carbaldehyde and isonicoti-
nylhydrazine (scheme 1). The lanthanide(III) complexes (2–10) were prepared from 1
and equivalent molar amounts of Ln(NO3)3 ꢀ 6H2O (Ln ¼ La3þ, Nd3þ, Sm3þ, Eu3þ
,
Gd3þ, Dy3þ, Ho3þ, Er3þ, Yb3þ), respectively. All the Ln(III) complexes are yellow
powders, stable in air, soluble in DMF and DMSO, and slightly soluble in methanol,
ethanol, acetonitrile, ethyl acetate, acetone, THF, and CHCl3. Elemental analyses

Lanthanide hydrazone
2047
4
5
6
CHCl3, EtOH
40% NaOH
95% EtOH
3
2
O
20
17
O
13
N
H
H
11
N
19
N
N
N
H2N
N
H
OH
O
OH
H
N
OH
16
N
Scheme 1. The synthetic route for 1 (H2L).
indicate that all these complexes are 1 : 1 metal to ligand and molar conductances in
DMF indicate that all are non-electrolytes [38].
3.2. Structures of Ln(III) complexes
Comparison of IR bands between ligand and Ln(III) complexes: (1) Bands at
3403ꢁ3369br assigned to ꢄ(OH) of H2O, 966ꢁ961w assigned to ꢅr (H2O), and 643ꢁ631w
assigned to ꢅw (H2O) indicate that coordinated water is present in the Ln(III) complexes
[35, 39]. (2) Bands at 1100ꢁ1095 assigned to ꢄ(C–OM) which are similar to m-O,
especially at the lower frequencies, compared with complexes derived from 8-
hydroxyquinoline-2-carbaldehyde with aroylhydrazines, indicate that binding of every
metal to ligand takes place through a m-O (M–O–M) linkage [20, 40]. (3) Bands at 1642 s
assigned to ꢄ(CO) and 3335vs assigned to ꢄ(NH) of isonicotinylhydrazine side chain of 1
disappear, indicating that they participate in the Ln(III) complexes with OC–NH–
–
probably enolizing and deprotonating into O–CN–. (4) Band at 1568 assigned to
ꢄ(CN) of azomethine of 1 disappears and bands at 1562ꢁ1555 assigned to ꢄ(CN) of
pyridines of quinolinato units of Ln(III) complexes shift by 9ꢁ4 cmꢁ1 in comparison
with 1 indicate that both nitrogen atoms participate in the Ln(III) complexes. However,
bands at 1591ꢁ1590 assigned to ꢄ(CN) of pyridines of isonicotinylhydrazine units of
Ln(III) complexes hardly shift in comparison with 1. (5) Bands at 536ꢁ533w assigned to
ꢄ(MO) and 451ꢁ436w assigned to ꢄ(MN) further indicate that oxygen and nitrogen
participate in complexes. (6) All the Ln(III) complexes show bands at 1469ꢁ1465 (ꢄ1),
1328ꢁ1318 (ꢄ4), 1046ꢁ1031 (ꢄ2), 840ꢁ839 (ꢄ3), 730ꢁ7121 (ꢄ5), and Dꢄ(ꢄ1 –
ꢄ4) ¼ 147 ꢁ 140 cmꢁ1, indicating that bidentate nitrate participate in the Ln(III)
complexes [20, 21].
The results of elemental analyses, molar conductance, IR spectra, and ESI-MS data
indicate that 1 is dibasic tetradentate, binding to Ln(III) through the phenolate oxygen,
–
nitrogen of quinolinate, CN and O–CN– (enolized and deprotonated from OC–NH–)
of the isonicotinylhydrazine side chain. Dimerization of this monomeric unit may occur
through the phenolate oxygen atoms leading to a central four-membered (LnO)2-ring.
