New class of potent antitumor acylhydrazone derivatives containing furan

Article abstract of DOI:10.1016/j.ejmech.2010.09.007

A pair of chemical isomeric structures of N-acylhydrazone compounds I and II were designed and synthesized. The reaction was carried out with high diastereoselectivity to obtain one configurational isomer in excellent yields. The exact configuration and conformation of IIa and IIe were confirmed by the X-ray single crystal diffraction. The antitumor bioassay revealed that some compounds exhibited excellent activity against the selected cancer cell lines. In particular, IIf (IC₅₀ = 16.4 μM) was better than doxorubicin (IC₅₀ = 53.3 μM) against human promyelocytic leukemic cells (HL-60). Their toxicities were predicted in silico. The results showed that compounds II were safe and eligible to be development candidates. IIf showed great promise as a novel lead compound for further anticancer discovery.

Full text of DOI:10.1016/j.ejmech.2010.09.007

European Journal of Medicinal Chemistry 45 (2010) 5576e5584
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
New class of potent antitumor acylhydrazone derivatives containing furan
,
Zining Cui a, Ying Li a, Yun Ling a, Juan Huang a, Jingrong Cui b, Ruiqing Wang b, Xinling Yang a
*
a Key Laboratory of Pesticide Chemistry and Application, Ministry of Agriculture, Department of Applied Chemistry, College of Science, China Agricultural University,
Beijing 100193, People’s Republic of China
b State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Science, Peking University, Beijing 100083, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A pair of chemical isomeric structures of N-acylhydrazone compounds I and II were designed and
synthesized. The reaction was carried out with high diastereoselectivity to obtain one configurational
isomer in excellent yields. The exact configuration and conformation of IIa and IIe were confirmed by the
X-ray single crystal diffraction. The antitumor bioassay revealed that some compounds exhibited
Received 11 May 2010
Received in revised form
2 September 2010
Accepted 2 September 2010
Available online 17 September 2010
excellent activity against the selected cancer cell lines. In particular, IIf (IC50 ¼ 16.4
mM) was better than
M) against human promyelocytic leukemic cells (HL-60). Their toxicities were
doxorubicin (IC50 ¼ 53.3
m
predicted in silico. The results showed that compounds II were safe and eligible to be development
candidates. IIf showed great promise as a novel lead compound for further anticancer discovery.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Acylhydrazone
Synthesis
Antitumor activity
Configurational isomer
Toxicity
1. Introduction
found in nature. These furan derivatives show broad-spectrum
pharmacological properties [30e32]. In our previous work, many
Recently metal ion chelation therapy [1e9] has attracted much
attention. Many in vitro studies as well as clinical trials have
revealed that some tumors, particularly leukemia and neuroblas-
toma are sensitive to metal ion chelation therapy. Tumor cells are
more susceptible than normal cells to ion chelators as shown with
the clinically used chelator desferrioxamine (DFO) [10e15] (Fig. 1).
However, DFO suffers some disadvantages, such as high cost,
a short plasma half-life, limited membrane permeability and poor
absorption from the gut, which has led to poor antitumor activity
[16]. In order to overcome these issues, it is necessary to develop
new compounds with more favorable characteristics.
As ligands with metal ions, hydrazone and acylhydrazone
moieties possess a wide range of excellent coordination properties
[17e20]. Some compounds, such as 1 [21], 2 [22], 3 [23] and 4 [6]
(Fig. 2), exhibited a variety of valuable biological effects [24e26],
especially as multidentate ligands to prevent proliferation of cancer
cells.
compounds containing this moiety were synthesized, in which the
bridge linkage (X) was modified with ureide, acylhydrazine, and
carbamic acid ester to obtain 5 [33], 6 [34], and 7 [35] (Scheme 1)
respectively. Bioassays indicated that the compounds with different
bridge linkages (X) showed different activities. For example, 5 had
insecticidal activity, 6 showed antitumor activity and 7 possessed
fungicidal activity. In the present work, structure optimization was
carried out by converting the bridge linkage to acylhydrazone
(Scheme 1). For the purpose of discovering novel lead compounds
with antitumor bioactivity, a pair of chemical isomeric structures of
N-acylhydrazone compounds I and II were designed and synthe-
sized by the route shown in Scheme 2. Their anticancer activity was
evaluated and their toxicity was predicted by in silico methods to
determine whether or not the title compounds were safe and
eligible to be lead compounds.
2. Results and discussion
Furan rings are electron-rich systems amenable to being good
ligands with metal ions [27e29]. It has been reported that deriva-
tives of furan substituted at the 2- and 5-positions are frequently
2.1. Synthesis
The synthetic route of compounds I and II is shown in Scheme 2.
Compounds of type I were obtained from starting materials of
substituted anilines and benzoic acid. The key intermediates 9 were
prepared from substituted aniline with furfural by the Meerwein
* Corresponding author. Tel./fax: þ86 10 62732223.
E-mail address: yangxl@cau.edu.cn (X. Yang).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.09.007

Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
5577
2.2. Crystallography
The single crystals of the target compounds IIa and IIe were
cultured for the X-ray diffractions to define the configuration. Their
crystal data are presented in Table 5. Their perspective views with
the atomic labeling system are shown in Figs. 5 and 6. Both IIa and
IIe are the E-isomers.
The conformation between the double bond in the furan ring
and the conjoint carbonyl group in IIa and IIe was different. IIa was
in the s-cis conformation and IIe was in the s-trans conformation. In
Fig. 7 the intermolecular hydrogen bonds between the target
compound IIa gave the s-cis conformation and via hydrogen bonds
led to infinite extending in the a-axis in the crystal lattice. Fig. 7
suggested that IIa possessed a dimer structure mode.
Fig. 8 shows the formation of a hydrogen bond between the
carbonyl group and the solvent methanol resulting in different
stabilization of the s-trans isomer. Two molecules of IIe were linked
by methanol via hydrogen bonds, which led to infinite extending in
the a-axis in the crystal lattice. The existence of the hydrogen bonds
can stabilize the pack of the crystal to form the single crystal. If the
methanol was replaced with other solvents (lower polarity and lack
of active hydrogen as the hydrogen bond donor, such as ethyl
acetate or ethyl ether), the single crystal could not be obtained.
Fig. 1. Chemical structure of the iron chelator desferrioxamine (DFO).
arylation reaction. All type I compounds were finally synthesized
by the condensation of substituted phenyl hydrazine 8 with
5-substituted phenyl-2-furfural 9 using acetic acid as the catalyst.
