Structure-activity relationship of selected polyphenol derivatives as inhibitors of Bax/Bcl-xL interaction

Article abstract of DOI:10.1016/j.ejmech.2012.02.036

This paper describes the synthesis of nine selected diaryl/heteroaryl- containing phenol and polyphenol derivatives which have been evaluated against Bax/Bcl-xL interaction in comparison with ABT-737. Using a BRET assay, six of these derivatives exhibit activity comparable to ABT-737 to disrupt Bax/Bcl-xL interaction. These preliminary results demonstrate that such polyphenol-derived molecules are attractive compounds regarding anticancer activity and that the phenol at position 3 is important regarding disruption of Bax/Bcl-xL interaction.

Full text of DOI:10.1016/j.ejmech.2012.02.036

European Journal of Medicinal Chemistry 51 (2012) 286e293
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Structureeactivity relationship of selected polyphenol derivatives as inhibitors
of Bax/Bcl-xL interaction
,
,
*
Duc Duy Vo a, Fabien Gautier b c, Philippe Juin b, René Grée a
a Université de Rennes1, Laboratoire Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France
b Université de Nantes, CRCNA INSERM U892, 8 quai Moncousu, 44007 Nantes Cedex 1, France
c Institut de Cancérologie de l’Ouest, Centre de Recherche en Cancérologie, Bd Jacques Monod 44805 Saint Herblain, Nantes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes the synthesis of nine selected diaryl/heteroaryl-containing phenol and polyphenol
derivatives which have been evaluated against Bax/Bcl-xL interaction in comparison with ABT-737. Using
a BRET assay, six of these derivatives exhibit activity comparable to ABT-737 to disrupt Bax/Bcl-xL
interaction. These preliminary results demonstrate that such polyphenol-derived molecules are attrac-
tive compounds regarding anticancer activity and that the phenol at position 3 is important regarding
disruption of Bax/Bcl-xL interaction.
Received 5 November 2011
Received in revised form
13 February 2012
Accepted 16 February 2012
Available online 25 February 2012
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
Phenol
Bax
Bcl-xL
Apoptosis
BRET
Cancer
1. Introduction
inhibitory strategies, aiming at disrupting these heterodimers, are
of therapeutic interest [3]. ABT-737 is a representative example of
Apoptosis is one of the major cell death pathways involved in
maintaining cell homeostasis, and escape from apoptosis is
understood to contribute to carcinogenesis [1]. The anti-apoptotic
Bcl-2 family of proteins (especially Bcl-2, Bcl-xL, Mcl-1) are
frequently overexpressed in cancer cells, including solid tumors.
Therefore, they prevent death in corresponding cells and increase
resistance to traditional treatments [2]. Current data indicate that
they contribute to the aberrant survival and/or maintenance of
cancer cells by counteracting death signals triggered by oncogenic
lesions and/or therapy. Anti-apoptotic Bcl-2 proteins homologs
exert their survival activity by engaging inhibitory proteineprotein
interactions. They are known, in particular, to exert an anti-
apoptotic effect by engaging the BH3 domain of pro-apoptotic
members of the Bcl-2 family, Bax, Bak, and their upstream effec-
tors the BH3-only proteins (e.g. Bad, Bid, Bim and PUMA) via a well
characterized binding interface. Thus, anti-apoptotic Bcl-2 proteins
a small molecule inhibitor, called “BH3-mimetic”, that binds to the
BH3-binding site of Bcl-2/Bcl-xL proteins at nanomolar concen-
tration and inhibits their survival activity [4]. This molecule also
induces apoptosis in some cancer cell as a single agent or enhances
the pro-apoptotic activity of other drugs, both in vitro and in vivo
[4]. However it is not binding efficiently to Mcl-1, a Bcl-2 homolog
which is also overexpressed in many cancer cells, and therefore
resistance to ABT-737 used as a single agent have appeared [5].
The polyphenol core is widely recognized as an attractive
structure-target towards new anticancer agents [6]. For instance,
gossypol showed good activities towards Bcl-2, Bcl-xL and Mcl-1
with Ki at submicromolar level and it has entered into clinical
trials [7]. Various molecules based on the gossypol structure were
designed [8]. In particular the benzophenone analog 1, developed
by the group of Wang, is a simplified pyrogallol-based analog which
showed good activities against Bcl-2 and Mcl-1 [8d]. Further, 1
induced apoptosis and cell death in the MDA-MB-231 and PC-3 cell
lines at IC50 values of 12.9
mM and 12.4 mM respectively. Later
developments from the same group showed that the isopropyl
group of 1 can be modified into more bulky hydrophobic groups to
improve activity [8d]. Fig. 1.
* Corresponding author. Tel.: þ33 0 2 23 23 57 15; fax: þ33 0 2 23 23 69 78.
E-mail address: rene.gree@univ-rennes1.fr (R. Grée).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.02.036

D.D. Vo et al. / European Journal of Medicinal Chemistry 51 (2012) 286e293
287
We chose to study this key proteineprotein interaction for two
reasons. First, we wanted to investigate whether the new poly-
phenol derivatives retained the ability to interfere with the BH3-
binding activity of the anti-apoptotic Bcl-xL protein previously
reported for gossypol. Second, we recently reported that disruption
of the specific interaction that this protein engages with the multi-
domain pro-apoptotic protein Bax is necessary and may be a suffi-
cient requirement for BH3-mimetic Bcl-xL inhibitors to promote
cell death [10]. This point appeared to us as a key issue for the
future development of new molecules in this area.
