Synthesis, characterization and DNA-binding properties of four Zn(II) complexes with bis(pyrrol-2-yl-methyleneamine) ligands

Article abstract of DOI:10.1016/j.bmcl.2007.10.085

A novel series of bis(pyrrol-2-yl-methyleneamine) ligands H₂Lⁿ (n = 1-4) were synthesized via condensation of diamines with two equivalents of 2-formyl-pyrrole (2). Their Zn(II) complexes were characterized by elemental analyses, mas

Full text of DOI:10.1016/j.bmcl.2007.10.085

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 298–303
Synthesis, characterization and DNA-binding properties of four
Zn(II) complexes with bis(pyrrol-2-yl-methyleneamine) ligands
Yuan Wang,a Zheng-Yin Yanga,* and Zhong-Ning Chenb
aCollege of Chemistry and Chemical Engineering and State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, PR China
bFujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China
Received 20 May 2007; revised 27 September 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—A novel series of bis(pyrrol-2-yl-methyleneamine) ligands H2Ln (n = 1–4) were synthesized via condensation of diamines
with two equivalents of 2-formyl-pyrrole (2). Their Zn(II) complexes were characterized by elemental analyses, mass spectra and IR
spectra. The crystal structures of [ZnL1]2 and [ZnL4]2 obtained from ethanol solution was determined by X-ray diffraction analysis,
each of them possesses a double-stranded helical geometry. In addition, the DNA-binding properties of the compounds have been
fully investigated by absorption, fluorescence and viscosity measurements.
ꢀ 2007 Elsevier Ltd. All rights reserved.
It is well known that DNA is an important cellular
receptor. The interaction of metal complexes with
DNA has recently gained much attention because it is
in close relationship with their potential biological and
pharmaceutical activity.1–5 Furthermore, the factors
that determine the affinity and selectivity in binding of
complexes to DNA would be valuable in the rational de-
sign of new diagnostic and therapeutic agents.6–8
few. These facts encouraged us to synthesize a novel ser-
ies of bis(pyrrol-2-yl-methyleneamine) ligands and their
Zn(II) complexes. In addition, the DNA-binding prop-
erties of all compounds were discussed in detail.
The ligands (H2Ln) were prepared as shown in Figure 1,
and were fully characterized by H NMR, MS and ele-
1
mental analysis (see Supplementary S1.1). Their Zn(II)
complexes were obtained from EtOH/H2O (1:1) solution
in the yields of 50–60% (see Supplementary S1.2). All
compounds, except for the complexes of H2L2 and
H2L3, are soluble in DMF, THF, and DMSO, slightly
soluble in methanol, ethanol, ethyl acetate, and acetone,
insoluble in water and ether. The elemental analyses
(Table 1) show that the formulas of the Zn(II) com-
plexes are [ZnLn]2 (n = 1–4).
The metal complexes of Schiff base bearing pyrrole units
have been extensively investigated for a long time.9,10
Most interesting research has been focused on macrocy-
cles, such as texaphyrins and expanded porphyrins,11–18
because they could stabilize mono- or binuclear metal
complexes which have various structures and special
properties. Due to the excellent fluorescent properties
and good solubilities of their complexes, linear spaced
bis(pyrrol-2-yl-methyleneamine) ligands have attracted
much recent attention through the work of Ma and his
co-workers.19–23 By varying the spacers between two
pyrrol-2-yl-methyleneamine units, dinuclear dimeric
helicates,19–22 trinuclear trimeric triangle19 and tetranu-
clear tetrameric square19 complexes have been gener-
ated. Yet it is noticed that the DNA-binding
investigations of such complexes have been relatively
Some main IR spectra data are listed in Table 1. The
free ligands exhibit bands of the mNH vibration at
3279–3317 cmÀ1, but they disappeared in the corre-
sponding complexes, showing that the nitrogen atoms
of the pyrrole rings take part in coordination and the
active H atoms are substituted by Zn(II) ions. The mC@N
bands of the ligands appear at 1617–1641 cmÀ1, they be-
come 1588–1597 cmÀ1 in the complexes, indicating that
the azomethine nitrogen atoms of the ligands should
coordinate to Zn(II) ions. It is also interesting that the
mC@O of the ester groups in the complexes (1693–
1700 cmÀ1) are higher than those in the ligands (1669–
1673 cmÀ1). This is probably due to the coordination be-
Keywords: Pyrrole; Complex; Schiff base; DNA-binding.
*
Corresponding author. Tel.: +86 931 8913515; fax: +86 931
8912582; e-mail: yangzy@lzu.edu.cn
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.085

Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 298–303
299
R
H2N
NH2
DMF, POCl3
O
O
CH2Cl2
N
H
N
H
OHC
O
O
(1)
(2)
R
O
O
N
H
C
N
H
CH
N
N
O
H
O
H2Ln
R=
;
;
;
;
n=
;
;
1
2
3
4
Figure 1. The preparation of the ligands.
Table 1. Elemental analyses and some main IR spectra data
Compound
C% (Cal)%
N% (Cal)%
H% (Cal)%
M% (Cal)%
IR data (cmÀ1
)
mNH
mC@O
mC@N
H2L1
63.43 (63.75)
54.68 (55.29)
64.29 (64.46)
55.76 (56.04)
66.00 (66.36)
58.64 (58.37)
67.30 (67.51)
58.79 (59.38)
12.96 (13.52)
11.13 (11.72)
12.73 (13.07)
11.51 (11.37)
12.34 (11.91)
10.31 (10.47)
12.25 (12.11)
10.15 (10.65)
6.91 (7.30)
5.41 (5.91)
7.20 (7.53)
6.34 (6.53)
7.93 (8.14)
7.31 (6.97)
6.71 (6.54)
4.92 (5.37)
3317
1672
1696
1667
1693
1669
1694
1673
1700
1639
1588
1638
1595
1641
1597
1617
1592
[ZnL1]2
H2L2
13.05 (13.68)
12.87 (13.27)
12.63 (12.22)
12.85 (12.43)
3296
3291
3279
[ZnL2]2
H2L3
[ZnL3]2
H2L4
[ZnL4]2
˚
tances of Zn–N span from 1.944(3) to 2.112(3) A. The
distance between two zinc centers is 4.389 A, which is
tween the nitrogen atoms of the pyrrole rings and Zn(II)
ions.
˚
a
longer than that of [ZnL ]2 (4.2 A). For [ZnL4]2, the
N–Zn–N angles range from 82.00(10)ꢁ to 147.31(11)ꢁ,
and the bond distances of Zn–N span from 1.964(2) to
22
˚
From the X-ray diffraction data given in Table 2, it can
be confirmed that the formulas of the Zn(II) complexes
with H2Ln are [ZnLn]2 (n = 1,4). The IR spectra indicate
that all complexes have similar structures. This means
that all Zn(II) complexes of H2Ln should be [ZnLn]2
(n = 1–4). As shown in Figure 2, the crystal structures
of [ZnL1]2 and [ZnL4]2 are similar. Each of them consists
of two unsymmetrical Zn(II) ions and each Zn(II)
ion binds to four nitrogen atoms from two ligands
with two covalent bonds and two coordination bonds,
and displays a distorted tetrahedral geometry. Their
molecular structures are similar to that of [ZnLa]2{H2
La = bis[3-ethyl-4-methyl-5-ethyloxy-carbonyl-pyrrol-2-
˚
2.101(2) A. The distance between two zinc centers is
b
3.588 A, which is somewhat shorter than that of [ZnL ]2
˚
19
˚
(3.7 A).
Because of their slight solubility in organic solvents, the
DNA-binding properties of [ZnL2]2 and [ZnL3]2 were
not measured. It is a general observation that varieties
in both the absorption spectra and the emission spectra
accompany the binding of molecules to DNA. The ex-
tent of spectral change is related to the strength of bind-
ing.1–7 Due to the obscure spectral changes (see
Supplementary data S2-4), the DNA-binding properties
of H2Ln (n = 1–3) were not discussed in this work. The
absorption and emission spectra of the other com-
pounds in the absence and presence of CT-DNA (at a
constant concentration of the compounds) are given in
Figures 4 and 5.
yl-methyleneamino]ethane}22
and
[ZnLb]2{H2Lb =
1,2-bis[3-ethyl-4-methyl-5-ethyloxy-carbonyl-pyrrol-2-
yl-methyleneamino]benzene}.19
X-ray analysis of [ZnLn]2 (n = 1, 4) also indicates that
each of them possesses a double-stranded helical geom-
etry (Fig. 3). The twist around the ethyl or phenyl bridge
divides the ligand into two pyrrol-2-yl-methyleneamine
subunits, each of which is bound to a different Zn(II)
ion. Selected bond lengths and angles are summarized
in Tables 3 and 4. For [ZnL1]2, the N–Zn–N angles
range from 82.42(9)ꢁ to 145.19(10), and the bond dis-
For [ZnL1]2 and H2L4, addition of increasing amounts
of CT-DNA (calf thymus DNA) results in observation
of weak hypochromicities in the absorption spectra,
indicating that [ZnL1]2 and H2L4 can bind to DNA. It
is generally accepted that the magnitude of both the