In general, the condensation yields of the products were more than
90% as detected by HPLC (Table 1). By the same procedure as that of
I, compounds of type II were obtained in higher yields of more than
95%. HPLC analysis (Table 1, Fig. 3 and Fig. 4) of the target
compounds indicated that the condensation reaction was highly
diastereoselective with only one isomer in excellent yields.
The structures of all the compounds were characterized by 1H
NMR, IR, UV and elemental analyses. In the IR spectra, the com-
pounds showed absorption bands around 3400 cmꢀ1 originating
from the NeH stretching vibration. The bands between 1690 and
1630 cmꢀ1 could be assigned to the C]N stretching vibration. The
strong bands around 1650 cmꢀ1 were carbonyl vibrations of the
secondary amide. Absorption bands around 1610, 1520 and
1480 cmꢀ1 were attributed to the frame vibration of the phenyl and
furan ring.
2.3. Bioassay
Compounds Id, If, IIa, IId, and IIf exhibited better antitumor
activity than the others in the preliminary test (Table 2). The IC50
values of these five compounds are shown in Table 3, in which the
In the 1H NMR spectrum, one sharp peak from 11.50 to
12.20 ppm was due to the presence of the proton in secondary
amide NH. Another sharp peak from 8.30 to 8.95 ppm was due to
the proton in the imine N]CH in the Schiff base. Mostly, the protons
on phenyl rings were split into multiple peaks from 7.10 to 8.30 ppm
and the protons on the furan ring were split into a doublet from 6.92
to 7.40 ppm. The splits of most compounds were normal, except for
the compounds with fluorine substitution, because of the coupling
and splitting between fluorine and hydrogen. The fluorine atom
splits a hydrogen proton into a doublet, which complicated the
signal. For example, one of the protons on the furan ring was split
into a triplet when the fluorine atom existed nearby.
Karabatsos et al. [36e38] reported that the presence of the
singlet signals related to the imine hydrogen was differently
attributed to the respective (E) and (Z)-diastereomers. The imine-
attached hydrogen signal of the (E)-diastereomer is downfielded by
0.2e0.3 ppm from the corresponding hydrogen atom signal in the
(Z)-diastereomer. The 1H NMR spectra of the title compound indi-
cated that only one isomer was obtained. However, its configura-
tion could not be determined according to the present 1H NMR
spectra since the different substituted groups in the benzene ring
lead to different effects on the shift of the imine hydrogen, which
caused different results from that of Karabatsos. Thus, an alterna-
tive method was necessary to unambiguously characterize the
geometry of the isomer and assure the relative configuration of the
imine double bond of acylhydrazone derivatives.
activity of IIf (IC50 ¼ 16.4
mM) was better than that of the doxoru-
M) to human promyelocytic leukemic cells (HL-
bicin (IC50 ¼ 53.3
m
60). IIf exhibited good activity against the solid human gastric
carcinoma cells (BGC-823) and human hepatocellular carcinoma
cells (Bel-7402). Its activity against BGC-823 (IC50 ¼ 9.6
Bel-7402 (IC50 ¼ 8.3 M) was close to that of doxorubicin (IC50 ¼ 4.8
and 5.0 M). Id also had good activity against BGC-823
(IC50 ¼ 9.5 M). However, the activity of these five compounds
mM) and
m
m
m
against human nasopharyngeal carcinoma cells (KB) was poor.
The preliminary structureeactivity relationship analysis indi-
cated that compounds in which the R1 was 2-hydroxyl (Id, If, IId,
and IIf) or 2-methoxyl (II e) group, showed better activity than the
others. The oxygen atom on the ortho-position might play an
important role on the chelation of ion combined with the nitrogen
atoms of imine and carbonyl amide to form bidentate or tridentate
ligands. The oxygen atom should make the coordination mode
more favorable for bioactivity.
2.4. Prediction of toxicity
The discovery of novel chemical agents with good biological
activity together with reduced mammalian toxicity is a difficult
process and it is essential that an indication of the toxicity of
selected compounds is established as rapidly as possible. Predictive
in silico methods have been shown to be a useful tool for the
generation of this information at a relatively low cost.
Fig. 2. Chemical structures of the iron chelators containing hydrazone moieties: di-2-pyridylketone isonicotinoyl hydrazone (HPKIH), 2-hydroxy-1-naphthaldehyde isonicotinoyl
hydrazone (NIH), di-2-pyridylketone thiobenzoyl hydrazone (HPKTBH) and 4-phenyl-1-(di(pyridin-2-yl)methylene) thiosemicarbazide (HDp4pT).

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Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
Scheme 1. Design strategy for compounds I and II.
All the predicted values of title compounds are listed in Table 4.
values of compounds I were less than 0.65, suggesting potential
carcinogenic toxicity.
For the carcinogenic toxicity, when the predicted value is more than
70%, and the value of CIP (Carcinogenic Impossibility) is more than
0.65, meanwhile its CIP value is greater than CP (Carcinogenic
Possibility), the compound is considered as non-carcinogenic.
Otherwise, they were considered to be carcinogenic. For the
mutagenic toxicity, if the predictability value was more than 70%
and its MIP (Mutagenic Impossibility) value was greater than the
MP (Mutagenic Possibility), the compound was considered as non-
mutagenic. Otherwise, they were considered to be mutagenic.
Based on the results in Table 4, the carcinogenic toxicity data of
compounds II were from 93% to 95% and their CIP values were from
0.849 to 0.951, much higher than their CP values of 0.001. The
mutagenic toxicity data of compounds II were from 97% to 98% and
their MIP values were from 0.630 to 0.950, much higher than the
MP values of 0.01. Thus, compounds II were considered to be low
carcinogenic toxicity and mutagenic toxicity. The results indicated
that IIf was safe and could be regarded as a candidate for further
study. Unfortunately, according to the judgement standard, the CIP
3. Conclusion
In summary, a pair of isomeric structures were designed and
synthesized. A single configurational isomer of each of the target
compounds was obtained through a highly diastereoselective reac-
tion. In general, the yields of the target compounds were more than
95%. The exact structures of IIa and IIe were confirmed by the X-ray
single crystal diffraction. Both of them had the E-configuration about
the C]N bond. The conformation about the single bond of the furan
arene-carbonyl system in IIa was s-cis and in IIe was s-trans. The
antitumor activity showed that some of the compounds exhibited
excellent activity against the selected cancer cell lines compared to
the positive control doxorubicin. The activity of IIf against human
promyelocytic leukemic cells (HL-60) was better than that of doxo-
rubicin. The predictive toxicity results showed that IIf was safe and
eligible to be a lead compound for further development.