NO2
NH
O
S
O
N
HN
O
N
N
S
ABT-737
Cl
K (Bcl-xL) < 0,5 nM
i
K (Bcl-2) < 1 nM
K (Mcl-1) > 20 µM
i
i
OH
HO
HO
O
OH
O
HO
OH
OH
2. Results and discussion
OH
O
OH
2.1. Chemistry
O
1
R-(-)-Gossypol
IC50 (Bcl-2) = 3,4 µM
i
In the present work, a series of selected diaryl/heteroaryl-
containing phenol and polyphenol derivatives was prepared,
starting from aromatic aldehydes 2e5 or bromo aromatic
compounds 6 and 17. The synthesis of our target molecules is
K (Bcl-xL) = 0,48 µM
i
K (Mcl-1) = 0,38 µM
M
K (Bcl-2) = 0,32 µ
i
K (Mcl-1) = 0,18 µM
i
Fig. 1. Selected inhibitors of Bcl-2 proteins.
described in Scheme
1 (compounds 12e16) and Scheme 2
(compounds 19aed). First, a series of ketones 7e10 was prepared
in a two-step sequence starting from aldehydes 2e5. On reaction
with p-PhOPhMgBr, latter compounds gave corresponding alcohols
which were immediately oxidized with IBX to afford the target
intermediates 7e10. The last target ketone 11 was obtained in
a three-steps sequence: metalation of bromo aromatic compound 6
with t-BuLi, followed by reaction with the required aldehyde to an
alcohol which was immediately oxidized with IBX. A similar
strategy (metalation/trapping by aldehyde and then oxidation) was
followed for the preparation of ketones 18aed, starting from bromo
aromatic compound 17 (Scheme 2). The final deprotection step was
successfully performed, with excess BBr3, for all derivatives having
methoxy-protected polyphenols. In the case of benzyl-protected
intermediate 10, deprotection was performed by hydrogenation
to give the target ketone 15. The structures and overall yields of
final molecules 12e16, 19aed are given in Fig. 2 and Table 1.
As part of our ongoing programme on the development of
anticancer molecules based on reinduction of apoptosis in cancer
cells [9], we started a preliminary structureeactivity relationship
study on selected polyphenol-derived molecules. In particular,
based on previous data, we intend to synthesize some selected
polyphenol compounds, analogous to 1 (Fig. 2), in which:
Fig. 2. General structure for our target molecules.
2.2. Biological evaluation: Bax/Bcl-xL disruption
- we used p-fluorobenzyl group to replace isopropyl substituent
and,
- we selected a few aromatic/heteroaromatic R groups and,
- on an active model compound, we modified the number and
position of the three OH phenolic groups (R1, R2 and R3) in
order to study their effect regarding Bax/Bcl-xL interaction.
The nine final molecules (12e16 and 19aed) were tested for
their ability to disrupt Bax/Bcl-xL interactions and to do so in
a whole cell configuration. For these studies, we used a method
which allows to monitor in-cell interactions between one tran-
siently transfected luciferase tagged protein [Bax in this work
R2
R1
R3
F
a, b
O
R2
R2
2
3
4
5
) R1=R2=R3=OMe
R1
O
R3
F
R1
O
R3
F
c
) R1=R2=OMe, R3=H
) R1=H, R2=R3=OMe
) R1=R2=OBn, R3=H
R
R
c' for 10
R = p-PhOPh-
R2
7
8
9
) R1=R2=R3=OMe
12) R1=R2=R3=OH
R1
Br
R3
F
13) R1=R2=OH, R3=H
14) R1=H, R2=R3=OH
15) R1=R2=OH, R3=H
16) R1=R3=H, R2=OH
) R1=R2=OMe, R3=H
) R1=H, R2=R3=OMe
a', b
10) R1=R2=OBn, R3=H
11) R1=R3=H, R2=OMe
6
) R1=R3=H, R2=OMe
Scheme 1. Synthesis of target molecules 12e16. Reagents and conditions: (a) p-PhOPhMgBr, THF, 0ꢀC-rt; (a‘) t-BuLi, Et2O, -78ꢀC, then p- PhOPhCHO, -78ꢀC − rt; (b) IBX, THF/DMSO,
reflux; (c) BBr3, CH2Cl2, 0ꢀC − rt; (c’) H2, Pd/C, CH2Cl2, rt; overall yields are given in Table 1.

288
D.D. Vo et al. / European Journal of Medicinal Chemistry 51 (2012) 286e293
R2
R2
R2
R1
Br
R3
F
R1
O
R3
F
R1
R3
F
c
a'', b
R
R
O
19a
17) R1=R2=R3=OMe
18a
-
d
) R1=R2=R3=OMe
-d) R1=R2=R3=OH
Scheme 2. Synthesis of target molecules 19aed (R see Table 1). Reagents and conditions: (a“) t-BuLi, Et2O, -78ꢀC, then RCHO, -78ꢀC − rt; (b) IBX, THF/DMSO, reflux; (c) BBr3, CH2Cl2,
0ꢀC − rt; overall yields are given in Table 1.
(Rluc-Bax)] and a second, yellow fluorescent tagged protein [Bcl-xL
in this work (eYFP-Bcl-xL)] by Bioluminescence Resonance Energy
Transfer (BRET). This method provides robust and reliable signals. It
allows to study directly the effects of compounds added in the
culture medium on intracellular interactions. Validation of this
BRET model is described in Fig. 3. Expression and interaction
between the two BRET partners was confirmed in co-
immunoprecipitation assays, followed by Western blotting
(Fig. 3a). Importantly, BRET signals between RLuc-Bax and eYFP-
Bcl-xL, and not between Rluc-Bax and eYFP, were found
saturable, demonstrating the specificity of the interaction (Fig. 3b).
ABT-737 was used as a reference compound, and its observed
ability to decrease BRET signals also confirmed the specificity of the
interaction evaluated by BRET analysis.
The results obtained with our new derivatives are given in Fig. 4,
and their analysis has to be done along three lines:
- First, regarding the choice of the alkyl/aryl-alkyl substituent on
the right part of polyphenol: the compound 1 has only half
activity compared to ABT-737 while molecule 12, in which the
isopropyl group was replaced bya p-fluorobenzyl,showedsimilar
activity to this reference compound. This result is in agreement
withliteraturedata[8d]and thereforethe molecule12 appears as
Table 1
Structure and overall yields for final compounds.
Entry Compound
R
R1 R2 R3 Yield (%)a
1
2
3
4
5
6
7
12
13
OH OH OH 59
OH OH
H
66
14
H
OH OH 53
15
OH
H
H
OH 34
16
OH
H
13
19a
19b
OH OH OH 21
OH OH OH 22
Fig. 3. (a) Co-immunoprecipitation of eYFP-Bcl-xL and Rluc-Bax: Protein lysate was
prepared in CHAPS buffer (PBS, CHAPS 1%, proteases inhibitors) on HeLa cells cultured
in 12 wells plate and transfected with 100 ng of pRluc-Bax and 500 ng of peYFP-Bcl-xL
vectors. Co-immunoprecipitation was performed using anti-eYFP antibody (Santa Cruz
8
19c
19d
OH OH OH 36
Biotechnology) and 500 mg of protein lysate with the Catch and Release immunopre-
cipitation system (Upstate) according to the manufacturer’s recommendations. (b)
BRET Saturation curves: Saturation curves were performed on Hela cells using
increasing amount of vectors encoding eYFP (black circles) alone, or eYFP-Bcl-xL
(white circles) in the presence of a fixed amount of the vector encoding Rluc-Bax.
