Synthesis and evaluation of novel ferrocenyl thiazole derivatives as anticancer agents

Article abstract of DOI:10.1080/15533170600651405

Novel ferrocenyl-containing thiazole derivatives have been synthesized from 2-amino-4-ferrocenyl-5-(1H-1,2,4-triazole-1-yl)-1,3-thiazole and substituted benzoyl chloride. The structures of these compounds have been characterized by ¹H NMR, elem

Full text of DOI:10.1080/15533170600651405

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Synthesis and Evaluation of Novel Ferrocenyl Thiazole
Derivatives as Anticancer Agents
Ling Shao a , Xin Zhou a , Yan Hu a , Zhong Jin a , Jianbing Liu a & Jian‐xin Fang a
a State Key Laboratory of Elemento‐Organic Chemistry , Institute of Elemento‐Organic
Chemistry, Nankai University , Tianjin, P. R. China
Published online: 15 Feb 2007.
To cite this article: Ling Shao , Xin Zhou , Yan Hu , Zhong Jin , Jianbing Liu & Jian‐xin Fang (2006) Synthesis and Evaluation of
Novel Ferrocenyl Thiazole Derivatives as Anticancer Agents, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-
Metal Chemistry, 36:4, 325-330
To link to this article: http://dx.doi.org/10.1080/15533170600651405
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Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 36:325–330, 2006
Copyright # 2006 Taylor & Francis Group, LLC
ISSN: 0094-5714 print/1532-2440 online
DOI: 10.1080/15533170600651405
Synthesis and Evaluation of Novel Ferrocenyl Thiazole
Derivatives as Anticancer Agents
Ling Shao, Xin Zhou, Yan Hu, Zhong Jin, Jianbing Liu, and Jian-xin Fang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin, P. R. China
Meanwhile, ferrocenyl units have been invoked as a bonus
Novel ferrocenyl-containing thiazole derivatives have been in the designing of new biologically active molecular, since
synthesized from 2-amino-4-ferrocenyl-5-(1H-1,2,4-triazole-1-yl)-
1,3-thiazole and substituted benzoyl chloride. The structures of
it is a neutral, chemically stable and non-toxic molecule, and
is able to cross cell membranes.[5] For example, ferrocifen,
which is a ferrocene derivative of tamoxifen, has been
these compounds have been characterized by 1H NMR, elemental
analysis and X-ray diffraction analysis. Evaluation of anticancer
prepared as an estradiol receptor site-directed cytotoxic agent
and was tested against a human breast cancer cell line, and
looks set to enter clinical trials in the near future.[6] Further-
more, if a molecule of an organic compound is incorporated
into a ferrocenyl moiety, it often obtains unexpected biological
activity, such as a new ferrocene-chloroquine analogue[7] and
novel ferrocenic artemisinin derivatives.[8]
activities showed that some of them possessed some degree of
anticancer activity.
Keywords 1,3-thiazole, ferrocenyl, anticancer activity
As a continuation of our studies on ferrocenyl-containing
derivatives[9–12] and our interest in 1,3-thiazole deriva-
tives,[13,14] and in a search for novel potent anticancer
compounds, we herein report the synthesis and structure of
a series of novel N-[4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-
1,3-thiazol-2-yl] substituted benzamide. New compounds
have been characterized by spectral data, elemental analysis
and crystal X-ray diffraction analysis. The anticancer effects
of the compounds from this series were investigated in vitro.
INTRODUCTION
Everyyear, millionsofpeopledie ofcancerinourworld.First-
line drugs, such as fluorouracil (5-FU), doxorubicin and camp-
tothecines, are effective against these cancer cells. These drugs,
however, result in irreversible damage to both normal and
tumorous cells, and bring toxicity and side-effects. So, we want
to provide some compounds that are useful as antitumor agents,
but without the drawbacks of the currently available anticancer
drugs.
