Synthesis of isoxazole moiety containing ferrocene derivatives and preliminarily in vitro anticancer activity

Article abstract of DOI:10.1039/c4md00151f

Seven new structures of an isoxazole moiety containing ferrocene derivatives (3a-3g) were firstly synthesized and characterized by ¹H NMR, ¹³C NMR, ESI-MS. Subsequently, their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines was preliminarily evaluated using the MTT method. Among them, 3d exhibited a wide spectrum and the most potent anticancer activity against A549 and HCT116 cell lines (IC₅₀s: 0.747 and 3.65 nM, respectively) as compared with the reference drug gefitinib (IC₅₀s: 17.90 and 21.55 μM, respectively). 3d can be seen as the best candidate for development of anticancer drugs.

Full text of DOI:10.1039/c4md00151f

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Synthesis of isoxazole moiety containing ferrocene
derivatives and preliminarily in vitro anticancer
activity
Cite this: Med. Chem. Commun., 2014,
5, 968
*
Jianping Yong, Canzhong Lu and Xiaoyuan Wu
Seven new structures of an isoxazole moiety containing ferrocene derivatives (3a–3g) were firstly
synthesized and characterized by 1H NMR, 13C NMR, ESI-MS. Subsequently, their in vitro anticancer
activity against A549, HCT116 and MCF-7 cell lines was preliminarily evaluated using the MTT method.
Among them, 3d exhibited a wide spectrum and the most potent anticancer activity against A549 and
HCT116 cell lines (IC50s: 0.747 and 3.65 nM, respectively) as compared with the reference drug gefitinib
(IC50s: 17.90 and 21.55 mM, respectively). 3d can be seen as the best candidate for development of
anticancer drugs.
Received 2nd April 2014
Accepted 21st May 2014
DOI: 10.1039/c4md00151f
www.rsc.org/medchemcomm
isoxazole moiety at the C-30 position of glycyrrhetinic acid and
11-deoxyglycyrrhetinic acid, and synthesized a series of iso-
1. Introduction
xazole-moiety-containing glycyrrhetinic acid amide derivatives.
The biological evaluation results showed that most compounds
exhibit higher activities of anti-inammatory, analgesic, cough
prevention and liver protection than those of glycyrrhetinic
acid, but what is most important is that some isoxazole rings
containing glycyrrhetinic acid derivatives greatly reduced the
pseudoaldosteronism caused by glycyrrhetinic acid. Deoxy-
glycychloxazol (TY501, Fig. 2) is the most potent compound
among these glycyrrhetinic acid derivatives and it is in pre-
clinical studies for the development of an anti-inammatory
drug.20–22
In recent years we have been devoted to the design and
synthesis of anticancer drugs based on the epidermal growth
factor receptor (EGFR) target, and we have achieved remarkable
results.23–25 Based on our previous results,20,23,24 in this current
work we have introduced the isoxazole moiety to the ferrocene
core and rst of all synthesized seven novel structures of iso-
xazole moiety containing ferrocene derivatives (3a–3g) (Scheme
1). Furthermore, their in vitro anticancer activity against the
breast cancer cell line MCF-7, lung cancer cell line A549 and
colorectal cancer cell line HCT116 was evaluated.
Cancer is the second most lethal disease with abnormal cellular
proliferation and metastasis, second only to cardiovascular and
cerebrovascular disease worldwide. Cancer types include lung
cancer, gastric cancer, liver cancer, colon cancer and breast
cancer, non-small cell lung cancer (NSCLC), etc. lung cancer
causes a h of all cancer-related deaths; moreover, NSCLC
accounts for most cases of lung cancer and is usually diagnosed
in advanced stages. Cancer is a great threat to human survival,
and there is an urgent need to discover new anticancer drugs.