The logarithmic shape of the regression curve for Rluc-Bax/eYFP-Bcl-xL complexes
indicates a specific interaction between the two proteins.
9
OH OH OH 44
a
overall yields for isolated compounds, after the 3 steps sequence.

D.D. Vo et al. / European Journal of Medicinal Chemistry 51 (2012) 286e293
289
Fig. 4. BRET assay on Bax/Bcl-xL interaction NT: non treated, ABT-737 used as positive control.
a good starting point for developing structureeactivity relation-
ships on the other side of this skeleton.
and their activity on other members of anti-apoptotic Bcl-2
proteins (especially Bcl-2, Mcl-1) will be presented in due course.
- Second, regarding the nature of the aromatic/heteroaromatic
substituents on the left part of the core structure: compounds
19aed showed various activities against Bax/Bcl-xL interac-
tions. The fluorine atom in para position (compound 19a)
slightly improved activity while the t-butyl group at ortho
position (compound 19b) lost near half of activity. Compound
19c showed an activity equivalent to ABT-737, indicating that
a quinoline ring can replace the corresponding benzene ring.
However, in this skeleton the replacement of the first benzene
ring by a thiophene group (compound 19d) reduces activity to
near half.
- Third, concerning the number and position of the phenol
groups: the 2,3-diphenolic compound 13 exhibit the same
activity as 12 while the 3,4-diphenolic compound 14 and the 3-
monophenolic compound 16 showed slightly better activity
than 12 and ABT-737. In contrast, the 2,4-diphenolic compound
15 was found inactive in this assay. These results concerning
this series of compounds containing different number and
position of the OH phenolic groups are particularly interesting:
they indicate that, for this type of molecules, three OH groups
are not absolutely required for disruption of Bax/Bcl-xL inter-
action. However the OH at position 3 is very important for
corresponding bioactivity.
4. Experimental section
All reagents were obtained commercially and used without
further purification. All reactions have been carried out under
a nitrogen atmosphere and anhydrous conditions. The solvents
used were freshly distilled under anhydrous conditions, unless
otherwise specified. The reaction mixtures have been magnetically
stirred with Teflon stirring bars, and the temperatures were
measured externally. Reactions that require anhydrous conditions
have been carried out by using oven dried (120 ꢀC, 24 h) glassware.
Yields refer to chromatographically and spectroscopically (1H and
13C NMR) homogeneous materials, and the reactions have been
monitored by thin layer chromatography (TLC), carried out on
0.25 mm Merck silica gel plates (60 F254). The eluents used were
mixtures of pentane and ethyl acetate (EA), with detection by UV
light, or a p-anisaldehyde staining solution. Acros silica gel (60,
particle size 0.040e0.063 mm) was used for column chromatog-
raphy. Nuclear magnetic resonance (NMR) spectra have been
recorded with Bruker Avance 400 and 300 spectrometers. 1H NMR
spectra:
using [
d (H) are given in ppm relative to tetramethylsilane (TMS),
d
(CHCl3) ¼ 7.26 ppm] as internal reference. 13C NMR spectra:
d
(C) are given in ppm relative to TMS, using [
d
(CDCl3) ¼ 77.0 ppm]
as internal reference. Multiplicities were designated as singlet (s),
doublet (d), triplet (t), quadruplet (q), multiplet (m) or br (broad).
Mass spectral analyses have been performed at the Centre Régional
de Mesures Physiques de l’Ouest (CRMPO) in Rennes (France).
3. Conclusion
The synthesis of a few selected diaryl/heteroaryl-containing
phenol and polyphenol derivatives was achieved. Six of these
new compounds showed activity comparable to ABT-737 with
regard to their ability to disrupt Bax/Bcl-xL interactions in a BRET-
based assay. These preliminary results indicate that molecules in
these series represent attractive hit compounds for further opti-
mization to develop new drugs that can overcome resistance of
cancer cells to apoptosis. It should nevertheless be noted that our
preliminary data suggests that these molecules exhibit much less
cytotoxic activity against reference cell lines than ABT-737 (data not
shown). This suggests that these tool compounds may not interfere
efficiently with all the proteineprotein interactions engaged by Bcl-
xL (such as those involving BH3-only proteins) or by other targets
of ABT-737 such as Bcl-2. Further study of this family of compounds
4.1. Chemistry
4.1.1. General procedure for synthesis of compounds 7e10, example:
synthesis of compound 7
First, to a stirred solution of p-phenoxyphenyl magnesium
bromide, prepared from p-bromodiphenylether (0.43 ml, 2 eq.) and
Mg (87.1 mg, 3 eq.) in THF (15 ml), cooled at 0 ꢀC under argon, was
added
5-(4-fluorobenzyl)-2,3,4-trimethoxybenzaldehyde
2
(368 mg, 1.21 mmol). The reaction mixture was allowed to come
back to rt and it was stirred for 2 h before quenching with saturated
ammonium chloride solution and extraction with Et2O. The
combined organic layers were dried over MgSO4 and concentrated

290
D.D. Vo et al. / European Journal of Medicinal Chemistry 51 (2012) 286e293
under reduced pressure. The crude product was purified by flash
column chromatography using a mixture pentane/EA 8/2 as eluent
to afford the alcohol intermediate (495 mg, 86%) as a colorless
viscous oil. A solution of alcohol obtained in this first step (326 mg,
0.69 mmol) and IBX (291 mg, 1.5 eq.) in a 3/1 mixture of THF/DMSO
(4 ml) were heated under reflux for 1 h, until total consumption of
alcohol. After cooling down to rt, the mixture was poured into
water and filtered on celite. The solution was then extracted with
Et2O, washed with water and brine. The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified on a silica gel column using the 9/1
mixture pentane/EA as eluent to afford 7 (291 mg, 89%) as a light
yellow viscous oil.