Scheme 2. The synthetic routes of compounds I and II.

Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
5579
Table 1
Yield and retention time analyses of I and II by HPLC.
Compd.
R1
R2
Yield/%
Rfa (min)
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
2-OCH3
4-Br
4-Cl
2-OH
H
2-OH
3-CH3
4-Br
2-OCH3
4-Br
4-Cl
2-OH
H
2-OH
3-CH3
2-Cl
2.4-2F
2-Cl
2-F
92.02
98.58
99.75
96.66
96.04
99.68
98.87
81.80
99.33
95.99
98.09
98.50
98.21
99.71
98.73
98.87
98.80
98.71
7.629
3.468
3.146
2.859
3.024
3.068
2.754
3.127
3.272
3.678
3.415
7.051
3.225
9.374
2.86
4-F
4-Cl
2.4-2F
2-NO2
3-F
2.4-2F
2-Cl
2-F
4-F
4-Cl
2.4-2F
2-NO2
4-F
4-F
2-F
3.304
2.668
3.433
4-OH
3-Br
a
Retention factor was determined by HPLC by using a Rexchrom 5 lm RP-18
column (125 ꢁ 4.6 mm) and a mixture of methanolewater (9:1 v/v) as eluent at flow
rate of 0.8 mL/min.
4. Materials and methods
4.1. Instruments
All the melting points were determined with a Cole-Parmer
melting point apparatus while the thermometer was uncorrected.
IR spectra were recorded on a NEXUS-470 FTIR(Nicolet) spectrom-
eter with KBr pellets. 1H NMR spectra were recorded with a Bruker
DPX300 instrument, while tetramethylsilane was used as the
internal standards. Analytical thin-layer chromatography (TLC) was
carried out on precoated plates (silica gel 60 F254), and spots were
visualized with ultraviolet (UV) light. Elemental analysis, which was
performed at the laboratories of the Institute of Chemistry, Chinese
Fig. 4. HPLC chromatogram of the target compound IIf. Only one isomer was found at
the retention time of 9.374 min.
Academy of Sciences, was carried out with a Flash EA 1112 ele-
mantal analyzer.
4.2. Synthetic procedures
4.2.1. General synthetic procedure for the key intermediates
Intermediates 8 and 11 were synthesized according to the
literature [34,39]. Intermediates 9 and 10 were synthesized from
substituted aniline by Meerwein arylation reaction using the
reported procedure [34,35,40].
Fig. 3. HPLC chromatogram of the target compound If. Only one isomer was found at
Fig. 5. Molecular structures of IIa. Displacement ellipsoids are drawn at the 30%
the retention time of 3.068 min.
probability level.

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Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
Fig. 6. Molecular structure of IIe. Displacement ellipsoids are drawn at the 30%
probability level.
4.2.2. General synthetic procedure for the target compounds
I and II
A mixture of aldehyde 9 (0.05 mol) and acylhydrazine 8
(0.05 mol) reacted in ethanol under reflux for 5 h. The reaction was
catalyzed by drops of acetic acid. After cooling, the solvent was
removed under reduced pressure, and the solid was recrystallized
from ethanol to obtain the target compounds I. Using the same
method, compound II was obtained by the reaction of substituted
aldehyde (0.05 mol) with 5-substituted phenyl-2-furoyl hydrazide
10 (0.05 mol).
Fig. 8. IIe: H-bond with the methanol to form the s-trans conformation.
4.2.2.2. (E)-5-(20-chlorophenyl)furan-2-carbaldehyde-4-bromo-
benzoyl hydrazone (Ib). Light yellow needle crystals: m.p.
200e201 ꢂC. IR (KBr) nmax: 3243.8, 3085.4, 3054.7, 1654.8, 1621.8,
1593.6, 1551.0, 1481.7, 1466.2, 1298.7, 1148.7, 1071.5, 1024.9, 900.7,
All the synthesized compounds were solid. Their structures
were confirmed by 1H NMR, IR, UV and elemental analysis.
835.8, 798.1, 760.2, 648.9 cmꢀ1 1H NMR (300 MHz, DMSO-d6)
. d:
4.2.2.1. (E)-5-(20,40-difluorophenyl)furan-2-carbaldehyde-2-methox-
ybenzoyl hydrazone (Ia). Light yellow powdery crystals: m.p.
171e172 ꢂC. IR (KBr) nmax: 3248.7, 2935.8, 1661.5, 1605.7, 1550.0,
1485.1, 1297.5, 1269.8, 1251.7, 1141.2, 1103.6, 1024.8, 966.8, 845.1,
7.14 (d, J ¼ 3.60 Hz, 1H, FuH), 7.29 (d, J ¼ 3.60 Hz, 1H, FuH), 7.41 (td,
J ¼ 1.68, 7.64 Hz, 1H, ArH-Fu), 7.48e7.53 (m, 1H, ArH-Fu), 7.60 (dd,
J ¼ 1.22, 7.89 Hz, 1H, ArH-Fu), 7.76 (d, J ¼ 8.49 Hz, 2H, ArH),
7.86e7.93 (m, 3H, ArH-Fu þ 2ArH), 8.41 (s, 1H, CH]N), 11.96 (s, 1H,
NH). MS/ESI: m/e (%) 427.1 [M þ Na]þ (20.7) 405.2 [M þ H]þ (100).
797.7, 751.8, 605.3 cmꢀ1 1H NMR (300 MHz, DMSO-d6)
. d: 3.89
UV (nm) lmax: 200.3 (p /
p*), 240.2 (n / s*), 350.7 (n / p*). Anal.
(s, 3H, OCH3), 6.97e7.00 (m, 1H, FuH), 7.05e7.10 (m, 2H,
FuH þ ArH), 7.17e7.19 (m, 1H, ArH), 7.26e7.27 (m, 1H, ArH-Fu),
7.46e7.55 (m, 2H, ArH þ ArH-Fu), 7.62 (dd, J ¼ 7.56, 1.74 Hz, 1H,
ArH), 7.90e7.93 (m, 1H, ArH-Fu), 8.31 (s, 1H, CH]N), 11.54 (s, 1H,
NH). MS/ESI: m/e (%) 395.0 [M þ K]þ (2.5), 379.0 [M þ Na]þ (19.0),
Calcd. (%) for C18H12BrClN2O2: C, 53.56; H, 3.00; N, 6.94. Found:
C, 53.94; H, 3.14; N, 7.04.
