Structure and urease inhibitory activity of copper(II) complex with (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic acid

Article abstract of DOI:10.1134/S0022476617040229

A new caffeic acid derivative ((E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic acid, HL¹)) is synthesized from caffeic acid, followed by the preparation of a Cu(II) complex, [Cu₂(L¹)₄DMSO₂]·2DMSO.

Full text of DOI:10.1134/S0022476617040229

Journal of Structural Chemistry. Vol. 58, No. 4, pp. 797-803, 2017.
Original Russian Text © 2017 X.-F. Chen, C.-F. Wang, S. Kong, C. Li, X. Zhou, C.-Y. Zhang, G.-H. Sheng, H.-L. Zhu.
STRUCTURE AND UREASE INHIBITORY
ACTIVITY OF COPPER(II) COMPLEX WITH (E)-
3-(2,3-DIHYDROBENZO[b][1,4]DIOXIN-6-yl)ACRYLIC ACID
X.-F. Chen, C.-F. Wang, S. Kong, C. Li, X. Zhou,
C.-Y. Zhang, G.-H. Sheng, and H.-L. Zhu*
UDC 548.73:541.49:546:546.562
1
A new caffeic acid derivative ((E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic acid, HL )) is
1
synthesized from caffeic acid, followed by the preparation of a Cu(II) complex, [Cu2(L )4DMSO2]⋅2DMSO.
The structure is determined by single crystal X-ray diffraction, and the urease inhibitory activity of the
complex is studied. The results show that IC50 of the complex is 0.56 μmol/L, which is superior to positive
control acetohydroxamic acid (AHA, IC50 was 10.95 μmol/l), i.e., the complex has strong inhibitory
activity towards urease.
DOI: 10.1134/S0022476617040229
Keywords: caffeic acid, copper(II) complex, crystal structure, urease inhibitory.
INTRODUCTION
Urease (urea amidohydrolase; E.C.3.5.1.5) is a nickel-containing metalloenzyme that rapidly catalyzes the
hydrolysis of urea to form ammonia and carbamate [1, 2]. Urease is widely distributed in a variety of algae, bacteria, fungi,
and plants. The reaction catalyzed by urease may cause an accumulation of ammonia and accompanying pH elevation, which
has important negative implications in medicine and agriculture [3-6]. The gram-negative bacterium Helicobacter pylori is
associated with severe gastric pathologies, including peptic ulcer, chronic active gastritis and gastric cancer. This
microorganism is able to invade and colonize human stomach, directly interacting with gastric epithelial cells mainly because
of its high urease activity. Already in 1994, H.pylori was classified as a type I carcinogen for humans by the IARC/WHO [7].
Urease inhibitors have a very important status in the treatment of the infections caused by urease producing bacteria [8].
There are many different kinds of urease inhibitors but they usually have strong side effects [9]. Therefore, it is necessary to
search for new urease inhibitors with low toxicity and good bioavailability. Transition metals have biological activity in many
biochemical processes [10]. Generally used transition metals include cobalt, zinc, nickel, copper etc. They act as cofactors in
some important enzymatic and organ functions, resulting in increased activities of these enzymes [11]. Complexes can
effectively reduce the side effects of the transition metal, and have become a hot spot in research. In recent years, some metal
complexes have been reported to show anticancer [12-16] and urease inhibitory activity [17-21].
Caffeic acid is an important natural antioxidant [22, 23], and has been widely applied in food, pharmaceuticals, and
cosmetics industries due to its biological or physiological activity as antioxidant [24], antitumor agent [25], antibiotic [26],
School of Life Sciences, Shandong University of Technology, P. R. China; *hailiang_zhu@163.com. The text was
submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 58, No. 4, pp. 827-833, July-August, 2017. Original
article submitted July 7, 2016.
0022-4766/17/5804-0797 © 2017 by Pleiades Publishing, Ltd.
797