bromodiphenylether (0.2 ml, 2 eq.), Mg (34.8 mg, 2.5 eq.), 2,4-
bis(benzyloxy)-5-(4-fluorobenzyl)benzaldehyde (249 mg,
5
0.58 mmol) and THF (10 ml) to afford the alcohol as a crude
product. Then, 7/10 of this alcohol crude product (<0.4 mmol) was
oxidized by using procedure 2 with IBX (168 mg, 1.5 eq.) in the
mixture THF/DMSO 5/1 (12 ml) to afford ketone 10 (167 mg, 70%
yield over 2 steps) as a light yellow viscous oil. 1H NMR (400 MHz,
CDCl3)
d
(ppm): 7.81 (d, J ¼ 8.8 Hz, 2H), 7.43e7.34 (m, 5H), 7.34 (s,
1H), 7.30e7.26 (m, 5H), 7.20 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.16 (dd, J ¼ 5.5,
8.7 Hz, 2H), 7.08e7.04 (m, 4H), 6.98 (d, J ¼ 8.8 Hz, 2H), 6.95 (t,
J ¼ 8.8 Hz, 2H), 6.61 (s, 1H), 5.08 (s, 2H), 4.97 (s, 2H), 3.95 (s, 2H). 13C
NMR (75 MHz, CDCl3)
d
(ppm): 194.4, 161.3, 161.2 (d, J ¼ 243.5 Hz),
159.5, 157.0, 155.8, 136.4, 136.3 (d, J ¼ 3.2 Hz), 136.2, 133.7, 132.3,
131.9, 130.1 (d, J ¼ 8.1 Hz), 128.5, 128.3, 128.1, 127.7, 127.3, 126.6,
124.2, 122.6, 121.6, 119.8, 117.1, 114.9 (d, J ¼ 21.1 Hz), 98.3, 70.7, 70.3,
4.1.1.1. (5-(4-Fluorobenzyl)-2,3,4-trimethoxyphenyl)(4-phenoxyphe-
nyl)methanone (7). 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.79 (d,
34.9. 19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ116.9. HRMS [ESI (þ)
J ¼ 8.9 Hz, 2H), 7.40 (dd, J ¼ 7.5, 8.3 Hz, 2H), 7.20 (tt, J ¼ 1.1, 7.4 Hz,
1H), 7.14 (dd, J ¼ 5.5, 8.4 Hz, 2H), 7.10e7.05 (m, 2H), 7.00e6.94 (m,
4H), 6.85 (s, 1H), 3.90 (s, 3H), 3.89 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H).
-MS]: C40H31FO5Na [M þ Na]þ m/z, calc. 617.2104 found. 617.2103.
4.1.2. General procedure for synthesis of compounds 11, 18aed,
exemple: synthesis of compound 11
13C NMR (75 MHz, CDCl3)
d (ppm): 194.1, 162.0, 161.3 (d,
J ¼ 243.9 Hz), 155.4, 153.9, 151.0, 146.2, 136.2 (d, J ¼ 3.2 Hz), 132.2,
130.1 (d, J ¼ 7.8 Hz), 130.0, 129.9, 128.8, 124.7, 124.6, 120.2, 117.0,
115.1 (d, J ¼ 21.2 Hz), 61.9, 60.8, 60.7, 35.2. 19F NMR (282.4 MHz,
To a solution of bromo compound 1-bromo-3-(4-fluorobenzyl)-
5-methoxybenzene 6 (464 mg, 1.57 mmol) in Et2O (10 ml) under
argon, was added dropwise t-BuLi (2.16 ml, 2.2 eq.) at. ꢁ78 ꢀC. The
mixture was stirred for 30 min at ꢁ78 ꢀC before adding a solution of
p-phenoxybenzaldehyde (373.7 mg, 1.2 eq.) in Et2O (3 ml). The
reaction mixture was allowed to come back to rt and stirred for 4 h
and then quenched with saturated ammonium chloride solution
and extracted with Et2O. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure to afford the
alcohol as a crude product. Then, this alcohol (<1.57 mmol) was
oxidized with IBX (659 mg, 1.5 eq.) in the mixture THF/DMSO 3/1
(8 ml) to afford ketone 11 (150 mg, 23%) as a light yellow viscous oil.
CDCl3)
d
(ppm): ꢁ117.4. HRMS [ESI (þ) -MS]: C29H25FO5Na
[M þ Na]þ m/z, calc. 495.1584 found. 495.1584.
4.1.1.2. (5-(4-Fluorobenzyl)-2,3-dimethoxyphenyl)(4-phenoxyphenyl)
methanone (8). First, the reaction was performed with p-bromodi-
phenylether (0.26 ml,
2 eq.), Mg (38.5 mg, 2.2 eq.), 5-(4-
fluorobenzyl)-2,3-dimethoxybenzaldehyde 3 (200 mg, 0.73 mmol)
and THF (10 ml) to afford the alcohol as a crude product. Then, this
alcohol (<0.73 mmol) was oxidized with IBX (306.6 mg, 1.5 eq.) in
the mixture THF/DMSO 4/1 (10 ml) to afford ketone 8 (248 mg, 77%
yield over 2 steps) as a light yellow viscous oil. 1H NMR (400 MHz,
4.1.2.1. (3-(4-Fluorobenzyl)-5-methoxyphenyl)(4-phenoxyphenyl)meth-
CDCl3)
d
(ppm): 7.81 (d, J ¼ 8.9 Hz, 2H), 7.39 (dd, J ¼ 7.5, 8.4 Hz, 2H),
anone (11). 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.80 (d, J ¼ 8.9 Hz,
7.19 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.14 (dd, J ¼ 5.4, 8.7 Hz, 2H), 7.08e7.05 (m,
2H), 6.98 (d, J ¼ 8.9 Hz, 4H), 6.80 (d, J ¼ 2.0 Hz, 1H), 6.72 (d,
J ¼ 2.0 Hz, 1H), 3.92 (s, 2H), 3.84 (s, 3H), 3.71 (s, 3H). 13C NMR
2H), (dd, J ¼ 7.6, 8.4 Hz, 2H), 7.21 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.17e7.08
(m, 6H), 7.04e6.93 (m, 4H), 6.91 (t, J ¼ 2.0 Hz, 1H), 3.97 (s, 2H),
3.81 (s, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm): 195.1, 161.6, 161.5
(100 MHz, CDCl3)
d
(ppm): 194.8,162.2, 161.5 (d, J ¼ 244.4 Hz),155.4,
(d, J ¼ 244.5 Hz), 159.6, 155.4, 142.5, 139.4, 135.9 (d, J ¼ 3.3 Hz),
132.4, 131.8, 130.2 (d, J ¼ 7.9 Hz), 130.0, 124.6, 122.9, 120.1, 118.9,
117.0, 115.3 (d, J ¼ 21.3 Hz), 112.1, 55.4, 40.9. 19F NMR (282.4 MHz,
152.6, 145.0, 137.0, 136.1 (d, J ¼ 3.2 Hz), 131.1, 132.3, 131.9, 130.2 (d,
J ¼ 7.9 Hz), 130.0, 124.6, 120.3, 120.2, 117.0, 115.3 (d, J ¼ 21.3 Hz),
114.6, 61.7, 55.9, 40.7. 19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ116.9.