4.2.2.3. (E)-5-(20-fluorophenyl)furan-2-carbaldehyde-4-chlor-
obenzoyl hydrazone (Ic). Yellow powdery crystals: m.p. 179e180 ꢂC.
IR (KBr) nmax: 3300.2, 3036.0, 1649.0, 1597.7, 1554.4, 1484.9, 1292.1,
357.1 [M þ H]þ (100). UV (nm) lmax: 199.1 (
p /
p*), 349.5 (n / p*).
Anal. Calcd. (%) for C19H14F2N2O3: C, 64.04; H, 3.96; N, 7.86. Found:
C, 63.92; H, 3.89; N, 7.92.
1273.4, 1220.5, 1147.0, 1030.2, 898.8, 805.6, 756.1, 661.8 cmꢀ1
.
Table 2
The antitumor activity of the target compounds I and II.a
Compd.
Inhibition rate (%)
HL-60
BGC-823
Bel-7402
KB
Ia
Ib
7.77
e
35.87
e
1.69
e
10.07
e
Ic
Id
Ie
If
6.13
31.54
71.53
19.44
68.43
36.09
46.74
66.76
e
2.96
4.62
84.59
3.20
61.81
5.90
25.96
59.54
e
ꢀ2.08
15.05
ꢀ9.50
6.25
25.91
27.41
e
81.64
ꢀ7.17
63.42
5.67
28.19
53.06
e
Ig
Ih
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
6.49
32.56
74.04
33.71
79.08
31.37
32.03
46.30
43.61
16.88
39.99
2.28
91.77
6.66
4.81
10.64
12.54
11.26
53.91
16.99
75.25
10.30
19.26
11.03
26.46
13.09
25.76
43.07
9.54
ꢀ3.22
1.07
27.65
e Means not detected.
a
Fig. 7. IIa: H-bond with each other to form the s-cis conformation.
Mean values based on three independent experiments.

Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
5581
Table 3
The IC50 values of antitumor activity of the target compounds I and II.
Method
Cell line
Human tumor
IC50 (mM)
Id
If
IIa
IId
63.1
180.4
50.3
IIf
16.4
9.6
8.3
Doxorubicin
MTT
SRB
SRB
SRB
HL-60
BGC-823
Bel-7402
KB
Leukemia
Gastric cancer
Hepatoma
61.6
9.5
15.2
39.0
125.2
46.6
19.3
55.3
>40
53.3
4.8
5.0
81.6
24.6
>40
Nasopharyngeal cancer
>40
>40
5.8
1H NMR (300 MHz, DMSO-d6)
d
: 7.03 (t, J ¼ 3.51 Hz, 1H, ArH-Fu),
4.2.2.6. (E)-5-(204,-difluorophenyl)furan-2-carbaldehyde-2-hydroxy-
benzoyl hydrazone (If). Light yellow powdery crystals: m.p.
248e249 ꢂC. IR (KBr) nmax: 3235.5, 3073.0, 2928.7, 1638.5, 1606.7,
1548.9, 1519.4, 1489.7, 1452.7, 1373.2, 1301.6, 1270.1, 1221.9, 1145.7,
1103.8,1027.2, 969.6, 908.6, 850.7, 783.8, 753.0, 621.9 cmꢀ1. 1H NMR
7.14 (d, J ¼ 3.57 Hz, 1H, FuH), 7.34e7.45 (m, 3H, 2ArH-Fu þ FuH),
7.62e7.65 (m, 2H, ArH), 7.86e7.96 (m, 3H, ArH-Fu þ 2ArH), 8.42
(s, 1H, CH]N),11.97 (s, 1H, NH). MS/ESI: m/e (%) 381.0 [M þ K]þ
(17.7), 365.2 [M þ Na]þ (100), 343.3 [M þ H]þ (28.3). UV (nm) lmax
:
197.9 (
p
/
p*), 233.2 (n / s*), 349.5 (n / p*). Anal. Calcd. (%) for
(300 MHz, DMSO-d6)
d
: 6.98e7.05 (m, 3H, 2ArH þ FuH), 7.13
C18H12ClFN2O2: C, 63.08; H, 3.53; N, 8.17. Found: C, 63.04; H, 3.58;
N, 8.15.
(d, J ¼ 3.54 Hz, 1H, FuH), 7.27 (td, J ¼ 8.45, 2.34 Hz, 1H, ArH-Fu),
7.41e7.48 (m, 2H, ArH-Fu þ ArH), 7.86e7.93 (m, 2H, ArH-Fu þ ArH),
8.42 (s, 1H, CH]N), 11.80 (s, 1H, OH), 11.87 (s, 1H, NH). MS/ESI: m/e
(%) 381.0 [M þ K]þ (4.8), 365.0 [M þ Na]þ (100), 343.2 [M þ H]þ
4.2.2.4. (E)-5-(40-fluorophenyl)furan-2-carbaldehyde-2-hydroxy-
benzoyl hydrazone (Id). Light yellow powdery crystals: m.p.
243e244 ꢂC. IR (KBr) nmax: 3243.8, 1626.4, 1545.9, 1520.3, 1493.7,
1456.6, 1373.9, 1235.8, 1144.3, 1025.4, 834.4, 783.1, 752.4,
(20.4). UV (nm) lmax: 200.3 (p /
p*), 353.1 (n / p*). Anal. Calcd.
Table 5
617.9 cmꢀ1 1H NMR (300 MHz, DMSO-d6)
. d: 6.94e7.00 (m, 2H,
Crystal structure data for compounds IIa and IIe.
ArH), 7.10 (d, J ¼ 3.60 Hz, 1H, FuH), 7.16 (d, J ¼ 3.60 Hz, 1H, FuH),
7.31e7.37 (m, 2H, ArH-Fu), 7.42e7.48 (m, 1H, ArH), 7.84e7.88 (m,
3H, ArH þ 2ArH-Fu), 8.39 (s, 1H, CH]N), 11.85 (br s, 2H, NH þ OH).
