Synthesis and pharmacological evaluation of 1H-imidazoles as ligands for the estrogen receptor and cytotoxic inhibitors of the cyclooxygenase

Article abstract of DOI:10.1021/jm050190u

The 1H-imidazoles 7a-e were synthesized and tested for biological activity in vitro. The results pointed to a clear structure-activity relationship. The introduction of an ethyl chain at C5 of the 1,2,4-tris(4-hydroxyphenyl)-1H- imidazole 7 a caused hormo

Full text of DOI:10.1021/jm050190u

6516
J. Med. Chem. 2005, 48, 6516-6521
Brief Articles
Synthesis and Pharmacological Evaluation of 1H-Imidazoles as Ligands for the
Estrogen Receptor and Cytotoxic Inhibitors of the Cyclooxygenase
Thomas Wiglenda,† Ingo Ott,† Brigitte Kircher,‡ Petra Schumacher,‡ Daniela Schuster,§ Thierry Langer,§ and
Ronald Gust†,*
Institute of Pharmacy, Free University of Berlin, Ko¨nigin-Luise Strasse 2+4, D-14195 Berlin, Germany, Laboratory for Tumor
and Immunobiology, Division of Hematology & Oncology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck,
Austria, and Institute of Pharmacy, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria
Received March 1, 2005
The 1H-imidazoles 7a-e were synthesized and tested for biological activity in vitro. The results
pointed to a clear structure-activity relationship. The introduction of an ethyl chain at C5 of
the 1,2,4-tris(4-hydroxyphenyl)-1H-imidazole 7a caused hormonal activity in estrogen receptor
positive MCF-7-2a cells. An o-chlorine substituent in the phenolic rings at C2 and C4 as realized
in 7b and 7c increased the antiproliferative effects against human breast cancer cell lines
MCF-7 and MDA-MB 231. Additionally, both compounds showed strong inhibitory effects on
cyclooxygenase enzymes. Therefore, a mode of action including the interference in the
arachidonic acid cascade might be possible.
Introduction
the COX-2 selective inhibitor 4-[5-(4-chlorophenyl)-3-
(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(SC-236).8 Furthermore, the induction of tumor cell
apoptosis was verified for both compounds as conse-
quence of a COX inhibition.9
Estradiol (E2) is one of the native ligands of the
estrogen receptor (ER) and plays an essential role in
regulating normal physiological processes such as the
development and function of the reproductive and
cardiovascular system or bone density.1-3 Nonsteroidal
estrogenic (e.g. diethylstilbestrol) and antiestrogenic
ligands (e.g. raloxifene) have been developed to regulate
these processes or their pathological dysfunction, in-
cluding breast cancer, osteoporosis, and infertility.
Selective estrogen receptor modulators (SERMs) are
the most recently approved class of antiresorptive drugs.
In some tissues, such as bone, SERMs imitate the effects
of estrogens, while they act as antiestrogens on uterine
and breast tissue and block unwanted estrogenic effects.
Most potent SERMs consist of a heterocyclic core (e.g.
pyrazoles,4 furans5 or 2-imidazolines,6 and piperazines7)
substituted with aromatic rings or alkyl chains and
resemble a large number of nonsteroidal antiinflamma-
tory drugs (NSAIDs) which exert their activity mainly
through inhibition of cyclooxygenases (COX) the key
enzymes of the prostaglandin (PG) biosynthesis.
These results and the high structural analogy of our
already described trisubstituted 1H-imidazoles to cele-
coxib and SC-236, but especially to the COX-inhibitors
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-(trifluorometh-
yl)-1H-imidazole (Im-I) and 2-(4-chlorophenyl)-1-[4-
(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole (Im-II),
induced us to use 1,2,4-tris(4-hydroxyphenyl)-1H-imi-
dazole 7a as a lead structure. We studied the influence
of an ethyl chain at C5, the 4-hydroxyphenyl-trifluoro-
methyl exchange at C4 and the introduction of o-
chlorine substituents in the C2/C4 standing phenolic
rings on hormonal, cytotoxic, and COX-inhibiting prop-
erties.
Chemistry. The 1,2-diaryl-, 1,2,4-triaryl-, and 1,2,4-
triaryl-5-alkyl-1H-imidazoles were prepared as depicted
in Scheme 1. N-Arylbenzamidines 3a and 3b were
synthesized as key intermediates from aryl nitriles (1,
2) and anisidine according to Gautier10 or Daoust11
using sodium amide as condensation agent.