CDCl3)
d
(ppm): ꢁ116.8. HRMS [ESI (þ) -MS]: C27H21FO3Na
HRMS [ESI (þ) -MS]: C28H23FO4Na [M þ Na]þ m/z, calc. 465.1478
[M þ Na]þ m/z, calc. 435.1372 found. 435.1373.
found. 465.1477.
4.1.2.2. (5-(4-Fluorobenzyl)-2,3,4-trimethoxyphenyl)(4-(4-fluoroph-
enoxy)phenyl)methanone (18a). First, the reaction was performed
with bromo compound 1-bromo-5-(4-fluorobenzyl)-2,3,4-
trimethoxybenzene 17 (405 mg, 1.14 mmol), t-BuLi (1.57 ml, 2.2
eq.), p-(4-fluorophenoxy)benzaldehyde (370 mg, 1.5 eq.) and Et2O
(10 ml) to afford the alcohol intermediate (306 mg, 54%) as a color-
less viscous oil. Then, this alcohol (306 mg, 0.62 mmol) was oxidized
with IBX (261 mg, 1.5 eq.) in the mixture THF/DMSO 5/1 (9 ml) to
afford ketone 18a (231 mg, 76%) as a light yellow viscous oil.1H NMR
4.1.1.3. (3-(4-Fluorobenzyl)-4,5-dimethoxyphenyl)(4-phenoxyphenyl)
methanone (9). First, the reaction was performed with p-bromodi-
phenylether(0.26 ml, 2 eq.), Mg (38.5 mg, 2.2 eq.), 3-(4-fluorobenzyl)-
4,5-dimethoxybenzaldehyde 4 (200 mg, 0.73 mmol) and THF (10 ml)
to afford the alcohol as a crude product. Then, this alcohol
(<0.73 mmol)wasoxidized with IBX (306.6 mg,1.5 eq.)inthe mixture
THF/DMSO 4/1 (10 ml) to afford ketone 9 (256 mg, 79% yield over 2
steps) as a light yellow viscous oil.1H NMR (400 MHz, CDCl3)
d (ppm):
7.76 (d, J ¼ 8.9 Hz, 2H), 7.41 (dd, J ¼ 7.5, 8.5 Hz, 2H), 7.32 (d, J ¼ 2.0 Hz,
1H), 7.21 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.16 (d, J ¼ 2.0 Hz,1H), 7.14 (dd, J ¼ 5.4,
8.7 Hz, 2H), 7.11e7.08(m, 2H), 7.00 (d, J¼ 8.9Hz, 2H), 6.94(t, J ¼ 8.7 Hz,
2H), 3.97 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H). 13C NMR (75 MHz, CDCl3)
(300 MHz, CDCl3)
d
(ppm): 7.79 (d, J ¼ 8.9 Hz, 2H), (dd, J ¼ 5.4, 8.7 Hz,
2H), 7.10e7.02 (m, 4H), 6.98e6.90 (m, 4H), 6.86 (s, 1H), 3.90 (s, 3H),
3.89 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
(ppm): 194.0, 162.2, 161.4 (d, J ¼ 243.9 Hz), 159.5 (d, J ¼ 243.5 Hz),
d
(ppm): 194.5,161.4, 161.3 (d, J¼244.0Hz),155.5,152.7,150.7,136.2(d,
153.9, 151.1 (d, J ¼ 2.7 Hz), 151.0, 146.2, 136.2 (d, J ¼ 3.2 Hz), 132.3,
132.2, 130.1 (d, J ¼ 7.8 Hz), 130.0, 128.8, 124.7, 121.8 (d, J ¼ 8.4 Hz),
116.7 (d, J ¼ 23.4 Hz),116.6,115.1 (d, J ¼ 21.2 Hz), 61.9, 60.8, 60.7, 35.2.
J ¼ 3.2 Hz), 134.3, 133.2,132.3, 132.1, 130.2, 130.1 (d, J ¼ 8.1 Hz), 125.4,
124.6,120.3,117.0,115.1 (d, J ¼ 21.1 Hz),112.1, 60.6, 55.9, 35.4. 19F NMR
(282.4 MHz, CDCl3)
d
(ppm): ꢁ117.3. HRMS [ESI (þ) -MS]:
19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ117.3, ꢁ118.1. HRMS [ESI (þ)
C28H23FO4Na [M þ Na]þ m/z, calc. 465.1478 found. 465.1478.
-MS]: C29H24F2O5Na [M þ Na]þ m/z, calc. 513.1489 found. 513.1488.
4.1.1.4. (2,4-Bis(benzyloxy)-5-(4-fluorobenzyl)phenyl)(4-phenoxyph-
enyl)methanone (10). First, the reaction was performed with p-
4.1.2.3. (4-(2-Tert-butylphenoxy)phenyl)(5-(4-fluorobenzyl)-2,3,4-tri-
methoxyphenyl)methanone (18b). First, the reaction was performed

D.D. Vo et al. / European Journal of Medicinal Chemistry 51 (2012) 286e293
291
with
bromo
compound
1-bromo-5-(4-fluorobenzyl)-2,3,4-
for 1 h before extracting with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified on a silica gel column using the
mixture pentane/AE 7/3 as eluent to afford compound 12 (170 mg,
77%) as a light yellow solid. Mp: 139e141 ꢀC.