IIa
IIe
Empirical formula
Formula weight
T
Wavelength
Crystal system
Space group
Unit cell
C19H14F2N2O3
356.32
113(2) K
0.71073 Å
Triclinic
C38H34Cl2N4O6
713.59
113(2) K
0.71073 Å
Triclinic
P1
UV (nm) lmax: 199.1 (p /
p*), 355.5 (n / p*). Anal. Calcd. (%) for
C18H13FN2O3: C, 66.66; H, 4.04; N, 8.64. Found: C, 66.53; H, 4.13; N,
8.91.
P1
a ¼ 8.767(4) Å,
a ¼ 6.4301(13) Å,
4.2.2.5. (E)-5-(40-chlorophenyl)furan-2-carbaldehyde benzoyl hydra-
dimensions
a
¼ 105.334(9)ꢂ
a
¼ 103.54(3)ꢂ
zone (Ie). White powdery crystals: m.p. 214e215 ꢂC. IR (KBr) nmax
:
b ¼ 13.404(7) Å,
b ¼ 9.1796(18) Å,
b
¼ 99.257(9)ꢂ
b
¼ 91.42(3)ꢂ
3224.4, 3194.8, 3032.8, 1651.0, 1616.5, 1555.0, 1473.5, 1279.9, 1146.6,
1090.5, 1026.1, 975.6, 829.4, 789.5, 689.6, 501.7 cmꢀ1 1H NMR
(300 MHz, DMSO-d6)
c ¼ 16.815(8) Å,
c ¼ 15.822(3) Å,
.
g
¼ 107.126(10)ꢂ
g
¼ 110.24(3)ꢂ
d
: 7.08 (d, J ¼ 3.48 Hz, 1H, FuH), 7.21 (d,
Volume
Z
Dx
Absorption
coefficient
F (0 0 0)
Crystal dimensions
1759.1(15) Å3
4
846.1(3) Å3
1
J ¼ 3.54 Hz,1H, FuH), 7.52e7.64 (m, 5H, 3ArH þ 2ArH-Fu), 7.81e7.84
(m, 2H, ArH), 7.91e7.93 (m, 2H, ArH-Fu), 8.40 (s, 1H, CH]N), 11.88
(s, 1H, NH). MS/ESI: m/e (%) 363.0 [M þ K]þ (7.8), 347.1 [M þ Na]þ
1.345 mg/m3
0.106 mmꢀ1
1.400 mg/m3
0.247 mmꢀ1
(100), 325.2 [M þ H]þ (63.0). UV (nm) lmax: 199 (
p /
p*), 232.0
736
372
(n / s*), 356.7 (n / p*). Anal. Calcd. (%) for C18H13ClN2O2: C,
0.30 ꢁ 0.20 ꢁ 0.10 mm
0.24 ꢁ 0.18 ꢁ 0.04 mm
66.57; H, 4.03; N, 8.63. Found: C, 66.51; H, 4.15; N, 8.40.
q
range for data
collection
1.30e25.02
2.45e25.02ꢂ
Limiting indices
ꢀ10 ꢃ h ꢃ 9,
ꢀ15 ꢃ k ꢃ 13,
ꢀ16 ꢃ l ꢃ 20
9215/6179
[R(int) ¼ 0.0390]
Semi-empirical
from
ꢀ7 ꢃ h ꢃ 6,
Table 4
ꢀ8 ꢃ k ꢃ 10,
The predictive toxicity of the target compounds I and II.
ꢀ18 ꢃ l ꢃ 18
Reflection
collected/unique
Absorption correction
4405/2820
Compd. Carcinogenic toxicity
Pred. (%) CP CIP
0.001 0.386 98
Mutagenic toxicity
Pred. (%) MP MIP
0.01 0.800 3.70
Clog P Mark
[R(int) ¼ 0.0935]
Semi-empirical
from equivalents
Ia
Ib
97
e
Cautiona
equivalents
e
e
e
e
e
e
Cautiona
Cautiona
Cautiona
Cautiona
Cautiona
Cautiona
Max. and min.
transmission
Data/restraints/
parameters
0.9895 and 0.9688
0.9902 and 0.9432
2820/0/229
3.331
Ic
Id
Ie
If
97
99
99
97
96
99
94
93
93
95
95
94
e
0.001 0.257 98
0.001 0.390 99
0.001 0.133 99
0.001 0.561 98
0.004 0.023 98
0.001 0.106 99
0.001 0.870 97
0.001 0.873 97
0.001 0.911 97
0.001 0.891 98
0.001 0.849 98
0.001 0.951 97
0.01 0.570 4.17
0.01 0.410 4.10
0.01 0.300 4.08
0.01 0.760 4.15
0.12 0.010 3.64
0.01 0.210 4.59
0.01 0.950 3.92
0.01 0.750 5.25
0.01 0.850 4.57
0.01 0.720 4.32
0.01 0.630 4.48
0.01 0.940 4.37
6179/0/471
1.007
Goodness-of-fit
Ig
on F2
Ih
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
Final R indices [
R1 ¼ 0.0529,
R1 ¼ 0.2656,
I > 2
qmax
s
(I)]
wR2 ¼ 0.0988
wR2 ¼ 0.6557
2
50.04ꢂ with Mo K
0.190 e Åꢀ3
a
50.04ꢂ with Mo K
1.820 e Åꢀ3
a
(
(
Dr
Dr
)
)
max
ꢀ0.174 e Åꢀ3
ꢀ1.308 e Åꢀ3
min
Program system
SHELXS-97,
SHELXS-97, SHELXL-97
SHELXL-97
Direct method
e
e
e
e
e
e
Structure
determination
Refinement
Direct method
94
95
93
0.001 0.947 98
0.001 0.748 98
0.001 0.899 97
0.01 0.830 4.18
0.01 0.670 3.45
0.01 0.890 4.77
Full-matrix
Full-matrix
least-squares on F2
least-squares on F2
761106
e means not detected.
CCDC No.
761107
a
the compound considered toxic.