and so on. However, caffeic acid has low solubility and stability in common solvent systems, which limits its application.
Caffeic acid derivatives can increase its solubility in hydrophobic media. The action of caffeic acid and its derivatives is
multiple, including removal of free radicals, metal ion chelating, inhibition of special enzyme ACTS to reduce the formation
of free radicals and lipid peroxide [27, 28]. Therefore, it acts as antioxidant to prevent the oxidation of fat and oily food
spoilage, and peroxide damage and disease, such as cancer, diabetes, coronary heart disease, etc [29]. Thus, study of caffeic
acid and its derivatives for food and other fields is important.
In this paper, we report the synthesis of a caffeic acid derivative ((E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic
acid) and a new Cu(II) complex with this derivative as ligand as well as its urease inhibitory activity.
EXPERIMENTAL
General methods and materials. Unless otherwise stated, all solvents were of reagent grade quality and purchased
commercially. All chemicals were also commercially available and used without further purification. Elemental analyses
were performed on a Perkin-Elmer 240C elemental analyzer.
1
1
Synthesis of HL ((E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic acid). HL was synthesized from caffeic
acid and 1,2-dibromoethane (Scheme 1). The steps from caffeic acid to sodium (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)acrylate acid include esterification, cyclization, hydrolysis and acid precipitation.
1
Scheme 1. Synthesis of the ligand HL . Reagents and
conditions: (a) MeOH, H2SO4, reflux, 8 h; (b)
Br(CH2)2Br, K2CO3, acetone, reflux, 24 h; (c) NaOH,
H2O, reflux, 12 h; (d) HCL, washing, drying
For etherification, caffeic acid (0.25 mol, 45 g) was dissolved in methanol (350 ml) with stirring, in the presence of
concentrated sulfuric acid as catalyst. The mixture was stirred for about 20 h at 63 °C to produce a clear solution. The
solution was poured into 400 ml ethyl acetate and 200 ml water. The ethyl acetate was evaporated to give yellow powdered
caffeic acid methyl ester.
Caffeic acid methyl ester (0.02 mol, 3.88 g) and 1,2-dibromoethane (0.06 mol, 5.2 ml) were dissolved in acetone
(100 ml) with stirring, using K2CO3 (0.06 mol, 8.28 g) as acid binding agent. The mixture was stirred at 56 °C. After the
reaction had been completed, the insoluble substance was removed by filtration, the solvent was evaporated to leave a brown
oily matter. The oily matter was stirred for about 20 h at 80 °C in the presence of NaOH (0.12 mol, 4.8 g) and H2O (100 ml).
The oily matter dissolved to give to a brown solution. The pH value of solution was adjusted to 1 and free acid precipitated.
The white precipitate was isolated by filtration and washed with H2O until the pH reached the value of 7.0, then dried. The
1
white powder was the (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic ligand (HL ). After keeping it in the methanol
798