trimethoxybenzene 17 (110 mg, 0.31 mmol), t-BuLi (0.43 ml, 2.2
eq.), p-(2-t-butylphenoxy)benzaldehyde (86.6 mg, 1.1 eq.) and Et2O
(5 ml) to afford the alcohol intermediate (61 mg, 37%) as a colorless
viscous oil. Then, this alcohol (61 mg, 0.11 mmol) was oxidized with
IBX (48 mg, 1.5 eq.) in the mixture THF/DMSO 4/1 (2.5 ml) to afford
ketone 18b (40 mg, 66%) as a light yellow viscous oil. 1H NMR
4.1.3.1. (5-(4-Fluorobenzyl)-2,3,4-trihydroxyphenyl)(4-phenoxyphe-
(300 MHz, CDCl3)
d
(ppm): 7.81 (d, J ¼ 8.7 Hz, 2H), 7.44 (dd, J ¼ 1.9,
nyl)methanone (12). 1H NMR (300 MHz, CDCl3)
d
(ppm): 12,63 (br s,
1H): 7.61 (d, J ¼ 8.6 Hz, 2H), 7.44 (t, J ¼ 7.8 Hz, 2H), 7.26e6.91 (m,
9H), 6.02 (br s, 2H), 3.89 (s, 2H). 13C NMR (75 MHz, CDCl3)
(ppm):
7.6 Hz, 1H), 7.24e7.10 (m, 4H), 6.99e6.88 (m, 6H), 3.92 (s, 3H), 3.91
(s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 1.39 (s, 9H). 13C NMR (75 MHz,
d
CDCl3)
d
(ppm): 194.0,162.3,161.3 (d, J ¼ 244.0 Hz),154.2153.8,151.0,
199.0, 161.3 (d, J ¼ 243.9 Hz), 161.1, 159.7, 115.5, 149.9, 148.2, 135.6
(d, J ¼ 3.2 Hz), 132.0, 131.5, 131.2, 130.1 (d, J ¼ 7.8 Hz), 130.0, 126.3,
124.6, 120.1, 119.2, 117.1, 115.1 (d, J ¼ 21.2 Hz), 112.6, 34.4. 19F NMR
146.6, 141.6, 136.2 (d, J ¼ 3.2 Hz), 132.2, 131.9, 130.1 (d, J ¼ 7.8 Hz),
129.8, 128.9, 127.6, 127.3, 124.7, 124.5, 121.4, 117.1, 115.1 (d,
J ¼ 21.2 Hz), 61.9, 60.8, 60.7, 35.2, 34.7, 30.2. 19F NMR (282.4 MHz,
(282.4 MHz, CDCl3)
d
(ppm): ꢁ117.1. HRMS [ESI (þ) -MS]:
CDCl3)
d
(ppm): ꢁ117.3. HRMS [ESI (þ) -MS]: C33H35FO5Na
C26H19FO5Na [M þ Na]þ m/z, calc. 453.1109 found. 453.1112.
[M þ Na]þ m/z, calc. 551.2210 found. 551.2210.
4.1.3.2. (5-(4-Fluorobenzyl)-2,3-dihydroxyphenyl)(4-phenoxyphenyl)
methanone (13). The reaction was performed with 8 (230 mg,
0.52 mmol), a 1M solution of BBr3 in DCM (3.1 ml, 6 eq.) and DCM
(10 ml) to afford 13 (186 mg, 86%) as a yellow viscous oil. 1H NMR
4.1.2.4. (5-(4-Fluorobenzyl)-2,3,4-trimethoxyphenyl)(4-(quinolin-8-
yloxy)phenyl)methanone (18c). First, the reaction was performed
with bromo compound 1-bromo-5-(4-fluorobenzyl)-2,3,4-
trimethoxybenzene 17 (355 mg, 1 mmol), t-BuLi (1.38 ml, 2.2 eq.),
p-quinolin-8-yloxy-benzaldehyde (274 mg,1.1 eq.) and Et2O (10 ml)
to afford the alcohol intermediate (258 mg, 49%) as a colorless
viscous oil. Then, this alcohol (258 mg, 0.49 mmol) was oxidized
with IBX (207 mg, 1.5 eq.) in the mixture THF/DMSO 4/1 (5 ml) to
afford ketone 18c (212 mg, 82%) as a light yellow viscous oil. 1H
(400 MHz, CDCl3)
d
(ppm): 12.01 (br, 1H), 7.67 (d, J ¼ 8.8 Hz, 2H),
7.43 (dd, J ¼ 7.4, 8.2 Hz, 2H), 7.23 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.13e7.06
(m, 4H), 7.03 (d, J ¼ 8.8 Hz, 2H), 7.00e6.92 (m, 4H), 5.76 (br, 1H),
3.84 (s, 2H). 13C NMR (100 MHz, CDCl3)
d (ppm): 199.8, 161.6, 161.5
(d, J ¼ 244.5 Hz),155.4,148.6,145.6,136.3 (d, J ¼ 3.2 Hz),131.8,131.5,
130.2,130.1 (d, J ¼ 8.1 Hz),124.7,123.7,120.7,120.2,118.8,117.1,115.3
NMR (300 MHz, CDCl3)
d
(ppm): 8.93 (d, J ¼ 3.9 Hz, 1H), 8.22 (d,
(d, J ¼ 21.2 Hz), 40.3. 19F NMR (282.4 MHz, CDCl3)
(ppm): ꢁ116.9.
d
J ¼ 8.4 Hz, 1H), 7.80 (d, J ¼ 8.7 Hz, 2H), 7.68 (d, J ¼ 8.4 Hz, 1H),
7.55e7.45 (m, 3H), 7.32 (d, J ¼ 7.5 Hz, 1H), 7.16e7.11 (m, 1H), 7.05 (d,
J ¼ 8.7 Hz, 2H), 6.93 (d, J ¼ 8.7 Hz, 1H), 6.89 (d, J ¼ 8.1 Hz, 1H), 3.89
HRMS [ESI (þ) -MS]: C26H19FO4Na [M þ Na]þ m/z, calc. 437.1165
found. 437.1162.
(s, 5H), 3.77 (s, 3H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
(ppm):
4.1.3.3. (3-(4-Fluorobenzyl)-4,5-dihydroxyphenyl)(4-phenoxyphenyl)
methanone (14). The reaction was performed with 9 (247 mg,
0.56 mmol), a 1M solution of BBr3 in DCM (5.6 ml, 10 eq.) and DCM
(10 ml) to afford 14 (156 mg, 67%) as a light orange solid. Mp:
194.2, 162.3, 161.3 (d, J ¼ 244.0 Hz), 159.7, 153.9, 151.6, 151.0, 150.4,
146.1, 141.1, 136.2 (d, J ¼ 3.2 Hz), 132.5, 132.2, 130.1 (d, J ¼ 7.8 Hz),
129.9, 129.8, 128.8, 126.6, 124.7, 124.2, 121.9, 118.7, 117.5, 115.1 (d,
J ¼ 21.2 Hz), 61.8, 60.8, 60.7, 35.2. 19F NMR (282.4 MHz, CDCl3)
171e173 ꢀC. 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.72 (d, J ¼ 8.8 Hz,
d
(ppm): ꢁ117.4. HRMS [ESI (þ) -MS]: C32H26FNO5Na [M þ Na]þ m/
2H), 7.50 (d, J ¼ 2.0 Hz, 1H), 7.41 (dd, J ¼ 7.5, 8.4 Hz, 2H), 7.21 (tt,
J ¼ 1.1, 7.4 Hz, 1H), 7.18 (dd, J ¼ 5.4, 8.7 Hz, 2H), 7.11 (d, J ¼ 1.9 Hz,
1H), 7.11e7.07 (m, 2H), 6.99 (d, J ¼ 8.8 Hz, 2H), 6.94 (t, J ¼ 8.7 Hz,
z, calc. 546.1693 found. 546.1691.