During the past few years, cyclooxygenases (COX-1
and COX-2) were discussed as new targets for antican-
cer drugs, since abnormally high levels of COX-2 protein
were observed in several types of cancer and precan-
cerous tissue, including breast cancer. COX-2 proteins
increase new blood vessel formation and proliferation.
A tumor growth inhibition can thus be achieved by
blocking COX-2 as demonstrated for indomethacin and
The subsequent reaction with the R-bromoketones12,13
(4, 5a-c) at room temperature in a mixture of CHCl3/
H2O (6/1) utilizing K2CO3 as base resulted in 1H-
imidazoles. This cyclization took place with high regio-
selectivity and quantity because neither regioisomers
of 6a-e nor 4-hydroxy-2-imidazolines as intermedi-
ates14,15 could be separated from the reaction mixture.
The necessary ether cleavage to afford the phenols 7a-e
was performed with boron tribromide.
* To whom correspondence should be addressed. Phone: 0049 (0)
30 838 53272. Telefax: 0049 (0) 30 838 56906. Email: rgust@
zedat.fu-berlin.de.
The structural characterization of the 1H-imidazoles
was exemplarily performed for compound 7a by double
resonance nuclear Overhauser enhancement experiment
† Free University of Berlin.
‡ Medical University Innsbruck.
§ University of Innsbruck.
10.1021/jm050190u CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/14/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20 6517
Scheme 1
conjugates to the estrogen response element (ERE) of
the plasmid leads to the expression of luciferase, which
correlates well with the estrogenic potency of the drug.17
As depicted in Figure 1A, the C(5)-ethyl derivative
7d activated the luciferase expression with an EC50
)
7.7 × 10-8 M (E2 ) 8.0 × 10-11 M). All other compounds
were inactive. Interestingly, the concentration activation
curves indicated for the 2-Cl substituted derivatives 7b
and 7c distinctly negative relative activations of -37%
at a concentration of 10 µM. This effect was the
consequence of a strong reduction of the cell density and
not of antiestrogenic properties because the compounds
were not able to antagonize the effect of estradiol (data
not shown) but indicated cytotoxic properties as verified
in time-dependent in vitro assays (Figure 2).18,19
Both compounds reduced the growth of hormone-
dependent MCF-7 breast cancer cells whereby 7b (T/C
≈ 50% at 10 µM, Figure 2A) proved to be less cytotoxic
than 7c (T/C ≈ 0% at 10 µM; see Figure 2B). Hormone
independent MDA-MB 231 cells treated with 7b and 7c
(Figure 2C, D) showed a growth characteristic at lower
concentrations (1 and 5 µM) comparable to MCF-7 cells
with the restriction that in the case of 7c the cells
recuperated after 90 h and showed an onset of prolifera-
tion. At 10 µM, however, the effects of 7b and 7c differ
from the one observed in the MCF-7 cell line: 7b was
more active than 7c and caused cytocidal effects (τ )
-20%) already after 80 h of incubation while 7c reached
its maximal effect at the end of the test (142 h). It should
be noted that the other compounds (7a, 7d, 7e) were
not able to exert an influence on the growth of MCF-7
and MDA-MB 231 cells (data not shown).
(NOESY) and confirmed the 1,2,4-tris(4-hydroxyphen-
yl)-1H-imidazole formation.
Biological Activity. A luciferase assay16 using ER
positive MCF-7 breast cancer cells stably transfected
with the plasmid EREwtcluc (MCF-7 2a cells) was used
to study the ER interaction of the 1H-imidazoles 7a-e
on molecular level. The binding of dimeric ER/drug
Figure 1. Activation (%) of luciferase gene expression in MCF-7 2a cells by the 1H-imidazoles 7a-e. Values expressed are the
means ( SE of 3-fold determination in a single experiment (A). Induction of apoptosis in MDA-MB 231 cells during the incubation
with imidazoles 7b and 7c. The mean apoptosis of three experiments is shown (B). Inhibition of COX-1 and COX-2 enzymatic
activity by the 1H-imidazoles 7a-e in concentrations of 1, 10, and 200 µM (C, D).