1
solution for 7 days, colorless block shaped single crystals of HL suitable for structure determination were obtained at the
bottom of the vessel. Yield 74%. Anal. Calc. for C11H10O4: C 64.08, H 4.85, O 31.07%. Found: C 64.03, H 4.77, O 31.02%.
1
Preparation of [Cu (L ) DMSO ]⋅2DMSO. The complex was prepared by addition of a water solution (10 ml) of
2
4
2
(E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic acid (2 mmol, 0.412 g) to a water solution (10 ml) of NaOH (2 mmol,
0.08 g) followed by addition of CuSO4 (1 mmol, 0.16 g). After stirring for 1 h at room temperature, the solution was filtered
to leave a green precipitate. It was dissolved in a minimal volume of DMSO. Keeping the solution in a refrigerator (4 °C) for
15 days yielded green block-shaped single crystals of the complex suitable for the structure determination at the bottom of the
vessel. Crystals were isolated by filtration and washed with cold H2O and then dried. Yield 75%. Anal. Calc. for
C52H60Cu2O20S4: C 49.55, H 4.80, O 25.39%. Found: C 49.51, H 4.68, O 25.32%.
Crystal structure determination. Single crystal X-ray diffraction data were collected at 150(2) K on a Nonius
Kappa CCD diffractometer with graphite monochromated MoK radiation (λ = 0.71073 Å). The data were processed by
α
using DENZO [30]. The structure was solved by direct methods implemented in SIR-97 [31] and refined by a full-matrix
2
least squares procedure based on F with SHELXL-97 [32]. All of atoms were refined anisotropically except the hydrogen
atom. Hydrogen atoms bound to O were first found in the Fourier map and then fixed at their ideal positions. The detailed
crystallographic data were summarized in Table 1.
Measurement of inhibitory activity against jack bean urease. Jack bean urease was purchased from Sigma-
Aldrich Co. (St. Louis, MO, USA). The measurement of urease activity was carried out according to the literature [33, 34].
Generally, the assay mixture, containing 25 μl of jack bean urease (10 kU/l) and 25 μl of the tested samples (complex, also
the parent ligands and metal salts) of various concentrations (dissolved in DMSO:H2O = 1:1 (v:v)), was pre-incubated for 1 h
at 37 °C in a 96-well assay plate. After preincubation, 200 μl of 100 mM HEPES (N-[2-hydroxyethyl] piperazine-N′-[2-
ethanesulfonic acid]) buffer pH = 6.8 containing 500 mM urea and 0.002% phenol red, was added and incubated at 37 °C
1 1
TABLE 1. Experimental Data for Crystal Structure of HL and [Cu2(L )4DMSO2]⋅2DMSO
1
1
[Cu2(L )4DMSO2]⋅2DMSO
Crystallographic parameter
HL
Molecular formula
Molecular weight
Temperature, K
Radiation λ, Å
Crystal system
Space group
C11H10O4
206.19
293
C48H48Cu2O18S2, 2(C2H6OS)
1260.38
273
MoK (0.7107)
α
MoK (0.7107)
α
Monoclinic
Triclinic
C2/c
P-1
a, b, c, Å
23.2671(17), 11.6009(8), 7.5005(6) 14.3915(11), 14.7299(11), 16.8817(13)
108.044(2), 107.509(2), 90.116(2)
α, β, γ, deg.
β 102.473(3)
1976.8(3)
3
V, Å
3227.1(4)
2
Z
8
3
Dc, g/cm
1.386
1.297
Crystal size, mm
F(000)
0.20×0.18×0.16
864
0.30×0.28×0.26
1308
3.2-25.1
2.2-25.2
θ range, deg.
Reflections collected / unique
Refns obs. I >2σ(I)
9222 / 1763 [Rint = 0.045]
1088
31099 / 11536 [Rint = 0.047]
7264
2
Goodness of fit on F
1.024
1.113
Data / restraints / parameters
1763 / 7 / 182
0.131 and –0.172
0.0485, 0.1070
0.0963, 0.1262
11536 / 494 / 703
1.630 and –0.921
0.0789, 0.2294
0.1298, 0.2552
3
Largest diff. peak and hole, e/Å
a
R1, wR2 [I >2σ(I)]
a
R1, wR2 (all data)
799

[35]. The reaction time was measured by microplate reader (570 nm), which was required to produce enough ammonium
carbonate to raise the pH of a HEPES buffer from 6.8 to 7.7, the endpoint being determined by the color of phenol red
indicator [36].
RESULTS AND DISCUSSION
1
Crystal structure of HL and complex. The crystal structure of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic
1
acid is shown in Fig. 1, and experimental data for crystal structure of HL and complex are listed in Table 1. The crystal
1
structure of the Cu(II) complex is shown in Fig. 2. Selected bond distances (Å) and angles (deg.) for HL and the complex are
collected in Table 2.
1
Complex [Cu2(L )4DMSO2]⋅2DMSO crystallizes in a triclinic space group P-1. The perspective view of the crystal
1
structures of the complex is shown in Fig. 2. Each molecule consists of two copper ions, four L anions, and four dimethyl
1
sulfoxide molecules. Each copper ion is five-coordinated with four O atoms of L and one O atom of DMSO in a square
pyramidal arrangement (τ = 0.0002 for Cu1 and Cu1A), thus forming a [CuO5] chromophore. Two copper ions are linked
1
1
together by four bridging bidentate carboxylic groups of four L . Four O atoms of four L anions form the basal plane and
one O atom of DMSO is in the axial position. The in-plane Cu–O bond distances average 2.05 Å and axial Cu–O bond
distances 2.139 Å, which are in the normal range (Fig. 2 and Table 2).
Inhibitory activity against jack bean urease. Inhibition of urease by the tested materials is shown in Table 3.
Fig. 1.
Crystal
structure
of
(E)-3-(2,3-
acid
dihydrobenzo[b][1,4]dioxin-6-yl)acrylic
1
(HL ).
1
Fig. 2. Crystal structure of [Cu2(L )4DMSO2]⋅2DMSO.
800