Radii of lanthanide(III) ions decrease gradually and the total difference of radii is only
14 pm from La3þ to Lu3þ; it is presumed that the metal complexes are structurally
similar with binuclear compositions [LnL(NO3)(H2O)2]2 (figure 1). However, the m/z
data (DMF solution) of complexes indicate that coordinated water of every powdered
Ln(III) complex can be replaced by DMF molecules when dissolved in DMF solution,
and that the composition of binuclear complex in DMF solution is
[LnL(NO3)(DMF)2]2. Additionally, the m/z peaks of [H2L þ H]þ, [M/2]þ, [M/2 þ
H]þ, [M]þ, [M þ H]þ and the isotope patterns of metal ions can be found

2048
Y. Liu et al.
H
C
O
N
O
N
N
N
H2O
C
N
OH2
-O
-O
O-
O-
O-
Ln3+
Ln3+
O
H2O
OH2
N
C
N
N
N
-O
N
C
O
H
Figure 1. The suggested structure of binuclear Ln(III) complexes.
(see Supplementary material, figure S1), indicating that the binuclear complex exists as
well as monomeric unit in DMF solution [41].
3.3. Viscosity titration measurements
Viscosity titration measurements were carried out to clarify the interaction modes
between the investigated compounds and ct-DNA. Hydrodynamic measurements that
are sensitive to length change of DNA (i.e., viscosity and sedimentation) are most
critical criteria for binding modes in solution in the absence of crystallographic
structural data, as viscosity is proportional to L3 for rod-like DNA of length L [26, 42].
Intercalation involves the insertion of a planar molecule between DNA base pairs,
resulting in a decrease in the DNA helical twist and lengthening of the DNA, therefore
intercalators cause the unwinding and lengthening of DNA helix as base pairs become
separated to accommodate the binding compound [26, 43]. Agents bound to DNA
through groove binding do not alter the relative viscosity of DNA, and agents bound to
DNA through electrostatic binding bend or kink the DNA helix, reducing its effective
length and its viscosity concomitantly [33, 44]. With the ratio of the investigated
compound to DNA (bps) increasing, the relative viscosity of DNA increases steadily
(figure S2), indicating that intercalation takes place between the compounds and DNA
helix. The increase in relative viscosity of DNA by every complex is more than by
ligand, indicating more unwinding and lengthening of the DNA helix and higher
affinity of complex binding to DNA than that of ligand.
3.4. UV-Vis spectroscopic study
The UV-Vis absorption spectra of the investigated compounds in the absence and
presence of the ct-DNA were obtained in DMF : Tris-HCl buffer (5 mmol Lꢁ1, pH 7.20)
containing 50 mmol Lꢁ1 NaCl of 1 : 100 solutions, respectively. The UV-Vis spectra of
H2L have absorptions at 246 nm (ꢀ ¼ 2.17 ꢆ 104 (mol L
present three bands at 248ꢁ262 nm (ꢀ ¼ 3.86ꢁ5.13 ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1) and 353 nm
(ꢀ ¼ 1.57 ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1), while the UV-Vis spectra of Ln(III) complexes
)
ꢁ1 ꢁ1 cmꢁ1),

Lanthanide hydrazone
2049
.
Table 1. Kb, KSV, FC50, SC50 (OH. and O2ꢁ ) for H2L and Ln(III) complexes.
FC50 (mmol Lꢁ1
)
Kb ꢆ 105
KSV ꢆ 105
(Ccompound
CDNA, nucleotides
/
SC50 (mmol Lꢁ1
)
SC50 (mmol Lꢁ1
)
.