6518 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20
Brief Articles
Figure 2. Growth curves of MCF-7 (A, B) and MDA-MB 231 (C, D) breast cancer cells in the presence of the 1,2,4-triaryl-1H-
imidazoles 7b and 7c. Cell density was determined by crystal violet staining expressed as T/Ccorr ) [(T - C0)/(C - C0)] × 100 [%]
with T (test), C (control), and C0 (cell extract immediately before compound treatment). Values expressed are the means ( SE of
16-fold determination in a single experiment.
To get more insight into the mode of action, we
quantified the ssDNA (single stranded DNA) in MDA-
MB 231 cells as an indicator of apoptosis.20 As expected,
neither the short time incubation (2 h) nor incubation
for 120 h of MDA-MB 231 cells (data not shown) with
7b nor 7c in lower concentrations induced apoptosis.
Only in concentrations of 25 and 50 µM ssDNA values
significantly increased (see Figure 1B). These concen-
trations correspond very well with those used in the
cytotoxicity assay because a significantly higher amount
of tumor cells was used in the apoptosis assay.
The knowledge of the relevance of cyclooxygenase
enzymes (COX-1 and COX-2) for the proliferation of
MCF-7 and MDA-MB 231 cells as well as the findings
that COX-inhibitors caused tumor cell apoptosis induced
us to evaluate the interaction of the 1H-imidazoles 7a-e
with isolated ovine COX-1 and human recombinant
COX-2 in an enzyme linked immunsorbant assay (ELISA,
see Figure 1C,D).
Three phenolic OH-groups (the respective methoxy
derivatives were inactive; data not shown) and espe-
cially a C(5)-ethyl chain (compare 7a and 7d) were
necessary for estrogenic activity. In contrast to the
results obtained with compounds out of the 2,3-dia-
rylpiperazine7,21 and 4,5-diaryl-2-imidazoline6,21 series,
the enhanced lipophilicity due to chlorination of the
C(2)- and C(4)-standing phenolic ring did not result in
estrogenically active compounds but led to derivatives
with enhanced antiproliferative properties. The 1H-
imidazoles 7b und 7c reduced the growth of MCF-7 as
well as MDA-MB 231 cells. The high activity at the
hormone-independent MDA-MB 231 cell line and the
lack of ability to antagonize the effects of estradiol made
an antiestrogenic mode of action unlikely. More likely
was an interference of 7b and 7c in the prostaglandin
biosynthesis, as previous examinations22 showed that
hormone-dependent MCF-7 cells exhibited a relatively
high expression of COX-1. COX-2 was barely detectable
but was transiently induced by treatment with tetra-
decanoyl phorbol acetate. The hormone-independent
MDA-MB 231 cell line showed a low COX-1 expression
but a high constitutive level of COX-2. 7b and 7c are
potent inhibitors of COX-1 and COX-2 and inhibited the
growth of both cell lines.
In these experiments the reference substance aspirin
showed only a weak inhibition of COX-1 (80% at 200
µM) and was inactive at COX-2 while the second
reference indomethacin was much more active (COX-1
inhibition: 56%; COX-2 inhibition: 100%; concentra-
tion: 10 µM).
The cytotoxic 1H-imidazoles 7b and 7c showed con-
centration-dependent effects and reduced both the
activity of COX-1 and COX-2. The IC50 value for COX-1
inhibition amounted to 8.4 µM for both compounds. At
COX-2 7c was slightly more active with IC50 ) 9.4 µM
(7b: IC50 ) 11.5 µM). Among the “noncytotoxic” com-
pounds, 7a (IC50 ) 12.2 µM) and 7d (IC50 > 200 µM)
were able to reduce the COX-1 activity slightly. At COX-
2, 7a, 7d, and 7e were inactive in the used concentra-
tions (see Figure 1C,D).
The COX inhibitory effects showed a clear structural
dependence. The C(4)-phenol ring was necessary for
high activity. Ortho-chlorination of the C(4)-phenol ring
at 7a increased the activity at both COX-1 and COX-2.