Several 2-amino-1,3-thiazole derivatives are known as syn-
thetic intermediates and therapeutic agents. For example,
5-alkyl-2-phenylalkylcarbonylamino-1,3-thiazoles are known
as protein kinase C inhibitors,[1] 5-arylthio-2-acylamino-1,3-
thiazoles are known as antitumor agents,[2] phenylacetamido-
thiazole derivatives are known as anticancer agents,[3] and
2-(arylmethyl-carbonylamino)-1,3-thiazole derivatives are
known as cyclin-dependent kinase inhibitors.[4]
RESULTS AND DISCUSSION
Synthesis of 2-amino-4-ferrocenyl-5-(1H-1,2,4-triazol-
1-yl)-1,3-thiazole
First, a-bromoacetylferrocene was prepared according to the
methodology as described by Tarraga and co-workers.[15] Acet-
´
ylferrocene with LDA at 2788C, followed by a sequential treat-
ment with trimethylchlorosilane and an excess of NBS provided
the a-bromoacetylferrocene in 80% yield, along with a small
amount of a,a-dibromoacetylferrocene. The a-bromoacetyl-
ferrocene was then reacted with 1H-1,2,4-triazole by using
anhydrous potassium carbonate as a base in acetone achieving
a-triazolylacetylferrocene in good yield[9] (Scheme 1).
a-Bromo-a-1H-1,2,4-triazol-1-yl-acetylferroene (1) was
obtained by the same method as that of the a-bromoacetylferro-
cene with a 73% yield and no by-products were found. Sequen-
tially, compound 1 was heated with thiourea in ethanol under
Received 11 January 2006; accepted 22 January 2006.
We gratefully acknowledge the National Natural Science Foun-
dation of China (NNSFC) (Nos. 29872022, 20172030) and the Key
Project of Chinese Ministry of Education (No. 105046) for financial
support. The anticancer data was obtained from the State Key Labora-
tory of Natural and Biomimetic Drugs, Peking University.
Address correspondence to Jian-xin Fang, Institute and State Key
Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China. E-mail: fjx@nankai.edu.cn
325

326
L. SHAO ET AL.
SCH. 1.
reflux and a nitrogen atmosphere for 8 hours; the reaction we chose pyridine, which possesses alkalescency and is a
mixture was then alkalified by ammonia solution (5%) and strong solvent, and used magnetic stirring at room temperature
2-amino-4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-1,3-thiazole
for 8 hours. Most of the substituted benzoyl chloride 3 could
(2) was obtained in 72% yield. This reaction was investigated react with 2 to give 4, but the yields were relatively low.
under various conditions, including solution (methanol, When compound 2 was suspended in chloroform and
ethanol, isopropanol, acetone, acetonitrile) and ratio of pyridine, compound 3 was added in dropwise and heated
reagents. The best yield was attained when compound 1 and under reflux and in a nitrogen atmosphere, we obtained 4 in
thiourea (1 : 2 mole ratio) was reacted in ethanol at reflux a good yield (Scheme 2). While the solvent was pyridine and
under a nitrogen atmosphere.
benzoyl chloride was in excess, diacylation would occur and
1
The structure of compound 2 was confirmed by H NMR, afford N-[4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-1,3-thiazol-2-
elemental analysis and X-ray diffraction analysis. Figure 1 yl]-N-benzoylbenzamide (5) (Scheme 2).
shows the structure of compound 2, which we have reported
on in a previous paper.[14]
The structures of all new compounds were characterized by
1H NMR, elemental analysis and X-ray diffraction analysis.
Figure 2 shows the molecular structure of 4o, on which we
have recently reported.[16]
Synthesis of N-[4-Ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-
1,3-thiazol-2-yl] Substituted Benzamide
Anticancer Evaluation
Because the amino of 2-amino-4-ferrocenyl-5-(1H-1,2,4-
triazol-1-yl)-1,3-thiazole (2) is not active and the solubility
of 2 is small in general solvent, the reaction of compound 2
and 3 could not afford 4 when triethylamine was used as the
base and the solvent was benzene, toluene or dioxane. Then
2-Aminothiazole containing ferrocenyl moiety derivatives
(4, 5) were evaluated for their potential anticancer activity in
vitro on three human cancer cell lines including HL-60
leukemia, BGC-823 gastric carcinoma cells and Hep-2
laryngic carcinoma cells. Using SRB (sulforhodamin B) and
MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
FIG. 1. Molecular structure and atom labeling for compound 2; 30% thermal
ellipsoid is shown.
SCH. 2.

NOVEL FERROCENYL THIAZOLE DERIVATIVES AS ANTICANCER DRUGS
327
and 4l. The best activity was achieved by methoxyl substitution
at the ortho-position. Substitution at the para-position showed
a decrease in activity in all cell lines. Although the meta- and
para-methoxyl on phenyl ring were less active than the
ortho-methoxyl compounds, methoxyl substitution at both
the meta- and ortho-position provided the most active
compound in this series.