4.1.2.5. (5-(4-Fluorobenzyl)-2,3,4-trimethoxyphenyl)(5-phenoxythi-
ophen-2-yl)methanone (18d). First, the reaction was performed
with bromo compound 1-bromo-5-(4-fluorobenzyl)-2,3,4-
trimethoxybenzene 17 (329 mg, 0.93 mmol), t-BuLi (1.27 ml, 2.2
eq.), 5-phenoxythiophene-2-carbaldehyde (209 mg, 1.1 eq.) and
Et2O (5 ml) to afford the alcohol intermediate (299 mg, 67%) as
a light yellow viscous oil. Then, this alcohol (258 mg, 0.54 mmol)
was oxidized with IBX (226 mg, 1.5 eq.) in the mixture THF/DMSO
5/1 (6 ml) to afford ketone 18d (223 mg, 87%) as a light yellow
2H), 6.04 (br, 1H), 3.98 (s, 2H). 13C NMR (100 MHz, CDCl3)
d (ppm):
195.1, 161.5 (d, J ¼ 244.5 Hz), 161.4, 155.5, 147.3, 143.3, 135.5 (d,
J ¼ 3.2 Hz), 132.3, 132.1, 130.2, 130.1 (d, J ¼ 8.1 Hz), 129.4, 126.8,
126.4, 124.6, 123.7, 120.3, 120.1, 118.8, 117.1, 115.2 (d, J ¼ 21.1 Hz),
35.0. 19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ116.9. HRMS [ESI (þ)
-MS]: C26H19FO4Na [M þ Na]þ m/z, calc. 437.1165 found. 437.1166.
4.1.3.4. (3-(4-Fluorobenzyl)-5-hydroxyphenyl)(4-phenoxyphenyl)met-
hanone (16). The reaction was performed with 11 (50 mg,
0.12 mmol), a 1 M solution of BBr3 in DCM (0.36 ml, 3 eq.) and DCM
(3 ml) to afford 16 (26.5 mg, 55%) as a white solid. Mp: 120e122 ꢀC.
viscous oil. 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.40 (dd, J ¼ 7.5,
8.4 Hz, 2H), 7.23 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.21e7.17 (m, 3H), 7.14 (dd,
J ¼ 5.4, 8.7 Hz, 2H), 6.95 (t, J ¼ 8.7 Hz, 2H), 6.90 (s, 1H), 6.41 (d,
J ¼ 4.2 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H). 13C
1H NMR (300 MHz, CDCl3)
d
(ppm): 7.77 (d, J ¼ 8.8 Hz, 2H), 7.41 (t,
J ¼ 8.1 Hz, 2H), 7.22 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.15e7.06 (m, 6H),
NMR (100 MHz, CDCl3)
d
(ppm): 186.6, 171.5, 161.3 (d, J ¼ 243.9 Hz),
7.01e6.91 (m, 4H), 6.86 (t, J ¼ 1.5 Hz, 1H), 6.34 (br s, 1H), 3.92 (s, 2H).
157.1, 153.8, 150.9, 146.4, 136.2 (d, J ¼ 3.2 Hz), 135.2, 133.3, 130.1 (d,
J ¼ 7.9 Hz), 130.0, 129.8, 128.2, 125.5, 124.5, 119.1, 115.1 (d,
J ¼ 21.2 Hz), 111.5, 62.2, 60.8, 60.7, 35.2. 19F NMR (282.4 MHz, CDCl3)
13C NMR (75 MHz, CDCl3)
d
(ppm): 195.7,161.9,161.5 (d, J ¼ 244.5 Hz),
156.1, 155.4, 143.0, 139.3, 135.8 (d, J ¼ 3.3 Hz), 135.6, 131.5, 130.3 (d,
J ¼ 7.9 Hz), 130.1, 124.7, 122.8, 120.2, 119.9, 117.0, 115.3 (d, J ¼ 21.3 Hz),
d
(ppm): ꢁ117.2. HRMS [ESI (þ) -MS]: C27H23FO5SNa [M þ Na]þ m/z,
114.6, 40.7. 19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ116.8. HRMS [ESI
calc. 501.1148 found. 501.1148.
(þ) -MS]: C26H19FO3Na [M þ Na]þ m/z, calc. 399.1396 found.
399.1396.
4.1.3. General procedure for synthesis of compounds 12e14, 16,
19aed, example: synthesis of compound 12
4.1.3.5. (5-(4-Fluorobenzyl)-2,3,4-trihydroxyphenyl)(4-(4-fluorophe-
noxy)phenyl)methanone (19a). The reaction was performed with
18a (231 mg, 0.47 mmol), a 1 M solution of BBr3 in DCM (4.23 ml, 9
eq.) and DCM (5 ml) to afford 19a (109 mg, 51%) as a yellow solid.
To a stirred solution of compound 7 (243 mg, 0.51 mmol) was
added dropwise BBr3 (4.6 ml, 9 eq., 1 M in CH2Cl2) in CH2Cl2 (5 ml)
at 0 ꢀC under nitrogen. The reaction mixture was allowed to warm
up to rt and stirred overnight. The mixture was then cooled again at
0 ꢀC and water was added, then CH2Cl2, and the mixture was stirred
Mp: 149e151 ꢀC. 1H NMR (300 MHz, CDCl3)
d
(ppm): 12.48 (br s,
1H), 7.59 (d, J ¼ 8.9 Hz, 2H), 7.17e7.03 (m, 6H), 6.99e6.90 (m, 5H),

292
D.D. Vo et al. / European Journal of Medicinal Chemistry 51 (2012) 286e293
6.09 (br s, 1H), 5.66 (br s, 1H), 3.88 (s, 2H). 13C NMR (75 MHz, CDCl3)
CDCl3)
d
(ppm): 198.7, 164.5, 161.4 (d, J ¼ 244.4 Hz), 161.0, 160.9,
d
(ppm): 198.8, 161.4 (d, J ¼ 244.1 Hz), 161.3, 159.5 (d, J ¼ 243.4 Hz),
155.5, 135.8, 135.4 (d, J ¼ 3.2 Hz), 132.2, 131.3, 130.1, 130.0 (d,
151.2 (d, J ¼ 2.7 Hz), 149.8, 147.9, 135.7 (d, J ¼ 3.3 Hz), 132.1, 131.5,
131.1, 130.1 (d, J ¼ 7.8 Hz), 126.2, 121.8 (d, J ¼ 8.4 Hz), 119.1, 116.7 (d,
J ¼ 23.4 Hz), 116.6, 115.1 (d, J ¼ 21.2 Hz), 112.6, 34.4. 19F NMR
J ¼ 7.8 Hz), 124.6, 120.1, 119.4, 117.2, 115.3 (d, J ¼ 21.2 Hz), 113.2, 34.5.