The attempt to further enhance the potency through the
introduction of an additional 2-Cl substituent in the
C(2)-phenol ring failed. The exchange of the C(4)-phenol
ring by a CF3 group, which is characteristic for a lot of
selective COX-2 inhibitors, led to a complete loss of
activity (see 7e). These findings (unselective COX
inhibition) are in accordance with an extensive number
of investigations which emphasized on the importance
of a p-SO2NH2- or p-SO2CH3-substituted phenyl for the
COX-2 selectivity as shown for celecoxib and SC-236 or
the 1H-imidazoles Im-I and Im-II.14,15 Additionally, the
studies with these compounds confirmed our findings
about the importance of the C(4)-aryl ring for high COX
inhibition. The 1,2,4-triaryl-1H-imidazole Im-II was
much more active than the C(4)-CF3 derivative Im-I.14
Discussion
This SAR study throws light on a widely examined
but unresolved aspect about the connection of antipro-
liferative effects on tumor cell lines and COX inhibition.
We synthesized 1,2,4-triaryl-1H-imidazoles in order to
get effective ligands for the ER. Although the number
of tested compounds is limited, some structure-activity
relationships can be worked out.

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20 6519
Figure 3. The active compounds 7b and 7c superimposed on the COX-1 model (left) and the COX-2 model (middle). The colored
spheres represent chemical features of the ligand: hydrophobic (cyan), hydrophobic aromatic (blue), hydrogen bond acceptors
(green). Amino acid residues flanking the binding pocket are represented by exclusion volume spheres depicted as black spheres.
Compound 7d (ball-and-stick style) and R,R-5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (mesh style) fitted into the
model for ER activators (right). The highlighted ethyl residue of 7d maps a hydrophobic feature of the model.
To get an insight into the possible mechanism of
interaction with the cyclooxygenase enzymes, we fitted
the compounds 7a-e into structure-based pharmaco-
phore models of COX-1 and COX-2.
To rationalize the potent ER activation observed with
7d, the compound was fitted into a structure-based
model of ER based on the PDB crystal structure 1l2i.25
The fitting conformation was then compared with the
bioactive conformation of the cocrystallized ER activator
R,R-5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-
diol (Figure 3 right).
7d maps well into the model for ER activators. The
ethyl group of 7d which is not present in all other
compounds from this series fits into a hydrophobic
feature and might thus constitute an essential interac-
tion site with the ER receptor.
In crystallization experiments, it was observed that
all COX-1 inhibitors interacted with the putative cata-
lytic amino acid residue Tyr385 and formed hydrogen
bonds with Arg120. Many COX-1 inhibitors additionally
interact with Tyr355 via a second hydrogen bond.23
When mapping the active compounds 7b and 7c into
the COX-1 model (Figure 3 left), it could be observed
that the HYDROPHOBIC-11 (HBA-11) feature in close
vicinity to Tyr385 was well mapped by the chlorinated
phenol ring. The 4-hydroxyphenyl ring might hypotheti-
cally bind via a hydrogen bond and charge-transfer
interaction to Tyr385. The HBA-11 feature representing
the hydrogen bond acceptor partner for Arg120 was also
well mapped by 7b and 7c. Because of the close vicinity
of Arg120 and Tyr355 to each other, a bifurcated
hydrogen bond between the phenolic hydroxyl group and
these residues could be possible.
For COX-2, three distinct anchoring sites that con-
tributed to substrate and inhibitor binding have been
identified in crystallization and site-directed mutagen-
esis experiments. One major anchor point lies at the
junction of Arg120 and Tyr355. The second anchor point
is a side pocket defined by the residues Tyr355, Val523,
His90, Gln192, and Arg513. At the top of the active site,
additional interactions with Tyr385 and Ser530 con-
tribute to inhibitor binding.24 In the COX-2 model, the
HYDROBHOB aromatic-11 feature represents an aro-
matic ligand substructure in the range of Tyr385. This
feature is well mapped by the highly active compounds
7b and 7c (Figure 3 middle). The HBA-fluor feature
localizes hydrogen bond acceptor structures that are in
an ideal position for forming bifurcated hydrogen bonds
with Arg120 and Tyr355. However, this feature is not
mapped by the active compounds and seems therefore
not to be essential for COX-2 inhibition. In the phar-
macophore model, interactions with the side pocket
anchor point are represented by the HYDROPHOB
aromatic-1 feature (hydrophobic interaction with Val523)
and the HBA-sulfonamide feature (hydrogen bond with
Arg513) which are well mapped by 7b and 7c.
Conclusion
1,2-Diaryl- and 1,2,4-triaryl-1H-imidazoles were syn-
thesized and investigated for pharmacological activity.