Compound
(mol Lꢁ1 ꢁ1
)
(mol Lꢁ1 ꢁ1
)
)
for OHꢂ
for Oꢁ2
1
2
3
4
5
6
7
8
9
10
6.94 ꢄ 0.01
9.5 ꢄ 0.1
10.6 ꢄ 0.1
11.1 ꢄ 0.2
17 ꢄ 1
0.208 ꢄ 0.001
1.50 ꢄ 0.04
1.29 ꢄ 0.03
1.18 ꢄ 0.03
1.51 ꢄ 0.04
1.70 ꢄ 0.02
1.09 ꢄ 0.02
1.40 ꢄ 0.02
1.00 ꢄ 0.01
1.02 ꢄ 0.02
45.82 (11.45)
7.191 (1.798)
8.497 (2.124)
8.894 (2.223)
7.684 (1.921)
6.333 (1.583)
8.356 (2.089)
7.377 (1.844)
9.232 (2.308)
8.867 (2.217)
143 ꢄ 3
4.365 ꢄ 0.006
3.45 ꢄ 0.05
2.3 ꢄ 0.2
179 ꢄ 5
12.2 ꢄ 0.8
15 ꢄ 3
28 ꢄ 5
8.8 ꢄ 0.7
11.4 ꢄ 0.8
9.4 ꢄ 0.7
4.5 ꢄ 0.1
9.5 ꢄ 0.5
6.24 ꢄ 0.07
16 ꢄ 2
12 ꢄ 1
13 ꢄ 1
16.7 ꢄ 0.1
10.5 ꢄ 0.1
12.2 ꢄ 0.1
10.2 ꢄ 0.1
8.2 ꢄ 0.5
4.99 ꢄ 0.05
3.64 ꢄ 0.06
5.3 ꢄ 0.1
377ꢁ356 nm
(ꢀ ¼ 2.34ꢁ3.52 ꢆ 104
(mol L
)
ꢁ1 ꢁ1 cmꢁ1),
and
393ꢁ408 nm
(ꢀ ¼ 2.38ꢁ3.25 ꢆ 104 (mol L
)
ꢁ1 ꢁ1 cmꢁ1), which can be assigned to ꢆ–ꢆ* transition of
aromatic rings, ꢆ–ꢆ* of conjugated aromatic rings and the charge transfer from ligand
to metal ions (L!Ln3þ), respectively [35, 39]. Isosbestic points at 453 nm for ligand and
at 453ꢁ485 nm for Ln(III) complexes indicate that equilibria take place between
compounds and DNA. Upon successive addition of ct-DNA (bps), the UV-Vis
absorption of ligand shows a progressive hypochromism of 67.4% at 246 nm and 68.1%
at 353 nm by approximately saturated titration end point at CDNA : Cligand ¼ 1.8 : 1.
Similarly, UV-Vis bands of complexes show progressive hypochromism of 13.8ꢁ63.6%
at 248ꢁ262 nm and another progressive hypochromism of 14.3ꢁ53.4% at 377ꢁ356 nm
by CDNA : Ccomplex ¼ 1.0ꢁ1.6 : 1. The obvious hypochromism indicates non-covalent
intercalative binding of compound to the DNA helix, due to strong stacking interaction
between the aromatic chromophore of the compound and base pairs of DNA [45, 46].
The magnitude of hypochromism is parallel to the intercalative strength and the affinity
of a compound binding to DNA [42]. Figures S3 and S4 show plots of the UV-Vis
titration and the plots of [DNA]/(ꢀf ꢁ ꢀa) versus [DNA] for ligand and Ln(III)
complexes, respectively. The binding constants (Kb ¼ 6.973–17.09 ꢆ 105 (mol Lꢁ1 ꢁ1
) )
between DNA and the investigated compounds were determined and the values of Kb
are listed in table 1. The value of Kb of EB (classical intercalative agent) binding to
DNA investigated with the same conditions is 0.3068 ꢆ 105 (mol Lꢁ1 ꢁ1
)
(figure S3).
Figure 2 shows the plot of Kb with 4f electron number of metal ions. It is obvious that
all the Ln(III) complexes have higher binding abilities to DNA than either ligand or EB;
Eu(III) and Dy(III) complexes have much higher binding abilities to DNA. These
Ln(III) complexes have stronger binding to ct-DNA via intercalation than those derived
from 3-carbaldehyde chromone with isonicotinyl hydrazine and 1-phenyl-3-methyl-4-
formyl-2-pyrazolin-5-one (PMFP) with isonicotinyl hydrazine, in which Kb ¼ 2.46–
7.6 ꢆ 105 (mol Lꢁ1 ꢁ1
)
and Ln ¼ La3þ, Nd3þ, Sm3þ, and Yb3þ [47, 48]. However, the
Sm(III) complex derived from 8-hydroxyquinoline-7-carbaldehyde-(isonicotinyl)hydra-
zone shows weaker binding to ct-DNA via intercalation than that of Sm(III) complex
derived from Congo red (CR) binding to herring sperm DNA, in which the Kb of
Sm(III)(CR)3 complex is 6.25 ꢆ 106 (mol Lꢁ1 ꢁ1
)
at 18ꢃC and 1.11 ꢆ 107 (mol Lꢁ1 ꢁ1
)
at
26ꢃC [49].