300
Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 298–303
Table 2. Crystal data and experimental data
[ZnL1]2
[ZnL4]2
Formula
C44H56N8O8Zn2
955.71
colorless
C52H56N8O8Zn2
1051.79
orange
Formula weight
Crystal color
Crystal size (mm)
Crystal system
Space group
Z
0.32 · 0.18 · 0.18
0.46 · 0.15 · 0.12
Monoclinic
P21/c
Monoclinic
P21/n
T (K)
˚
4
294 (2)
4
294 (2)
a (A)
˚
b (A)
˚
c (A)
20.899 (3)
14.918 (2)
14.4772 (7)
21.4823 (11)
16.3439 (8)
90.00
a (ꢁ)
b (ꢁ)
c (ꢁ)
14.787 (2)
90.00
90.00
90.00
92.655 (2)
90.00
5077.6 (4)
3
˚
V (A )
Dcalc (g cmÀ3
)
4610.3 (12)
1.377
˚
Radiation (A) (Mo Ka)
Reflections collected
Independent reflections (Rint
F(000)
0.71073
24,291
1.376
0.71073
)
8554 (0.0345)
2000
29,107
10,370 (0.0530)
Number of parameters refined
Final R indices [I > 2a (I)]
R indices (all data)
572
R1 = 0.0383, wR2 = 0.1086
R1 = 0.0649, wR2 = 0.1311
2192
653
R1 = 0.0464, wR2 = 0.0956
R1 = 0.0908, wR2 = 0.1145
Measurement
CCD area detector
Graphite
Monochromator
Structure determination
Refinement
SHELXS-97 and SHELXL-97
Full-matrix least-squares on F2
Figure 2. X-ray crystal structures of [ZnL1]2 (left) and [ZnL4]2 (right); H atoms are omitted for clarity.
red shift and hypochromism in the absorption spectra is
found to correlate with the strength of the intercalative
interaction.7 The hypochromicity is mostly attributed
to the interaction between the electronic states of the
compound chromophore and those of the DNA bases.
On the other hand, the red shift is associated with a de-
crease in the energy gap between the highest and the
lowest occupied molecular orbitals (HOMO and
LUMO) when the drug compound binds to DNA.24
The lack of the red shift suggests that the major binding
modes of both [ZnL1]2 and H2L4 with DNA are not clas-
sical intercalative interaction. However, for [ZnL4]2, the
prime three additions of increasing amounts of CT-
DNA result in hypochromicities, but the subsequent

Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 298–303
301
two result in hyperchromicity. It shows that there may
be two phases of binding between the [ZnL4]2 and
DNA.6,8 Since [ZnL4]2 contains phenyl ring in its ligand
structure, the spectral changes observed in the presence
of DNA may be rationalized in terms of partial interca-
lation and groove binding.25
In the emission spectra, for [ZnL1]2, with increasing CT-
DNA concentration the emission intensity is decreased
seriously, due to self-stacking of some free bases in the
compound along the DNA surface.26 According to the
classical Stern–Volumer equation, a plot of F0/F versus
[Q] gave the binding constant 1.866 · 106 MÀ1. How-
ever, for H2L4 and [ZnL4]2, upon addition of CT-
DNA, the notable emission intensity enhancement is ob-
served, indicating that a certain extent of partial interca-
lation should occur in the DNA-binding progress.7,27
According to the Scatchard equation, a plot of r/Cf
versus r from the fluorescence data gave the binding
constant 8.567 · 106 MÀ1 and 1.527 · 106 MÀ1, respec-
tively5 (see Supplementary S5). It is noticed that our
experimental Kb values are much higher than the tested
zinc complex ([Zn(Me-HctC)2(OH2)2]Æ4H2O 3.9 · 104;
[Zn(Ph-HctC)2(OH2)2]Æ4H2O, 8.1 · 103 in 5 mM Tris–
HCl/50 mM NaCl buffer, pH = 7.2)27 and comparable
with the classical intercalators (EB–DNA, 3.0 · 106 in
5 mM Tris–HCl/50 mM NaCl buffer, pH = 7.2).28 These
also indicate that such three compounds can bind to
DNA effectively.
Figure 3. Spacefill structures of [ZnL1]2 (left) and [ZnL4]2 (right).
1
˚
Table 3. Selected bond lengths [A] and angles [ꢁ] of [ZnL ]2
˚
Bond lengths [A]
Zn(1)–N(5)
Zn(1)–N(6)
Zn(1)–N(7)
Zn(1)–N(8)
1.955(2)
2.099(2)
2.110(2)
1.954(2)
Zn(2)–N(1)
Zn(2)–N(2)
Zn(2)–N(3)
Zn(2)–N(4)
2.112(3)
2.102(2)
1.964(3)
1.944(3)
Bond angles [ꢁ]
N(8)–Zn(1)–N(5) 145.19(10) N(4)–Zn(2)–N(3) 136.23(11)
N(8)–Zn(1)–N(6) 116.65(10) N(4)–Zn(2)–N(2) 125.98(11)
N(5)–Zn(1)–N(6) 82.80(10)
N(8)–Zn(1)–N(7) 82.42(9)
N(5)–Zn(1)–N(7) 119.38(9)
N(6)–Zn(1)–N(7) 110.42(9)
N(3)–Zn(2)–N(2) 82.50(11)
N(4)–Zn(2)–N(1) 82.64(11)
N(3)–Zn(2)–N(1) 117.15(10)
N(2)–Zn(2)–N(1) 115.56(9)
4
˚
Table 4. Selected bond lengths [A] and angles [ꢁ] of [ZnL ]2
The emission spectra of DNA–EB system upon the
addition of increasing amounts of the compounds were
measured (see Supplementary S6). It is well known that
EB can intercalate nonspecifically into DNA, which
causes it to fluoresce strongly. Competitive binding of
other drugs to DNA and EB will result in displacement
of bound EB and a decrease in the fluorescence inten-
sity. However, there are even no changes with increasing
compound concentrations in the spectra.7,8 This proba-
bly means that such three compounds bind to DNA not
via classical intercalative interaction.5–8 It is in accor-
dance with the results obtained from the absorption
and emission titration experiments.
˚
Bond lengths [A]
Zn(1)–N(4)
Zn(1)–N(8)
Zn(1)–N(6)
Zn(1)–N(2)
1.964(3)
1.967(3)
2.082(3)
2.101(2)
Zn(2)–N(7)
Zn(2)–N(3)
Zn(2)–N(1)
Zn(2)–N(5)
1.964(2)
1.965(3)
2.083(3)
2.092(3)
Bond angles [ꢁ]
N(4)–Zn(1)–N(8) 146.78(11) N(7)–Zn(2)–N(3) 147.31(11)
N(4)–Zn(1)–N(6) 110.55(11) N(7)–Zn(2)–N(1) 111.85(10)
N(8)–Zn(1)–N(6) 83.00(11)
N(4)–Zn(1)–N(2) 82.00(10)
N(3)–Zn(2)–N(1) 83.01(10)
N(7)–Zn(2)–N(5) 82.79(10)
N(8)–Zn(1)–N(2) 113.43(10) N(3)–Zn(2)–N(5) 111.42(10)
N(6)–Zn(1)–N(2) 129.42(10) N(1)–Zn(2)–N(5) 128.35(10)
a
b
c
0.5
0.2
0.1
0.0
1
5
4
2
0.5
0.0
3
0.0
300
400
300
400
300
400
Wavelength (nm)
Wavelength (nm)
Wavelength (nm)
Figure 4. (a) Electronic spectra of [ZnL1]2 (10 lM) in the presence of increasing amounts of CT-DNA. [CT-DNA] = 0–10 lM. Arrow shows the
absorbance changes upon increasing CT-DNA concentration. (b) Electronic spectra of H2L4 (10 lM) in the presence of increasing amounts of CT-
DNA. [CT-DNA] = 0.7.5 lM. Arrow shows the absorbance changes upon increasing CT-DNA concentration. (c) Electronic spectra of [ZnL4]2
(10 lM) in the presence of increasing amounts of CT-DNA. [CT-DNA] = 0–10 lM. Lines 1–5 show the absorbance changes upon increasing CT-
DNA concentration.

302
Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 298–303
Figure 5. (a) The emission decrease spectra of [ZnL1]2 (10 lM) in the presence of increasing amounts of CT-DNA. [CT-DNA] = 0–4 lM. Arrow
shows the emission intensity changes upon increasing CT-DNA concentration. (b) The emission enhancement spectra of H2L4 (10 lM) in the
presence of increasing amounts of CT-DNA. [CT-DNA] = 0.10 lM. Arrow shows the emission intensity changes upon increasing CT-DNA
concentration. (c) The emission enhancement spectra of [ZnL4]2 (10 lM) in the presence of increasing amounts of CT-DNA. [CT-DNA] = 0–20 lM.
Arrow shows the emission intensity changes upon increasing CT-DNA concentration.
number CCDC634595 (for [ZnL4]2) and 634596 (for
[ZnL1]2).
Acknowledgment
This project was supported by the National Natural sci-
ence Foundation in China (20475023).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.10.085.
Figure 6. Effect of increasing amounts of [ZnL1]2, H2L4, and [ZnL4]2
on the relative viscosity of CT-DNA at 25 ꢁC.
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