5582
Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
(%) for C18H12F2N2O3: C, 63.16; H, 3.53; N, 8.18. Found: C, 63.04; H,
3.71; N, 7.85.
nmax: 3404.6, 3027.4, 2883.7, 1650.6, 1622.9, 1604.4, 1586.6, 1486.0,
1375.2, 1315.8, 1274.3, 1234.3, 1160.5, 1035.1, 981.4, 959.9, 837.7,
810.3, 752.0, 601.9, 513.9 cmꢀ1 1H NMR (300 MHz, DMSO-d6)
. d:
4.2.2.7. (E)-5-(20-nitrophenyl)furan-2-carbaldehyde-3-methylbenzoyl
hydrazone (Ig). Yellow powdery crystals: m.p. 160e161 ꢂC. IR (KBr)
nmax: 3192.8, 3015.1, 1644.0, 1605.6, 1559.2, 1527.0, 1346.8, 1306.5,
6.91e6.96 (m, 2H, ArH), 7.19 (d, J ¼ 3.66 Hz, 1H, FuH), 7.29e7.42 (m,
4H, 2ArH þ ArH-Fu þ FuH), 7.59e7.61 (m, 1H, ArH), 8.01e8.05 (m,
2H, ArH-Fu), 8.73 (s, 1H, CH]N), 11.10 (s, 1H, OH), 12.06 (s, 1H, NH).
MS/ESI: m/e (%) 363.0 [M þ K]þ (5.8), 347.1 [M þ Na]þ (100), 325.3
1287.9, 1220.1, 1036.5, 850.3, 785.9, 744.2, 703.9 cmꢀ1 1H NMR
.
(300 MHz, DMSO-d6)
d
: 2.40 (s, 3H, CH3), 7.06 (d, J ¼ 3.63 Hz, 1H,
[M þ H]þ (47.5). UV (nm) lmax: 214.4 (
p /
p*), 279.3 (n / s*), 341.1
FuH), 7.11e7.12 (m, 1H, ArH), 7.41e7.45 (m, 2H, ArH þ FuH),
7.62e7.82 (m, 4H, 2ArH-Fu þ 2ArH), 7.90e7.99 (m, 2H, ArH-Fu), 8.38
(s, 1H, CH]N), 11.86 (s, 1H, NH). MS/ESI: m/e (%) 388.0 [M þ K]þ
(n / p*). Anal. Calcd. (%) for C18H13FN2O3: C, 66.66; H, 4.04; N, 8.64.
Found: C, 66.51; H, 4.16; N, 8.70.
(2.3), 372.1 [M þ Na]þ (100), 350.2 [M þ H]þ (33.8). UV (nm) lmax
:
4.2.2.13. (E)-benzaldehyde 5-(4-chlorophenyl)-2-furoyl hydrazone
(IIe). Light yellow needle crystals: m.p. 188e189 ꢂC. IR (KBr) nmax
:
197.9 (
p
/
p*), 332.8 (n / p*). Anal. Calcd. (%) for C19H15N3O4: C,
65.32; H, 4.33; N, 12.03. Found: C, 65.15; H, 4.27; N, 12.14.
3430.8, 3057.4, 2946.2, 1649.3, 1524.2, 1475.0, 1410.5, 1346.2,
1279.4, 1092.1, 1017.7, 949.5, 833.4, 754.9, 691.5, 506.0 cmꢀ1 1H
NMR (300 MHz, DMSO-d6)
7.26 (d, J ¼ 3.63 Hz, 1H, FuH),
.
4.2.2.8. (E)-5-(30-fluorophenyl)furan-2-carbaldehyde-4-bromobenzoyl
hydrazone (Ih). Yellow powdery crystals: m.p. 181e182 ꢂC. IR (KBr)
nmax: 3444.4, 3209.4, 3062.8, 1658.7, 1598.6, 1571.5, 1479.7, 1313.4,
1270.5, 1220.0, 1173.8, 1070.2, 1039.8, 982.5, 955.4, 898.1, 814.9,
d:
7.41e7.61 (m, 6H, FuH þ 2ArH-Fu þ 3ArH), 7.74e7.77 (m, 2H, ArH),
7.99e8.01 (m, 2H, ArH-Fu), 8.53 (s, 1H, CH]N), 11.86 (s, 1H, NH).
MS/ESI: m/e (%) 363.2 [M þ K]þ (51.8), 347.3 [M þ Na]þ (91.4), 325.4
781.6, 754.8, 703.1, 680.0 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6)
d
:
[M þ H]þ (100). UV (nm) lmax: 197.9 (
p /
p*), 331.6 (n / p*). Anal.
Calcd. (%) for C18H13ClN2O2: C, 66.57; H, 4.03; N, 8.63. Found:
C, 66.44; H, 4.00; N, 8.61.
7.11e7.28 (m, 3H, 2FuH þ ArH-Fu), 7.48e7.70 (m, 3H, ArH-Fu),
7.73e7.75 (m, 2H, ArH), 7.86e7.89 (m, 2H, ArH), 8.40 (s, 1H, CH]N),
11.96 (s, 1H, NH). MS/ESI: m/e (%) 410.9 [M þ Na]þ (43.4), 389.1
[M þ H]þ (100). UV (nm) lmax: 199.1 (
p
/
p*), 234.4 (n / s*), 353.1
4.2.2.14. (E)-2-hydroxybenzaldehyde-5-(2,4-difluorophenyl)-2-
furoyl hydrazone (IIf). Yellow powdery crystals: m.p.165e166 ꢂC. IR
(KBr) nmax: 3411.1, 3023.6, 2875.0, 1643.2, 1579.4, 1484.4, 1431.5,
(n / p*). Anal. Calcd. (%) for C18H12BrFN2O2: C, 55.83; H, 3.12; N,
7.23. Found: C, 55.65; H, 3.38; N, 7.20.
1376.2, 1316.3, 1274.1, 1038.9, 969.8, 849.4, 810.2, 751.8, 602.9 cmꢀ1
.
4.2.2.9. (E)-2-methoxybenzaldehyde-5-(2,4-difluorophenyl)-2-furoyl
hydrazone (IIa). Light yellow powdery crystals: m.p. 197e198 ꢂC. IR
(KBr) nmax: 3196.1, 3034.2, 2939.9, 2837.9, 1655.0, 1602.4, 1550.9,
1487.4, 1464.4, 1432.4, 1358.1, 1274.3, 1251.9, 1155.8, 1106.6, 1068.8,
1H NMR (300 MHz, DMSO-d6)
d
: 6.92e7.03 (m, 3H, 2ArH þ FuH),
7.29e7.37 (m, 2H, ArH-Fu þ ArH), 7.44e7.53 (m, 2H, ArH-Fu þ FuH),
7.60e7.62 (m, 1H, ArH), 8.18e8.26 (m, 1H, ArH-Fu), 8.74 (s, 1H, CH]
N), 11.07 (s, 1H, OH), 12.11 (s, 1H, NH). MS/ESI: m/e (%) 381.0
[M þ K]þ (5.9), 365.1 [M þ Na]þ (100), 343.4 [M þ H]þ (20.6). UV
.