Ferrocene has attracted signicant interest, mainly due to its
aromaticity, chemical stability and low toxicity; it has been used
as the most attractive pharmacophore for drug design and
discovery. Edwards et al.1 synthesized ferrocenyl-penicillin
(Fig. 1) and tested it against penicillin-resistant bacteria. The
results showed that ferrocenyl-penicillin can increase the anti-
bacterial activity and it is more active than penicillin. Ferro-
quine (FQ, SSR97193, Fig. 1) is another ferrocene core con-
taining quinoline derivative, which exhibits
a
higher
antimalarial activity than chloroquine (CQ, Fig. 1); it is also
more active against chloroquine-resistant malaria. FQ may be
useful as an alternative drug for treating chloroquine-resistant
malaria2,3 and it is about to complete phase-II clinical trials. To
date, different kinds of ferrocene derivatives, together with
different biological activities, especially anticancer activity, have
been reported.4–19
2. Experimental
2.1 Materials and apparatus
The isoxazole moiety, as a potential functional group, is
usually introduced into drug molecules to improve their bio-
logical activities. In our previous work, we introduced the
All melting points were determined on a X-4 micro melting
point apparatus, and values are uncorrected; 1H (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a 400 MHz Bruker
AVANCE III spectrometer in CDCl3, with the chemical shis
expressed in ppm relative to tetramethylsilane (TMS) as the
internal standard; ESI-MS was performed on a DECAX-30000
LCQ Deca XP(70 Ev); column chromatography was performed
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China.
E-mail: czlu@irsm.ac.cn; Fax: +86-591-83705794
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Fig. 1 Chemical structures of ferrocenyl-penicillin, FQ and CQ.
5 mL dry THF was added to the reaction system using a syringe,
and the mixture was stirred in a cold bath for an additional 30
min. Subsequently, 1.0 mmol 2a in 5 mL THF was added drop-
wise to the reaction system using a syringe, at which time the
temperature rose to room temperature. TLC conrmed the
completion of the reaction. The reaction mixture was evapo-
rated under reduced pressure, and the residue was directly
puried by column chromatography on silica gel with elution by
petroleum ether and ethyl acetate (5 : 1 / 2 : 1). Fractions with
similar Rf values were combined to obtain the target compound
Fig. 2 Chemical structure of deoxyglycychloxazol (TY501).
on silica gel (100–200 mesh, Qingdao Haiyang Chemical Co. 3a. Other ferrocene derivatives, 3b–3g, were synthesized using
Ltd); MTT {[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetra- the same process as for 3a.
zolium bromide], Amresco} and dimethyl sulfoxide (DMSO)
Ferrocene carboxylic acid 3-phenyl-isoxazol-5-ylmethyl ester
were purchased from Sigma; getinib was purchased from the (3a). Yield 84%. Light yellow solid: mp 138–139 ꢀC; 1H NMR
Hubei Prosperity Galaxy Chemical Co. Ltd., China; Dulbecco's (CDCl3, 400 MHz) d 4.19 (s, 5H, C5H5), 4.45 (s, 2H, C5H4), 4.87 (s,
modied essential medium (DMEM) was purchased from Invi- 2H, C5H4), 5.38 (s, 2H, isoxazole-CH2), 6.70 (s, 1H, isoxazole-H),
trogen; 10% fetal bovine serum (FBS) and 1% penicillin–strep- 7.45–7.46 (m, 3H), 7.81–7.83 (m, 2H); 13C NMR (CDCl3, 100
tomycin were purchased from Invitrogen; the intermediates MHz) 56.09, 69.75, 69.83, 70.39, 71.80, 102.25, 126.88, 126.90,
3-[(R)-substituted-phenyl]-isoxazole-5-methanol (2a–2g) were 126.95, 126.98, 128.98, 129.00, 130.18, 130.20, 171.5. ESI-MS (m/
prepared according to the published procedures reported by z, 100%) 388 ([M + 1]+, 6). Anal. calcd for C21H17FeNO3: C, 65.11;
us;28 other chemicals were commercially available, and used H, 4.40; N, 3.62. Found: C, 65.04; H, 4.46; N, 3.47%.
without further purication; tetrahydrofuran (THF) was
Ferrocene carboxylic acid 3-(4-methyl-phenyl)-isoxazol-5-
distilled over sodium and benzophenone before use.