Comparison of the results of compounds 4a and 5, the inhi-
bition percentage of 5 are higher than that of 4a on all cancer
cell lines. It is suggested that introducing a big unit on the
side chain of the amino group could enhance anticancer
activity.
Summary
FIG 2. Molecular structure and atom labeling for compound 4o; 30% thermal
ellipsoid is shown.
In summary, we have synthesized a series of N-[4-ferro-
cenyl-5-(1H-1,2,4-trizaol-1-yl)-1,3-thiazol-2-yl] substituted
benzamide, 4a–4o, and their structures were established on
bromide] assay, the result of inhibition percentages of human
tumor cell lines in the presence of selected compounds 4 and
5 in DMSO are presented in Table 1. Some compounds were
found to have good activity against these three human tumor
cell lines on tested concentrations (10 mM). Compound 4j
showed good cytotoxic activities on HL-60 leukemia, BGC-
823 gastric carcinoma cells and Hep-2 laryngic carcinoma
cells with 81.40, 63.41, and 53.11% inhibition percentages,
respectively, on the tested concentration (10 mM).
Compound 4 had similar structure and differed only in the
substitution on the phenyl ring. The results strongly suggest
that these differences influenced the activities of compounds.
Thiazole 4f with an electron-withdrawing para-chloro substitu-
ent on phenyl ring showed increased efficacy over the electron-
1
the basis of H NMR spectral data and elemental analysis.
Finally, the structures of compounds 2 and 4o were confirmed
by X-ray crystallographic studies. These novel ferrocenyl-
containing thiazole derivatives have also been screened for
their anticancer activity against three human cancer cell
lines. Thiazole 4j, 4k and 5 all showed good inhibition percen-
tages against human cancer cell lines. These compounds
represent promising lead compounds for the development of
thiazole-containing anticancer agents and are candidates for
further studies.
EXPERIMENT
All melting points were determined on a Yanaco-241 appar-
donating para-methoxyl thiazole 4l in all human cell lines. atus and the thermometer was uncorrected. The 1H NMR
Methoxyl substitution at the ortho-, meta- and para-positions spectra were measured on a Brucker AC-300 spectrometer in
on phenyl ring was also investigated with compounds 4j, 4 k DMSO-d6 or CDCl3 solution with TMS as the internal standard.
Elemental analyses were determined on a Yanaco CHN
CORDER MT-3 elemental analyser. X-ray diffraction data
TABLE 1
were recorded at 293 K on a Bruker Smart1000 diffractometer
Inhibition percentages of three human tumor cell lines in
the presence of selected compounds 4 (%)
˚
(graphite-monochromatized Mo Ka radiation, l ¼ 0.71073 A).
HL-60
(leukemia)
(MTT)
BGC-823
(gastric)
(SRB)
Hep-2
(laryngic)
(SRB)
Synthesis of a-Bromo-a-1H-1,2,4-triazol-1-yl-
acetylferrocene (1)
Comp.
(10 mM)
A
solution of a-1H-1,2,4-triazol-1-yl-acetylferrocene
(12.3 g, 43.8 mmol) in anhydrous THF (150 ml) was added in
dropwise to a solution of LDA (72.3 mmol) in anhydrous
THF (20 ml) at 2788C and under a nitrogen atmosphere. The
reaction mixture was stirred at 2788C for 2 hr and then tri-
methylchlorosilane (57 mmol) was added. After 4 hr under
these reaction conditions, NBS (9.92 g, 57 mmol) was added
and the solution was stirred until the reaction reached room
temperature (8 h). The reaction mixture was filtered through
a silica gel layer, and the resulting solution was evaporated
to dryness and chromatographed on a silica gel column using
ethyl acetate/petroleum ether (V/V ¼ 1/3) as eluent to give
compound 1 11.96 g in 73% yield; m.p. 114–1168C.