1028.6, 969.3, 886.5, 844.9, 806.2, 753.3 cmꢀ1 1H NMR (300 MHz,
DMSO-d6)
d
: 3.90 (s, 3H, OCH3), 6.98e7.08 (m, 2H, FuH þ ArH),
(nm) lmax: 199.1 (p /
p*), 213.2 (n / s*), 340.0 (n / p*). Anal.
7.12e7.15 (m, 1H, ArH), 7.33 (td, J ¼ 8.38, 1.79 Hz, 1H, ArH-Fu),
7.42e7.52 (m, 3H, ArH-Fu þ ArH þ FuH), 7.90 (d, J ¼ 6.81 Hz,1H, ArH),
8.25e8.27 (m, 1H, ArH-Fu), 8.88 (s,1H, CH]N), 11.90 (s, 1H, NH). MS/
Calcd. (%) for C18H12F2N2O3: C, 63.16; H, 3.53; N, 8.18. Found:
C, 62.99; H, 3.78; N, 8.14.
ESI:m/e(%)379.0[M þ Na]þ (6.5),357.1[M þ H]þ (100). UV(nm)lmax
:
4.2.2.15. (E)-3-methylbenzaldehyde-5-(2-nitrophenyl)-2-furoyl
hydrazone (IIg). Light brown powdery crystals: m.p. 152e153 ꢂC. IR
(KBr) nmax: 3252.0, 3091.7, 2915.8, 2858.0, 1659.6, 1554.4, 1534.1,
1461.8,1358.5,1301.1,1183.3,1163.9,1066.2, 981.1, 850.5, 830.6, 793.8,
199.1 (p /
p*), 337.6 (n / p*). Anal. Calcd. (%) for C19H14F2N2O3: C,
64.04; H, 3.96; N, 7.86. Found: C, 64.13; H, 4.06; N, 7.80.
4.2.2.10. (E)-4-bromobenzaldehyde-5-(2-chlorophenyl)-2-furoyl hydra-
zone (IIb). Light yellow powdery crystals: m.p. 189e190 ꢂC. IR (KBr)
nmax: 3433.8, 3263.1, 3076.5, 1665.3, 1591.9, 1549.0, 1484.7, 1465.6,
749.8, 696.3, 595.8 cmꢀ1. 1H NMR (300 MHz, DMSO-d6)
d: 2.37 (s, 3H,
CH3), 6.99 (br s, 1H, FuH), 7.26e7.28 (m, 1H, ArH), 7.34e7.39 (m, 1H,
ArH), 7.45 (br s, 1H, FuH), 7.51e7.57(m, 2H, ArH), 7.68e7.74 (m, 1H,
ArH-Fu), 7.82e7.87 (m, 1H, ArH-Fu), 7.99e8.05 (m, 2H, ArH-Fu), 8.42
(s, 1H, CH]N), 11.85 (s, 1H, NH). MS/ESI: m/e (%) 388.0 [M þ K]þ
1356.2, 1299.8, 1249.7, 1169.6, 1069.0, 1027.7, 839.7, 809.3, 757.7 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6)
d
: 7.33 (d, J ¼ 3.69 Hz, 1H, FuH),
7.42e7.56 (m, 3H, FuH þ 2ArH-Fu), 7.61e7.74 (m, 5H, 4ArH þ ArH-Fu),
(10.9), 372.1 [M þ Na]þ (100), 350.2 [M þ H]þ (52.0). UV (nm) lmax
:
8.15e8.17 (m, 1H, ArH-Fu), 8.50 (s, 1H, CH]N), 11.94 (s, 1H, NH). MS/
200.3 (p /
p*), 313.7 (n / p*). Anal. Calcd. (%) for C19H15N3O4: C,
ESI: m/e (%) 405.1 [M þ H]þ (100). UV (nm) lmax: 199.1 (
p
/
p*), 329.2
65.32; H, 4.33; N, 12.03. Found: C, 65.07; H, 4.35; N, 12.13.
(n / p*). Anal. Calcd. (%) for C18H12BrClN2O2: C, 53.56; H, 3.00; N,
6.94. Found: C, 53.34; H, 3.19; N, 7.02.
4.2.2.16. (E)-2-chlorobenzaldehyde-5-(4-fluorophenyl)-2-furoyl
hydrazone (IIh). Yellow powdery crystals: m.p.182e183 ꢂC. IR (KBr)
nmax: 3204.0, 3025.0, 1646.1, 1595.1, 1547.2, 1484.9, 1366.6, 1297.4,
1276.8, 1234.3, 1155.9, 1047.9, 1022.2, 882.7, 836.2, 797.6, 753.6,
4.2.2.11. (E)-4-chlorobenzaldehyde-5-(2-fluorophenyl)-2-furoyl
hydrazone (IIc). White powdery crystals: m.p. 209e210 ꢂC. IR (KBr)
nmax: 3234.3, 3057.6, 3035.5, 1672.7, 1647.7, 1598.4, 1552.8, 1485.9,
1357.5, 1295.5, 1222.5, 1154.4, 1088.7, 1069.9, 1023.2, 835.0, 801.6,
613.7 cmꢀ1. 1H NMR (300 MHz, DMSO-d6)
d
: 7.19 (d, J ¼ 3.63 Hz, 1H,
FuH), 7.35e7.57 (m, 6H, FuH þ 2ArH-Fu þ ArH), 8.04e8.07 (m, 3H,
754.5,585.6 cmꢀ1 1H NMR (300 MHz, DMSO-d6)
. d: 7.05 (t,
ArH þ 2ArH-Fu), 8.92 (s, 1H, CH]N), 12.08 (s, 1H, NH). MS/ESI: m/e
J ¼ 3.48 Hz,1H, ArH-Fu), 7.36e7.56 (m, 6H, 2FuH þ 2ArH-Fu þ 2ArH),
7.77e7.80 (m, 2H, ArH), 8.15e8.20 (m, 1H, ArH-Fu), 8.52 (s, 1H, CH]
N), 11.96 (s, 1H, NH). MS/ESI: m/e (%) 381.0 [M þ K]þ (12.6), 365.2
[M þ Na]þ (100), 343.4 [M þ H]þ (23.8). UV (nm) lmax: 199.1
(%) 380.9 [M þ K]þ (14.4), 365.1 [M þ Na]þ (100). UV (nm) lmax
:
200.3 (p /
p*), 313.7 (n / p*). Anal. Calcd. (%) for C18H12ClFN2O2:
C, 63.08; H, 3.53; N, 8.17. Found: C, 63.39; H, 3.65; N, 7.93.