1 1
TABLE 2. Selected Bond Distances (Å) and Angles (deg.) for HL and [Cu2(L )4DMSO2]⋅2DMSO
1
HL
O(1)–C(7)
C(1)–O(3)
1.371(2)
1.274(19)
1.430(15)
1.429(2)
0.9300
O(1)–C(8)
C(1)–O(4)
1.434(2)
1.327(12)
1.366(2)
1.308(13)
1.571(8)
0.8200
C(1)–C(2)
O(2)–C(10)
O(2)–C(9)
C(2)–C(3)
C(2)–H(2A)
C(3)–C(4)
C(3)–H(3A)
0.9300
O(3)–H(3B)
C(4)–C(11)
1.377(3)
1.368(3)
1.375(3)
1.384(3)
1.371(3)
113.06(16)
124.2(11)
112.77(16)
121.4(7)
107.4(4)
121.0(2)
118.49(19)
119.10(19)
110.74(17)
122.09(17)
C(4)–C(5)
1.385(3)
0.9300
C(5)–C(6)
C(5)–H(5)
C(6)–C(7)
C(6)–H(6)
0.9300
C(7)–C(10)
C(8)–C(9)
1.474(3)
120.4(12)
115.4(11)
120.4(7)
117.6(2)
135.0(4)
120.7(2)
122.41(17)
110.76(18)
118.44(18)
119.47(18)
122.1(2)
C(10)–C(11)
C(7)–O(1)–C(8)
O(3)–C(1)–C(2)
C(10)–O(2)–C(9)
C(2)–C(3)–C(4)
C(11)–C(4)–C(3)
C(6)–C(5)–C(4)
O(1)–C(7)–C(6)
C(6)–C(7)–C(10)
O(2)–C(9)–C(8)
O(2)–C(10)–C(7)
O(3)–C(1)–O(4)
O(4)–C(1)–C(2)
C(3)–C(2)–C(1)
C(11)–C(4)–C(5)
C(5)–C(4)–C(3)
C(5)–C(6)–C(7)
O(1)–C(7)–C(10)
O(1)–C(8)–C(9)
O(2)–C(10)–C(11)
C(11)–C(10)–C(7)
C(10)–C(11)–C(4)
Complex
Cu(1)–O(6)
Cu(1)–O(9)
1.956(4)
1.967(4)
Cu(1)–O(16)
Cu(1)–O(18)
1.965(4)
2.152(4)
1.950(4)
2.139(4)
2.6211(12)
1.967(4)
1.967(4)
88.0(2)
Cu(2)–O(3)
1.942(4)
Cu(2)–O(13)
Cu(2)–O(12)
1.972(4)
Cu(2)–O(17)
Cu(1)–O(15)#1
1.961(4)
Cu(1)–Cu(1)#1
O(15)–Cu(1)#1
1.961(4)
Cu(2)–O(14)#2
Cu(2)–Cu(2)#2
2.6286(13)
168.19(19)
90.34(19)
95.30(19)
89.14(16)
168.87(16)
95.75(17)
169.04(16)
90.93(16)
85.73(12)
84.38(12)
178.29(12)
90.26(19)
168.65(17)
83.53(14)
85.65(12)
O(14)–Cu(2)#2
O(3)–Cu(2)–O(13)
O(13)–Cu(2)–O(12)
O(13)–Cu(2)–O(17)
O(6)–Cu(1)–O(16)
O(16)–Cu(1)–O(9)
O(16)–Cu(1)–O(18)
O(6)–Cu(1)–O(15)#1
O(15)#1–Cu(1)–O(9)
O(6)–Cu(1)–Cu(1)#1
O(16)–Cu(1)–Cu(1)#1
O(18)–Cu(1)–Cu(1)#1
O(3)–Cu(2)–O(14)#2
O(14)#2–Cu(2)–O(12)
O(3)–Cu(2)–Cu(2)#2
O(14)#2–Cu(2)–Cu(2)#2
O(3)–Cu(2)–O(12)
O(3)–Cu(2)–O(17)
O(12)–Cu(2)–O(17)
O(6)–Cu(1)–O(9)
O(6)–Cu(1)–O(18)
O(9)–Cu(1)–O(18)
O(15)#1–Cu(1)–O(16)
O(15)#1–Cu(1)–O(18)
96.51(19)
99.51(16)
88.72(17)
95.98(16)
95.33(17)
89.10(16)
94.96(16)
83.33(11)
84.57(12)
89.0(2)
O(15)#1–Cu(1)–Cu(1)#1
O(9)–Cu(1)–Cu(1)#1
O(13)–Cu(2)–O(14)#2
O(17)–Cu(2)–Cu(2)#2
O(14)#2–Cu(2)–O(17)
O(13)–Cu(2)–Cu(2)#2
O(12)–Cu(2)–Cu(2)#2
177.48(12)
91.83(16)
84.67(14)
83.00(12)
801