4a
4b
4d
4e
4f
4g
4j
4k
4l
23.40
30.51
21.53
27.66
24.32
8.22
20.74
9.85
5.24
4.01
7.65
21.38
9.63
2.04
25.96
27.43
1.15
21.22
53.11
31.56
20.70
12.31
32.90
81.40
62.00
12.03
15.88
76.14
63.41
30.15
23.08
27.52
27.18
4m
5

328
L. SHAO ET AL.
Synthesis of 2-amino-4-ferrocenyl-5-(1H-1,2,4-triazol-
1-yl)-1,3-thizole (2)
washed with water and dried. Purification by chromatograph
on a silica gel column using ethyl acetate/petroleum ether
(V/V ¼ 1/3) as eluent afforded 4a–4o in various yields. The
physical properties, elemental analysis data and 1H NMR
data of compound 4 thus synthesized are reported in Table 2
and Table 3, respectively.
A
mixture of a-bromo-a-1H-1,2,4-triazol-1-yl-acetyl-
ferrocene (1) (10.85 g, 29 mmol) and thiourea (4.41 g,
58 mmol) in anhydrous ethanol was refluxed for 8 hr under a
nitrogen atmosphere. Then the mixture was alkalified by
ammonia solution (5%). Allowed to cool overnight, the preci-
pitated product was collected by filtration, washed with water
and dried. Recrystallization from methanol afforded the
Synthesis of N-[4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-
1,3-thiazol-2-yl]-N-benzoylbenzamide (5)
desired
2-amino-4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-1,
Benzoyl chloride (1.4 g, 10 mmol) was added dropwise to a
solution of 2-amino-4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-
1,3-thiazole (0.35 g, 1.0 mmol) in dry pyridine (20 ml). After
stirring for 8 hr at room temperature, the reaction mixture
was poured into water (150 ml). After 2 days the precipitate
was collected, washed with water and dried. Recrystallization
from ethanol, 0.26 g red crystalloid (5) was obtained (yield
46.48%). m.p. 277–2798C. Anal. (%) C, 62.41; H, 3.65; N,
12.47; Calc. for C29H21FeN5O2S: C, 62.26; H, 3.78; N,
12.52; 1H NMR d (DMSO-d6): 9.00 (s, 1H, Tr-H), 8.42
(s, 1H, Tr-H), 7.92–7.56 (m, 10H, phenyl-H), 4.19 (s, 2H,
Fc-H), 3.77 (s, 2H, Fc-H), 3.70 (s, 5H, Fc-H).
3-thiazole 7.33 g, in 72% yield; m.p. 248–2508C. Anal. (%)
C, 51.30; H, 3.73; N, 19.94; Calc. for C15H13FeN5S: C,
51.35; H, 3.61; N, 19.72; 1H NMR d (DMSO-d6): 8.88
(s, 1H, Tr-H), 8.34 (s, 1H, Tr-H), 7.44 (s, 2H, NH2), 4.07
(s, 5H, Fc-H), 4.22–4.20 (t, 2H, Fc-H), 3.93–3.91 (t, 2H, Fc-
H).
Synthesis of N-[4-ferrocenyl-5-(1H-1,2,4-triazol-1-yl)-
1,3-thiazol-2-yl] substituted Benzamide (4)
To
a suspended solution of 2-amino-4-ferrocenyl-5-
(1H-1,2,4-triazol-1-yl)-1,3-thiazole (0.35 g, 1.0 mmol) and
pyridine (0.12 g, 1.5 mmol) in chloroform (20 ml), the
solution of substituted benzoyl chloride (1.2 mmol) in chloro-
form (5 ml) was added in dropwise under a nitrogen atmos-