2050
Y. Liu et al.
18
16
14
12
10
8
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
KSV
Kb
0
2
4
6
8
10 12 14
4f electron number of metal ions
Figure 2. Plots of Kb and KSV with 4f electron number of metal ions.
3.5
(4)
(8)
(5)
(3)
(6)
(2)
(7)
(10)
3.0
2.5
2.0
1.5
1.0
(9)
0
2
4
6
8
10 12 14 16 18 20 22
[Q] (µM)
Figure 3. The Stern–Volmer plots for ligand and Ln(III) complexes in EB-DNA systems. ꢂex ¼ 525 nm,
ꢂem ¼ 587 nm, 298 K. The concentration of DNA is 4.0 mmol Lꢁ1 (nucleotides) and the concentration of EB is
0.32 mmol Lꢁ1
.
3.5. DNA-EB quenching assay
The fluorescence emission intensity of DNA-EB system decreased dramatically upon
increasing amounts of either ligand or Ln(III) complexes, as shown in figure 3 and
table 1, the values of KSV are 0.2080ꢁ1.702 ꢆ 105 (mol Lꢁ1 ꢁ1
)
for ligand and Ln(III)
complexes. The Stern–Volmer quenching constant can be interpreted as the association
or binding constant of the complexation reaction [26, 33, 50]. The loss of fluorescence
intensity at the maximum wavelength indicates that most of the EB molecules have been
displaced from EB-DNA complex and that the intercalative binding takes place
between the investigated compound and DNA. The data of KSV present a Gd(III) hump
and the order that is not consistent with those of Kb determined by UV-Vis titration,
indicating that the interaction mechanism is determined not only by complex formation

Lanthanide hydrazone
2051
6
5
4
3
2
1
0
G
F
E
D
C
B
0
2
4
6
8
10
12
14
4f electron number of metal ions
Figure 4. Plots of KSV with 4f electron number of metal ions for Ln(III) complexes of Schiff bases B, C, D,
E, F, and G.
but also by some weak interactions [30]. DNA intercalators have been used extensively
as antitumor, antineoplastic, antimalarial, antibiotic, and antifungal agents [26]. There
is a criterion for screening out antitumor drugs from others by the DNA-EB fluorescent
tracer method, i.e., a compound may be used as a potential antitumor drug if it causes a
50% loss of DNA-EB fluorescence intensity by fluorescent titration before the molar
concentration ratio of the compound to DNA (nucleotides) does not exceed 100 : 1 [51].
FC50 is introduced to denote the molar concentration of a compound that causes 50%
loss in the fluorescence intensity of the EB-DNA system. According to the data of FC50
and the molar ratios of compounds to DNA (table 1), for FC50, all the molar
concentration ratios of the investigated compounds to DNA (1.583ꢁ11.45 : 1) are under
100 : 1, indicating that all these investigated compounds could be used as potential
antitumor drugs and the antitumor activities of Ln(III) complexes may be better than
that of ligand. However, their pharmacodynamical, pharmacological, and toxicological
properties should be further studied in vivo. Figure 4 shows the plots of KSV with 4f
electron number of metal ions for Ln(III) complexes of Schiff bases 8-hydroxyquino-
line-7-carbaldehyde-(isonicotinyl)hydrazone (B), 8-hydroxyquinoline-7-carbaldehyde-
(benzoyl)hydrazone (C), 8-hydroxyquinoline-2-carbaldehyde-(benzoyl)hydrazone (D),
8-hydroxyquinoline-2-carbaldehyde-(o-hydroxybenzoyl)hydrazone (E), 8-hydroxyqui-
noline-2-carbaldehyde-(p-hydroxybenzoyl)hydrazone (F), and 8-hydroxyquinoline-2-
carbaldehyde-(isonicotinyl)hydrazone (G). From this we can note that: (1) Ln(III)
complexes of ligand C have higher binding abilities to DNA than those of ligand B; (2)
the light rare-earth metal complexes of ligand D, E, and F present higher binding
abilities to DNA, especially for La(III) and Nd(III) complexes; (3) every plot of KSV has
a slight Gd(III) hump, which may be related to the 4f7 electron effect.