While a (C5)-ethyl chain and the presence of three
phenolic rings led to a compound with hormonal activity,
o-chlorine substituents in the aromatic rings increased
the cytotoxicity but not the estrogenicity. A mode of
action might be possible in which inhibition of COX
enzymes plays a major role.
Experimental Section
General Procedure for the Ether Cleavage with BBr3.
A solution of the methyl ether (1.00 mmol) in 20 mL of dry
CH2Cl2 was cooled to -60 °C. BBr3 (4.5 mmol) in 5 mL of dry
CH2Cl2 was added at this temperature under N2 atmosphere.
Then the reaction mixture was allowed to warm to room
temperature and was stirred for further 18 h. After the
reaction mixture was cooled with an ice bath, the surplus of
BBr3 was hydrolyzed three times with methanol and the
phenolic product was dissolved in 10% NaHCO3 (50 mL). The
solution was extracted with CH2Cl2 (3 × 20 mL), and the
organic layers were combined and dried over Na2SO4. The
solvent was removed under reduced pressure, and the result-
ing crude product was purified by chromatography on silica
gel.
1,2,4-Tris(4-hydroxyphenyl)-1H-imidazole (7a). From
6a (429 mg, 1.11 mmol) and BBr3 (420 µL, 4.44 mmol); column
chromatography with gradual elution, CH2Cl2/methanol: 95/
5, 9/1, 3/1. Yield: 375 mg (98%); colorless solid (mp: 147-152
°C). TLC Si2O (CH2Cl2/MeOH: 9/1): Rf ) 0.3. 1H NMR
(DMSO-d6): δ ) 9.80 (s, 1H, OH), 9.64 (s, 1H, OH), 9.34 (s,
1H, OH), 7.65 (d, 2H, J ) 8.5 Hz, ArH), 7.58 (s, 1H, 5-H), 7.18

6520 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20
Brief Articles
(d, 2H, J ) 8.7 Hz, ArH), 7.12 (d, 2H, J ) 8.7 Hz, ArH), 6.82
(d, 2H, J ) 8.7 Hz, ArH), 6.77 (d, 2H, J ) 8.6 Hz, ArH), 6.67
(d, 2H, J ) 8.7 Hz, ArH). MS (EI, 60°C): m/z (%) ) 344 [M]+•
(100), 225 (79). IR (KBr): νj ) 3389 (m), 1612 (m), 1514 (s),
1444 (m), 1246 (s), 1170 (m), 836 (s). Anal. (C21H16N2O3) C, H,
N.
4-(2-Chloro-4-hydroxyphenyl)-1,2-bis(4-hydroxyphenyl)-
1H-imidazole (7b). From 6b (125 mg, 0.30 mmol) and BBr3
(127 µL, 1.34 mmol); column chromatography with CH2Cl2/
methanol: 9/1. Yield: 112.4 mg (89%); colorless solid (mp: 262
°C). TLC Si2O (CH2Cl2/methanol: 9/1): Rf ) 0.6. 1H NMR
(DMSO-d6): δ ) 12.14 (s, 1H, OH), 9.90 (s, 1H, OH), 9.78 (s,
1H, OH), 7.90 (s, 1H, 5-H), 7.82 (d, 1H, J ) 8.3 Hz, ArH), 7.22-
7.18 (m, 4H, ArH), 6.94 (d, 1H, J ) 2.1 Hz, ArH), 6.90 (dd,
1H, J ) 2.1 Hz, J ) 8.3 Hz, ArH), 6.86 (d, 2H, J ) 8.7 Hz,
ArH), 6.72 (d, 2H, J ) 8.7 Hz, ArH). MS (EI, 340 °C): m/z (%)
) 378 [M]+• (100), 212 (57), 44 (36). IR (KBr): νj ) 3427 (m),
1612 (m), 1518 (s), 1439 (m), 1245 (m), 838 (m). Anal. (C21H15-
ClN2O3) C, H, N.