TABLE 3. Inhibition of Urease by the Tested Materials
Tested materials
Tested materials
IC50, μmol/l
IC50, μmol/l
1
[Cu2(L )4DMSO2]⋅2DMSO
DMSO
>100
1.99
0.56
AHA
10.95
CuSO4⋅6H2O
1
HL
>100
1
The HL , AHA, CuSO4⋅6H2O and the complex were evaluated for inhibitory activity against jack bean urease by the
1
phenol red method. The results are summarized in Table 3. The IC50 value of HL was >100 μM. The IC50 value of the
CuSO4⋅6H2O was 1.99 μM. Under the same conditions, the IC50 of the complex was 0.56 μM, which is better than positive
control AHA 10.95 μM and CuSO4⋅6H2O 1.99 μM. The results of the urease test showed that the complex had obvious
inhibitory activity against urease. This offers some hope for the complex to be developed as a drug to treat diseases caused by
H.pylori.
1
UV-Vis and IR spectra. The UV-Vis spectra for the complex and HL on TU-1801 were obtained in assay
1
conditions (DMSO). The electronic spectra of the complex and HL show intense UV band near 300 nm. In the visible
region, one low-intensity band is observed for the complex in the region 650-800 nm assigned to d–d transitions.
1
The IR spectra of the complex on Nicolet 5700 are compared with the HL in order to determine the coordination
sites that may be involved in coordination complex. The important IR bands with their tentative assignments are depicted as
1
follow. Some important calculated and experimental stretching vibrational frequencies of the HL and complex are listed in
–1
supplementary material. The medium band at 2986.5 cm is attributed to the ν(OH) vibration of the ligands. In the complex the
–1
ν(OH) vibration disappears. The characteristic bands of the carboxylate anions have typical ν(OCO)asym {1582.2 cm in
–1
complex} and ν(OCO)sym {1399.7 cm in complex} values. The calculated Δ(OCO) values {ν(OCO)asym – ν(OCO)sym} are
–1
182.5 cm as typical of bidentate/bridging carboxylate.
CONCLUSIONS
A new Cu(II) complex was synthesized with the (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic as first ligand,
DMSO as the second ligand. The complex exhibit urease inhibitory activity higher than that shown by the parent ligand and
2+
2+
Cu ion separately. The activity is probably due to synergy between strong Lewis acid properties of Cu and the ligands.
Crystallographic data for the structural analysis has been deposited with the Cambridge Crystallographic Data
Centre (CCDC-1446504 for (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylic acid and CCDC-1415174 for complex).
These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or www:http://www.ccdc.cam.ac.uk).
We thank the financial support from National Natural Science Foundation of China (Grant No. 31200090),
Scientific Research Foundation for Returned Scholars, Ministry of Education of China and National College Students′
Innovative and Entrepreneurial Training Plan of China (Grant No. 201410433033), by the Projects (nos CXY1409) from the
Science & Technology Bureau of Lianyungang City of Jiangsu Province.
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