ylmethyl ester (3b). Yield 83%. Light yellow solid: mp 145–146
1
ꢀC; H NMR (CDCl3, 400 MHz) d 2.40 (s, 3H, Ph-CH3), 4.21 (s,
5H, C5H5), 4.47 (s, 2H, C5H4), 4.88 (s, 2H, C5H4), 5.37 (s, 2H,
isoxazole-CH2), 6.69 (s, 1H, isoxazole-H), 7.27 (d, 2H, J ¼ 8.0 Hz),
7.71 (d, 2H, J ¼ 8.0 Hz); 13C NMR (CDCl3, 100 MHz) 21.44 (Ph–
CH3), 56.09, 69.83, 69.96, 70.39, 71.81, 102.18, 126.76, 129.67,
140.33, 140.53, 162.56, 167.49, 171.21. ESI-MS (m/z, 100%) 401
([M]+, 100). Anal. calcd for C22H19FeNO3: C, 65.83; H, 4.74; N,
3.49. Found: C, 65.89; H, 4.76; N, 3.36%.
2.2 Synthesis
In the general process for synthesis of 3a, ferrocene carboxylic
acid 1 (0.23 g, 1 mmol) and DCC (0.22 g, 0.55 mmol) were added
into a 25 mL one-necked round-bottomed ask with 5 mL dry
THF. The mixture was stirred in a cold bath and protected under
nitrogen for about 10 min. Then DMAP (0.14 g, 0.11 mmol) in
Scheme 1 The synthetic route for ferrocene derivatives.
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Ferrocene carboxylic acid 3-(4-methoxyl-phenyl)-isoxazol-5-yl- with DMSO for eight different concentrations (500 mM, 50 mM,
methyl ester (3c). Yield 79%. Light yellow solid: mp 128–130 ꢀC; 5 mM, 500 nM, 50 nM, 5 nM, 500 pM and 50 pM, respectively) as
1H NMR (CDCl3, 400 MHz) d 3.85 (s, 3H, Ph–OCH3), 4.18 (s, 5H, stock solution for the experiments described below.
C5H5), 4.44 (s, 2H, C5H4), 4.85 (s, 2H, C5H4), 5.36 (s, 2H, isoxazole-
In relation to the procedure for anticancer evaluation, target
CH2), 6.64 (s, 1H, isoxazole-H), 6.98 (d, 2H, J ¼ 8.8 Hz), 7.76 (d, cancer cell lines were seeded in 96-well plates with 100 mL DMEM
2H, J ¼ 8.8 Hz); 13C NMR (CDCl3, 100 MHz) 26.31 (Ph–OCH3), supplemented with 10% fetal bovine serum, and cultured at
55.39, 69.76, 69.93, 70.29, 71.18, 102.03, 125.89, 126.81, 129.72, 37 ꢀC in a humidied CO2 incubator (95% air, 5% CO2) for 24 h.
140.50, 162.63, 167.52, 171.23. ESI-MS (m/z, 100%) 417 ([M]+, 30). While the cell lines grew to 90% in logarithmic growth, a 1 mL
Anal. calcd for C22H19FeNO4: C, 63.31; H, 4.56; N, 3.36. Found: C, solution of different concentrations of each compound was
63.38; H, 4.52; N, 3.31%.
added into each well (every concentration was repeated three
Ferrocene carboxylic acid 3-(2-chloro-phenyl)-isoxazol-5-yl- times), and the plates were incubated for another 18 h at 37 ꢀC.
methyl ester (3d). Yield 70%. Light yellow solid: mp 110–111 ꢀC; Then, 20 mL of PBS containing 5 mg mLꢁ1 of MTT was added to
1H NMR (CDCl3, 400 MHz) d 4.19 (s, 5H, C5H5), 4.45 (s, 2H, each well. Four hours later, the culture medium was removed
C5H4), 4.87 (s, 2H, C5H4), 5.40 (s, 2H, isoxazole-CH2), 6.87 (s, 1H, from the well, and 150 mL DMSO was added to each well. The
isoxazole-H), 7.33–7.41 (m, 2H), 7.48–7.50 (m, 1H), 7.73–7.75 optical density was measured at a wavelength of 595 nm on an
(m, 1H); 13C NMR(CDCl3, 100 MHz) 55.98, 69.78, 69.95, 70.39, ELISA microplate reader. DMSO was used as a negative control.
71.81, 105.49, 127.18, 128.08, 130.46, 131.04, 132.97, 161.24, The results were expressed as the inhibition calculated as the
169.98, 171.12. ESI-MS (m/z, 100%) 421 ([M]+, 10). Anal. calcd for percentage [(1 ꢁ (OD595 treated/OD595 negative control)) ꢂ 100].