phere. Then the mixture was heated under reflux for 3–5 hr,
Supplementary Material
Crystallographic data for the structure 2 and 4o have been
cooled and freed from solvent in vacuum. The residue was deposited with the Cambridge Crystallographic Data Center,
TABLE 2
Physical properties and elemental analysis of compound 4
Elemental analysis (%); Found (Calcd)
Yield
Component
R1
(%)
m.p. (8C)
Formula (g/mol)
C
H
N
4a
4b
4c
4d
4e
H
41.7
44.4
42.3
48.6
49.0
271–273
174–176
216–218
248–250
237–239
C22H17FeN5OS 455.31
C22H16FFeN5OS 473.30
C22H16FFeN5OS 473.30
C22H16FFeN5OS 473.30
C22H16ClFeN5OS
489.76
57.90 (58.03)
55.88 (55.83)
55.63 (55.83)
55.81 (55.83)
53.80 (53.95)
3.78 (3.76)
3.59 (3.41)
3.43 (3.41)
3.84 (3.41)
3.33 (3.29)
15.11 (15.38)
14.70 (14.80)
14.79 (14.80)
14.79 (14.80)
14.48 (14.30)
o-F
m-F
p-F
o-Cl
4f
p-Cl
o-Br
p-Br
51.0
43.1
44.9
223–225
254–256
C22H16ClFeN5OS
489.76
53.96 (53.95)
49.33 (49.46)
49.31 (49.46)
3.39 (3.29)
3.22 (3.02)
3.19 (3.02)
14.44 (14.30)
12.98 (13.11)
13.07 (13.11)
4g
4h
C22H16BrFeN5OS
534.21
246 darkness C22H16BrFeN5OS
534.21
4i
4j
m-I
53.4
43.3
41.2
45.4
46.9
47.6
46.0
144–147
190–193
188–191
C22H16FeIN5OS 581.21
C23H19FeN5O2S 485.34
C23H19FeN5O2S 485.34
45.46 (45.46)
56.78 (56.92)
57.09 (56.92)
56.84 (56.92)
58.76 (58.86)
59.51 (59.64)
53.68 (53.71)
3.00 (2.77)
3.82 (3.95)
3.79 (3.95)
4.01 (3.95)
4.04 (4.08)
4.40 (4.38)
3.73 (3.53)
11.87 (12.05)
14.42 (14.43)
14.48 (14.43)
14.46 (14.92)
14.80 (14.92)
14.24 (14.49)
16.63 (16.34)
o-OCH3
m-OCH3
p-OCH3
p-CH3
4k
4l
4m
4n
4o
275 darkness C23H19FeN5O2S 485.34
239–242
233–235
231–233
C23H19FeN5OS 469.34
C24H21FeN5OS 483.37
C22H16FeN6O3S 500.31
p-C2H5
o-NO2

NOVEL FERROCENYL THIAZOLE DERIVATIVES AS ANTICANCER DRUGS
329
TABLE 3
1H NMR spectral data of compounds 4
Component
1H NMR (DMSO or CDCl3/TMS, d)
4a (DMSO)
9.382 (s, 1H, N-H); 9.024 (s, 1H, Tr-H); 8.439 (s, 1H, Tr-H); 8.180, 8.156 (d, 2H, Ph-H); 7.711–7.560 (m, 3H,
Ph-H); 4.324, 4.319, 4.313 (t, 2H, Fc-H); 4.125, 4.119, 4.113 (t, 2H, Fc-H), 4.092 (s, 5H, Fc-H)
9.929, 9.881 (d, 1H, N-H); 8.281 (s, 1H, Tr-H); 8.246 (s, 1H, Tr-H); 7.687–7.280 (m, 4H, Ph-H); 4.264 (s, 2H,
Fc-H); 4.198 (s, 2H, Fc-H); 4.111 (s, 5H, Fc-H)
4b (CDCl3)
4c (CDCl3)
4d (DMSO)
4e (DMSO)
4f (DMSO)
4g (DMSO)
4h (CDCl3)
4i (CDCl3)
4j (CDCl3)
4k (CDCl3)
4l (CDCl3)
4m (CDCl3)
4n (CDCl3)
9.647 (s, 1H, N-H); 8.290 (s, 1H, Tr-H); 8.259 (s, 1H, Tr-H); 7.792–7.331 (m, 4H, Ph-H); 4.279 (s, 2H, Fc-H);
4.175 (s, 2H, Fc-H); 4.117 (s, 5H, Fc-H)
9.375 (s, 1H, N-H); 9.009 (s, 1H, Tr-H); 8.435 (s, 1H, Tr-H); 8.263–8.215 (q, 2H, Ph-H); 7.453–7.394 (q, 2H,
Ph-H); 4.330, 4.324, 4.317 (t, 2H, Fc-H); 4.120, 4.117, 4.107 (t, 2H, Fc-H); 4.091 (s, 5H, Fc-H)