2,4-Bis(2-chloro-4-hydroxyphenyl)-1-(4-hydroxyphenyl)-
1H-imidazole (7c). From 6c (233 mg, 0.51 mmol) and BBr3
(218 µL, 2.30 mmol); column chromatography with CH2Cl2/
methanol: 9/1. Yield: 206 mg (95%); colorless solid (mp: 257
°C). TLC Si2O (CH2Cl2/methanol: 9/1): Rf ) 0.5. 1H NMR
(DMSO-d6): δ ) 11.84 (s, 1H, OH), 10.26 (s, 1H, OH), 9.77 (s,
1H, OH), 8.02 (s, 1H, 5-H), 7.83 (d, 1H, J ) 8.3 Hz, ArH), 7.31
(d, 1H, J ) 8.4 Hz, ArH), 7.07 (d, 2H, J ) 8.6 Hz, ArH), 6.94-
6.90 (m, 2H, ArH), 6.82 (d, 1H, J ) 2.1 Hz, ArH), 6.78-6.74
(m, 3H, ArH). MS (EI, 280 °C): m/z (%) ) 412 [M]+• (100), 378
(26), 246 (77). IR (KBr): νj ) 3409 (m), 1610 (m), 1581 (m),
1518 (s), 1431 (m), 1275 (m), 1232 (m), 1202 (m), 899 (m), 836
(m), 810 (m). Anal. (C21H14Cl2N2O3) C, H, N.
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5-Ethyl-1,2,4-tris(4-hydroxyphenyl)-1H-imidazole (7d).
From 6d (97 mg, 0.26 mmol) and BBr3 (99 µL, 1.05 mmol);
column chromatography with CH2Cl2/methanol: 9/1. Yield: 34
mg (39%); colorless solid (mp: 163 °C). TLC Si2O (CH2Cl2/
1
methanol: 9/1): Rf ) 0.1. H NMR (DMSO-d6): δ ) 9.92 (s,
1H, OH), 9.59 (s, 1H, OH), 9.39 (s, 1H, OH), 7.50 (d, 2H, J )
8.4 Hz, ArH), 7.12-7.18 (m, 4H, ArH), 6.87 (d, 2H, J ) 8.6
Hz, ArH), 6.82 (d, 2H, J ) 8.4 Hz, ArH), 6.62 (d, 2H, J ) 8.6
Hz, ArH), 2.53 (q, 2H, J ) 7.7 Hz, CH2CH3), 0.92 (t, 3H, J )
7.4 Hz, CH2CH3). MS (EI, 80 °C): m/z (%) ) 372 [M]+• (100),
357 (84), 119 (26). IR (KBr): νj ) 3401 (m), 2971 (w), 2934 (w),
1611 (m), 1512 (s), 1457 (m), 1382 (w), 1247 (m), 1172 (m),
837 (m). Anal. (C23H20N2O3) C, H, N.
1,2-Bis(4-hydroxyphenyl)-4-(trifluoromethyl)-1H-imi-
dazole (7e). From 6e (286 mg, 0.82 mmol) and BBr3 (235 µL,
2.49 mmol); column chromatography with gradual elution,
CH2Cl2/methanol: 98/2, 95/5, 9/1. Yield: 83 mg (32%); colorless
solid (mp: 163 °C). TLC Si2O (CH2Cl2/methanol: 9/1): Rf )
1
0.2. H NMR (DMSO-d6): δ ) 9.94 (s, 1H, OH), 9.45 (s, 1H,
OH), 7.29 (d, 2H, J ) 8.7 Hz, ArH), 7.01 (s, 1H, 5-H), 6.82 (d,
2H, J ) 8.8 Hz, ArH), 6.67 (d, 2H, J ) 9.2 Hz, ArH), 6.65 (d,
2H, J ) 9.0 Hz, ArH). MS (EI, 80 °C): m/z (%) ) 320 [M]+•
(100). IR (film): νj ) 3383 (w), 3072 (w), 3007 (w), 2840 (w),
1611 (s), 1511 (s), 1253 (s), 1181 (s), 1031 (m), 838 (m). Anal.
(C16H11F3N2O2) C, H, N.
Acknowledgment. The technical assistance of S.
Bergemann and I. Schnautz is acknowledged. The study
presented was supported by Grants Gu285/3-1 and
Gu285/3-2 from the Deutsche Forschungsgemeinschaft.
Supporting Information Available: Elemental analyses
of the target compounds 7a-e. Synthesis of the compounds
3a,b, 5a-c, and 6a-e. Biological methods: transcriptional
binding assay; in vitro chemosensitivity assay, COX-inhibitor
screening assay; ssDNA apoptosis ELISA. Molecular modeling.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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