C
21H16FeClNO3: C, 59.86; H, 3.80; N, 3.33. Found: C, 60.04; H, Data analysis was performed using GraphPad Prism soware,
4.06; N, 3.43%. and 50% of cell growth inhibition (IC50) was determined by non-
Ferrocene carboxylic acid 3-(4-chloro-phenyl)-isoxazol-5-yl- linear regression. The inhibitory potentials of ferrocene deriva-
methyl ester (3e). Yield 81%. Light yellow solid: mp 152–153 ꢀC; tives were comparable to that of the reference drug getinib.
1H NMR (CDCl3, 400 MHz) d 4.19 (s, 5H, C5H5), 4.46 (s, 2H,
C5H4), 4.87 (s, 2H, C5H4), 5.37 (s, 2H, isoxazole-CH2), 6.67 (s, 1H,
3. Results and discussion
Chemistry
We used our optimized conditions28–31 to synthesize ferrocene
isoxazole-H), 7.45 (d, 2H, J ¼ 8.4 Hz), 7.77 (d, 2H, J ¼ 8.4 Hz); 13
C
NMR (CDCl3, 100 MHz) 56.02, 69.73, 69.95, 70.39, 71.86, 102.12,
124.75, 125.85, 127.26, 128.13, 129.29, 168.05, 170.29. ESI-MS
(m/z, 100%) 422 ([M + 1]+, 10). Anal. calcd for C21H16FeClNO3: C,
59.86; H, 3.80; N, 3.33. Found: C, 60.24; H, 4.08; N, 3.33%.
Ferrocene carboxylic acid 3-(2,4-dichloro-phenyl)-isoxazol-5-yl-
methyl ester (3f). Yield 68%. Light yellow solid: mp 100–101 ꢀC;
1H NMR (CDCl3, 400 MHz) 4.18 (s, 5H, C5H5), 4.45 (s, 2H, C5H4),
4.86 (s, 2H, C5H4), 5.40 (s, 2H, isoxazole-CH2), 6.86 (s, 1H, iso-
xazole-H), 7.35 (dd, 1H, J ¼ 2.0, 2.0 Hz), 7.52 (d, 1H, J ¼ 1.6 Hz),
7.71 (d, 1H, J ¼ 8.4 Hz); 13C NMR (CDCl3, 100 MHz) 55.91, 69.69,
69.93, 70.38, 71.82, 105.27, 126.62, 127.63, 130.33, 131.76, 133.66,
136.52, 160.37, 167.32, 171.11. ESI-MS (m/z, 100%) 457 ([M + 1]+,
20). Anal. calcd for C21H15FeCl2NO3: C, 55.26; H, 3.29; N, 3.07.
Found: C, 55.24; H, 3.30; N, 3.09%.
ester derivatives (3a–3g) in high yield, and their structures were
1
conrmed by H and 13C NMR mass spectrometry.
There were three kinds of proton signals for the ferrocene ring
1
of the ferrocene derivatives (3a–3g) in the H NMR spectra. The
proton of C5H5 ring showed a singlet at 4.0 ppm, while the proton
of C5H4 showed two singlets at 4.45 and 4.87 ppm, respectively.
The proton of the isoxazole ring showed a singlet at 6.7 ppm.
Three signals of the carbon atoms of the C5H4 ring and one
singlet of the carbon atom of the C5H5 appeared in the 13C NMR
spectra, while two carbon signals of the C5H4 ring appeared
upeld and one carbon signal of the C5H4 ring appeared down-
1
eld compared with the carbon signal of the C5H5 ring. The H
and 13C chemical shis of ferrocene ring and isoxazole ring in
these isoxazole-moiety-containing ferrocene derivatives are very
consistent with those reported in the literature.32,33
Ferrocene carboxylic acid 3-(4-bromo-phenyl)-isoxazol-5-yl-
methyl ester (3g). Yield 82%. Light yellow solid: mp 158–159 ꢀC;
1H NMR (CDCl3, 400 MHz) d 4.22 (s, 5H, C5H5), 4.48 (s, 2H,
C5H4), 4.89 (s, 2H, C5H4), 5.36 (s, 2H, isoxazole-CH2), 6.66 (s, 1H,
isoxazole-H), 7.61 (d, 2H, J ¼ 8.4 Hz), 7.70 (d, 2H, J ¼ 8.4 Hz); 13
C
Anticancer activity
NMR (CDCl3, 100 MHz) 56.03, 69.71, 69.93, 70.40, 71.83, 102.10,
124.735, 125.84, 127.25, 128.10, 129.28, 168.04, 170.10. ESI-MS The target compounds were preliminarily screened for their in
(m/z, 100%) 466 ([M]+, 35). Anal. calcd for C21H16FeBrNO3: C, vitro anticancer activity against the breast cancer MCF-7 cell
54.08; H, 3.43; N, 3.00. Found: C, 54.00; H, 3.45; N, 2.97%.