3.6. Scavenging activities for HO. and O2ꢁ
.
As shown in table 1, values of SC50 of ligand and Ln(III) complexes for HOꢂ are 143.1
and 2.344ꢁ13.33 mmol Lꢁ1, respectively. Scavenging effects of Ln(III) complexes for

2052
Y. Liu et al.
G
F
E
D
C
B
25
20
15
10
5
0
0
2
4
6
8
10 12 14
4f electron number of metal ions
Figure 5. Plots of SC50 (mmol Lꢁ1) of Ln(III) complexes of Schiff bases B, C, D, E, F, and G for OHꢂ with 4f
electron number of metal ions.
100
G
F
E
80
D
B
60
40
20
0
0
2
4
6
8
10 12 14
4f electron number of metal ions
.
Figure 6. Plots of SC50 (mmol Lꢁ1) of Ln(III) complexes of Schiff bases B, D, E, F, and G for Oꢁ2 with 4f
electron number of metal ions.
HO. are much higher than that of ligand, possibly in that the conjugated metal
complexes can react with HO. to form larger stable macromolecular radicals by typical
H-abstraction reaction [52]. Additionally, values of SC50 of ligand and Ln(III)
.
complexes for Oꢁ2 are 178.9 and 4.459ꢁ28.48 mmol Lꢁ1, respectively. Scavenging effects
.
of Ln(III) complexes and ligand for both HO. and O2ꢁ are much better than that of
ascorbic acid (standard anti-oxidative agents for non-enzymatic reaction), whose value
.
of SC50 for HO. is 1.537 mg mLꢁ1 (8.727 mmol Lꢁ1) and the value of SC50 for Oꢁ2 is
only 25% at 1.75 mg mLꢁ1 (9.94 mmol Lꢁ1) [53]. Figure 5 shows plots of SC50
(mmol Lꢁ1) of Ln(III) complexes of Schiff bases B, C, D, E, F, and G for OH. and
figure 6 shows the plots of SC50 (mmol Lꢁ1) of Ln(III) complexes of Schiff bases B, D,
.
E, F, and G for Oꢁ2 with 4f electron number of metal ions, respectively. The conclusions
are that: (1) La(III), Nd(III), Sm(III), and Ho(III) complexes and all the complexes of E

Lanthanide hydrazone
2053
and F, especially complexes of F, have stronger scavenging abilities for OH. , however,
.
the Eu(III) complexes of E and F have the lower scavenging abilities for Oꢁ2 ; (2)
Eu(III), Gd(III), Dy(III), Er(III), and Yb(III) complexes have weaker scavenging
abilities for OH. , especially complexes of D and G. However, almost all complexes of D
.
and G have stronger scavenging abilities for Oꢁ2 , especially complexes of G; (3) there
.
are different mechanisms for scavenging OH. and O2ꢁ . Furthermore, the scavenging
.
abilities for OH. and Oꢁ2 have no notable differences between these Ln(III) complexes
and those derived from 3-carbaldehyde chromone with isonicotinyl hydrazine and
PMFP with isonicotinyl hydrazine. Structurally, complex containing hydroxyl unit may
increase the scavenging abilities for OH. , while complex containing N-heteroaromatic
.
substituent shows stronger scavenging abilities for Oꢁ2 .
Acknowledgments
This study was supported by China NNSF (20975046) and Gansu Educational Fund
SRP (1010B-04).
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