(p
/
p*), 328.0 (n / p*). Anal. Calcd. (%) for C18H12ClFN2O2: C,
4.2.2.17. (E)-4-hydroxybenzaldehyde-5-(4-fluorophenyl)-2-furoyl
63.08; H, 3.53; N, 8.17. Found: C, 63.22; H, 3.53; N, 8.51.
hydrazone (IIi). Yellow powdery crystals: m.p. 246e247 ꢂC. IR (KBr)
nmax: 3332.4, 3236.7, 3062.5, 1643.4, 1602.6, 1514.0, 1485.1, 1441.8,
1378.0, 1280.0, 1236.5, 1160.4, 1018.3, 836.6, 789.9, 527.2 cmꢀ1. 1H
4.2.2.12. (E)-2-hydroxybenzaldehyde-5-(4-fluorophenyl)-2-furoyl
hydrazone (IId). Yellow powdery crystals: m.p. 113e114 ꢂC. IR (KBr)
NMR (300 MHz, DMSO-d6)
d: 6.85e6.88 (m, 2H, ArH), 7.16 (d,

Z. Cui et al. / European Journal of Medicinal Chemistry 45 (2010) 5576e5584
5583
J ¼ 3.60 Hz, 1H, FuH), 7.32e7.40 (m, 3H, 2ArH-Fu þ FuH), 7.57e7.60
(m, 2H, ArH), 8.00e8.04 (m, 1H, ArH-Fu), 8.41 (s, 1H, CH]N), 9.98
(s, 1H, OH), 11.63 (s, 1H, NH). MS/ESI: m/e (%) 347.0 [M þ Na]þ (100),
48 h (Table 3). 20 mL of RPMI-1640 medium was added to the control
cells. HL-60 cells were assayed by MTT, and the Bel-7402, BGC-823
and KB cells were assayed by SRB. The absorbance of each well was
measured using a microculture plate reader at 570 nm (MTT) and
540 nm (SRB). The inhibition rate was calculated according to the
following formula:
325.1 [M þ H]þ (78.9). UV (nm) lmax: 197.9 (
p /
p*), 336.4
(n / p*). Anal. Calcd. (%) for C18H13FN2O3: C, 66.66; H, 4.04; N, 8.64.
Found: C, 66.59; H, 4.16; N, 8.61.
Inhibition rate ¼ ðODcontrol ꢀ ODtreatedÞ=ODcontrol ꢁ 100%
4.2.2.18. (E)-3-bromobenzaldehyde-5-(2-fluorophenyl)-2-furoyl
hydrazone (IIj). Yellow powdery crystals: m.p. 144e145 ꢂC. IR (KBr)
nmax: 3169.9, 3059.2, 2961.2, 1650.7, 1564.6, 1520.9, 1482.4, 1447.0,
1392.6, 1344.5, 1268.0, 1218.1, 1174.5, 1032.3, 941.8, 881.0, 814.4,
4.5. Prediction of toxicity
757.9, 733.8, 678.5, 587.1 cmꢀ1 1H NMR (300 MHz, DMSO-d6)
. d:
The database (Prediction System of Carcinogenic Toxicity
Version1.0, Prediction System for Mutagenic Toxicity Version1.0
and CISOC-LOGP Version1.0) [48] of SIOC, CAS (Shanghai Institute
of Organic Chemistry, Chinese Academy of Science) was used to
predict the carcinogenic toxicity, mutagenic toxicity and the Log P
value of the target compounds. The prediction consists of following
steps: (1) reading a structure file, (2) generating all structural
descriptors, and (3) calculating corresponding data.
7.06 (t, J ¼ 3.39 Hz, 1H, ArH-Fu), 7.37e7.51 (m, 5H, 2FuH þ 2ArH-
Fu þ ArH), 7.64e7.67 (m, 1H, ArH), 7.75e7.78 (m, 1H, ArH),
7.93e7.97 (m, 1H, ArH), 8.15e8.20 (m, 1H, ArH-Fu), 8.49 (s, 1H, CH]
N), 12.03 (s, 1H, NH). MS/ESI: m/e (%) 411.0 [M þ Na]þ (78.6), 389.1
[M þ H]þ (100). UV (nm) lmax: 197.9 (
p /
p*), 329.2 (n / p*). Anal.
Calcd. (%) for C18H12BrFN2O2: C, 55.83; H, 3.12; N, 7.23. Found: C,
55.49; H, 3.26; N, 7.18.
4.3. Crystallography
Acknowledgements
Compounds IIa and IIe were recrystallized from methanol to give
colorless crystals suitable for X-ray single crystal diffraction. Cell
constants at 173(2) K were determined by a least-square fit to the
setting parameters. Cell constants at 113 K were determined by
a least-square fit to the setting parameters of independent reflec-
tions measured on a Bruker SMART [41] 1000 CCD area-detector
We are thankful to Dr. Leonard G. Copping for carefully
reviewing and polishing this manuscript. We also express our
gratitude to Prof. Yao Jianhua (Shanghai Institute of Organic
Chemistry, Chinese Academy of Science) for her kind help in
toxicity prediction work. We greatly acknowledge the financial
support for this work from the National Key Project for Basic
Research (2010CB126104) and the National High Technology
Research and Development Program of China (2006AA10A201). We
also thank the financial support from the Scientific Research
Foundation of the Graduate School of China Agricultural University.
diffractometer with a graphite-monochromated Mo K
a radiation
(l
¼ 0.071073 nm) and operating in the phi and scan modes. The
structure was solved by the direct method with SHELXS-97 [42,43]
and refined by the full-matrix least-squares method on F2 data
using SHELXL-97 [43,44]. The empirical absorption corrections were
applied to all intensity data. H atom of NeH was initially located in
a different Fourier map and was refined with the restraint Uiso(H) ¼
1.2 Ueq(N). Other H atoms were positioned geometrically and
refined using a riding model, with d(C.H) ¼ 0.093e0.097 nm and
Uiso(H) ¼ 1.2 Ueq(C) or 1.5 Ueq(C-methyl). The crystal data in CIF
format have been deposited at the Cambridge Crystallographic Data
Centre with deposition numbers CCDC 761106 and 761107.
Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmech.2010.09.007.
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