line, lung cancer A549 cell line and colorectal cancer HCT116
cell line. The anticancer efficacy was comparable with that of
the reference drug getinib, and the results are summarized in
Table 1. As evidenced from Table 1, most of the target
2.3 Anticancer evaluation
The anticancer activity of 3a–3g was evaluated against MCF-7, compounds exhibit a wide spectrum of anticancer activity
HCT116 and A549 cell lines using the MTT {(3-(4,5-dimethyl-2- against MCF-7, HCT116 and A549 cell lines. As to the
thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide)} method. The compounds 3a–3c, these exhibit higher anticancer activity
evaluation process has been described elsewhere, with some against MCF-7, HCT116 and A549 cell lines, but the efficacy is
modications.26,27 Briey, each compound was dissolved in not notable. This indicates that introducing the methyl and
DMSO at a concentration of 500 mM, then diluted successively methoxy groups to the benzene ring of the isoxazole moiety
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Table 1 In vitro anticancer activity of compounds 3a–3g
IC50 ꢃ SD (mM)
Compd
A549
HCT116
MCF-7
3a
3b
3c
3d
3e
3f
3g
Getinib
78.11 ꢃ 0.0241
36.22 ꢃ 0.0306
1.01 ꢂ 103 ꢃ 0.0781
a
34.18 ꢃ 0.0431
45.91 ꢃ 0.0290
—
3.27 ꢂ 105 ꢃ 0.0727
7.47 ꢂ 10ꢁ4 ꢃ 0.1221
6.38 ꢂ 105 ꢃ 0.0178
3.65 ꢂ 10ꢁ3 ꢃ 0.1103
46.80 ꢃ 0.0232
274.50 ꢃ 0.0437
698.10 ꢃ 0.1154
442.00 ꢃ 0.0587
a
—
a
a
—
582.70 ꢃ 0.1336
443.80 ꢃ 0.0629
21.55 ꢃ 0.0129
—
a
—
1.97 ꢂ 105 ꢃ 0.0024
20.68 ꢃ 0.0384
17.90 ꢃ 0.0074
a
The IC50 values cannot be calculated.
cannot greatly improve the anticancer activity. Indeed, intro-
ducing the methoxy group to the benzene ring will greatly
reduce the anticancer activity against HCT116 and A549 cell
lines (for example, 3a is 4186-fold more active than 3c against
the A549 cell line, and 17 614-fold more active than 3c against
the HCT116 cell line). For 3d–3f (the benzene ring substituted
by Cl), 3d and 3e (benzene ring substituted by a single chlorine
atom) are more potent than 3f (benzene ring substituted by two
chlorine atoms); however, 3d (2-position of benzene ring
substituted by chlorine) is much more potent than 3e (4-posi-
tion of benzene ring substituted by chlorine), and 3d is the most
potent among 3a–3g. In fact 3d is 23 962-fold more active than
getinib against the A549 cell line, and 5904-fold more active
than getinib against the HCT116 cell line. This trend is
consistent with the isoxazole ring containing glycyrrhetinic acid
derivatives as anti-inammatory agents, as studied by us before
(for example, TY501 is the most potent among the isoxazole ring
containing glycyrrhetinic acid derivatives).20–22
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Acknowledgements
This work was nancially supported by the 973 key program of
the MOST (2010CB933501, 2012CB821705), the Chinese
Academy of Sciences (KJCX2-YW-319, KJCX2-EW-H01), the
National Natural Science Foundation of China (21373221,
21221001, 91022008, 91122027, 51172232) and Postdoctoral
Foundation of Fujian Province.
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