9.375 (s, 1H, N-H); 9.018 (s, 1H, Tr-H); 8.438 (s, 1H, Tr-H); 7.726–7.464 (m, 4H, Ph-H); 4.316, 4.310, 4.304
(t, 2H, Fc-H); 4.087 (s, 7H, Fc -H)
9.375 (s, 1H, N-H); 9.009 (s, 1H, Tr-H); 8.435 (s, 1H, Tr-H); 8.263–8.215 (q, 2H, Ph-H); 7.453–7.394 (q, 2H,
Ph-H); 4.330, 4.324, 4.317 (t, 2H, Fc-H); 4.120, 4.117, 4.107 (t, 2H, Fc-H); 4.091 (s, 5H, Fc-H)
9.374 (s, 1H, N-H); 9.016 (s, 1H, Tr-H); 8.439 (s, 1H, Tr-H); 7.779–7.495 (m, 4H, Ph-H); 4.322, 4.316, 4.310
(t, 2H, Fc-H); 4.088 (s, 7H, Fc-H)
9.749 (s, 1H, N-H); 8.278 (s, 1H, Tr-H); 8.257 (s, 1H, Tr-H); 7.903, 7.875 (d, 2H, Ph-H, J ¼ 8.4); 7.733, 7.705
(d, 2H, Ph-H, J ¼ 8.4); 4.276 (s, 2H, Fc-H); 4.169 (s, 2H, Fc-H); 4.113 (s, 5H, Fc-H)
8.341 (s, 1H, N-H); 8.304 (s, 1H, Tr-H); 8.269 (s, 1H, Tr-H); 7.995–7.309 (m, 4H, Ph); 4.281 (s, 2H, Fc);
4.172 (s, 2H, Fc); 4.120 (s, 5H, Fc)
9.358 (s, 1H, N-H); 9.003 (s, 1H, Tr-H); 8.432 (s, 1H, Tr-H); 7.736–7.090 (m, 4H, Ph-H); 4.316, 4.311 (d, 2H,
Fc-H); 4.084, 4.079 (d, 7H, Fc-H); 3.964, 3.930 (d, 3H, OCH3)
9.371 (s, 1H, N-H); 9.011 (s, 1H, Tr-H); 8.435 (s, 1H, Tr-H); 7.750–7.224 (m, 4H, Ph-H); 4.329, 4.323, 4.317
(t, 2H, Fc-H); 4.125, 4.119, 4.113 (t, 2H, Fc-H); 4.092 (s, 5H, Fc-H); 3.883 (s, 3H, OCH3)
9.483 (s, 1H, N-H); 8.280 (s, 1H, Tr-H); 8.256 (s, 1H, Tr-H); 7.984, 7.955 (d, 2H, Ph-H, J ¼ 8.7); 7.053, 7.024
(d, 2H, Ph-H, J ¼ 8.7); 4.260 (s, 2H, Fc-H); 4.163 (s, 2H, Fc-H); 4.109 (s, 5H, Fc-H); 3.912 (s, 3H, OCH3)
9.628 (s, 1H, N-H); 8.269 (s, 1H, Tr-H); 8.247 (s, 1H, Tr-H); 7.924, 7.897 (d, 2H, Ph-H, J ¼ 8.1); 7.385, 7.358
(d, 2H, Ph-H, J ¼ 8.1); 4.267 (s, 2H, Fc-H); 4.170 (s, 2H, Fc-H); 4.114 (s, 5H, Fc-H); 2.472 (s, 3H, CH3)
9.513 (s, 1H, N-H); 8.272 (s, 1H, Tr-H); 8.246 (s, 1H, Tr-H); 7.941, 7.914 (d, 2H, Ph-H, J ¼ 8.1); 7.407, 7.380
(d, 2H, Ph-H, J ¼ 8.1); 4.272 (s, 2H, Fc-H); 4.176 (s, 2H, Fc-H); 4.119(s, 5H, Fc-H); 2.804–2.727 (q, 4H,
CH2); 1.326, 1.300, 1.275 (t, 3H, CH3)
4o (DMSO)
9.377 (s, 1H, N-H); 9.019 (s, 1H, Tr-H); 8.433 (s, 1H, Tr-H); 8.245–7.839 (m, 4H, Ph); 4.325, 4.319, 4.312
(t, 2H, Fc); 4.088, 4.078, 4.072 (t, 7H, Fc)
(Tr: triazole; Fc: ferrocenyl).
Phenylacetamido-thiazole derivatives, process for the prep-
aration and their use as antitumor agents. US Patent
2,004,235,919, 2004.
CCDC Nos. 277231 and 285959. Copies of this information
may be obtained free of charge from: The Director, CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK kFax: þ44-1223-
336033; email: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.ukl.
4. Arylmethyl-carbonylamino-thiazole derivatives and their use as
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