19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ116.8. HRMS [ESI (þ) -MS]:
C26H19FO4Na [M þ Na]þ m/z, calc. 437.1165 found. 437.1166.
(282.4 MHz, CDCl3)
d
(ppm): ꢁ117.2, ꢁ118.1. HRMS [ESI (þ) -MS]:
C26H18F2O5Na [M þ Na]þ m/z, calc. 471.1020 found. 471.1019.
4.2. BRET assay
4.1.3.6. (4-(2-Tert-butylphenoxy)phenyl)(5-(4-fluorobenzyl)-2,3,4-
trihydroxyphenyl)methanone (19b). The reaction was performed
with 18b (40 mg, 0.08 mmol), a 1 M solution of BBr3 in DCM (0.7 ml,
9 eq.) and DCM (5 ml) to afford 19b (33 mg, 90%) as a yellow solid.
Briefly, Hela cells were seeded on 6-well plates and transfected
with 200ꢀng/well of plasmid pRLuc-Bax coding for BRET donor and
1mg/well of peYFP-Bcl-xL coding for BRET acceptor (or with pCMV-
Bcl-xL for control). Twenty-four hours after transfection, cells were
trypsinized and re-seeded into white 96 flat well plate, incubated
for another day, and then treated with drugs for 16 h at 10 mM. Light
emission at 485 nm and 530 nm was measured consecutively by
using the Mithras fluorescence-luminescence detector LB 940
(Berthold) after adding the luciferase substrate, coelenterazine H
(Uptima) at a final concentration of 5 mM. BRET ratios were calcu-
lated as described [11].
Mp: 89e91 ꢀC. 1H NMR (300 MHz, CDCl3)
d (ppm): 8.92 (br s, 3H),
7.59 (d, J ¼ 8.6 Hz, 2H), 7.45 (dd, J ¼ 1.7, 7.8 Hz, 1H), 7.22 (dt, J ¼ 1.8,
7.4 Hz, 1H), 7.17e7.11 (m, 3H), 6.98 (d, J ¼ 8.6 Hz, 2H), 6.96e6.85 (m,
4H), 3.88 (s, 2H), 1.41 (s, 9H). 13C NMR [75 MHz, (CD3)2CO)]
d (ppm):
200.3, 163.1 (d, J ¼ 241.8 Hz), 162.7, 156.3, 153.1, 153.0, 140.1, 138.7
(d, J ¼ 3.0 Hz), 134.5, 133.4, 132.4 (d, J ¼ 7.8 Hz), 129.4, 129.3, 127.3,
126.4, 123.1, 121.8, 118.9, 116.6 (d, J ¼ 21.2 Hz), 113.6, 36.3, 36.1, 31.6.
19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ117.5. HRMS [ESI (þ) -MS]:
C30H27FO5Na [M þ Na]þ m/z, calc. 509.1740 found. 509.1741.
Acknowledgments
4.1.3.7. (5-(4-Fluorobenzyl)-2,3,4-trihydroxyphenyl)(4-(quinolin-8-
yloxy)phenyl)methanone (19c). The reaction was performed with
18c (182 mg, 0.35 mmol), a 1 M solution of BBr3 in DCM (3.5 ml, 10
eq.) and DCM (7 ml) to afford 19c (155 mg, 89%) as a yellow solid.
We thank Laboratoires Servier and Société de Chimie Thér-
apeutique for a fellowship to V. D. D. We thank the Ligue contre le
Cancer for support to this research.
Mp: 69e71 ꢀC. 1H NMR [400 MHz, (CD3)2SO)]
d (ppm): 12.17 (br s,
Appendix. Supplementary material
1H), 9.83 (br s, 1H), 9.05 (br s, 1H), 8.87 (dd, J ¼ 1.4, 4.1 Hz, 1H), 8.50
(dd, J ¼ 1.3, 8.3 Hz, 1H), 7.95 (d, J ¼ 7.4 Hz, 1H), 7.70 (t, J ¼ 8.0 Hz,
2H), 7.62 (dd, J ¼ 4.2, 8.3 Hz, 1H), 7.57 (d, J ¼ 8.4 Hz, 2H), 7.17 (d,
J ¼ 8.4 Hz,1H), 7.15 (d, J ¼ 8.2 Hz,1H), 7.00 (t, J ¼ 8.8 Hz, 2H), 6.94 (d,
J ¼ 8.7 Hz, 2H), 6.81 (s, 1H), 3.78 (s, 2H). 13C NMR [75 MHz,
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2012.02.036.
References
(CD3)2SO)]
d
(ppm): 197.8,160.8 (d, J ¼ 244.0 Hz),159.6,158.9,150.9,
150.8, 148.3, 148.1, 142.0, 136.6 (d, J ¼ 3.2 Hz), 135.2, 133.1, 132.3,
131.4, 130.2 (d, J ¼ 7.8 Hz), 129.9, 128.6, 125.0, 124.7, 122.7, 120.6,
119.7, 117.4, 114.7 (d, J ¼ 21.2 Hz), 111.8, 34.0. 19F NMR [282.4 MHz,
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tion was performed with 18d (198 mg, 0.41 mmol),a 1M solution of
BBr3 in DCM (3.73 ml, 9 eq.) and DCM (10 ml) to afford 19d (137 mg,
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d
(ppm): 12.10 (br s, 1H), 7.42 (dd, J ¼ 7.5, 8.5 Hz, 2H), 7.35 (d,
J ¼ 4.3 Hz, 1H), 7.28e7.16 (m, 6H), 6.97 (t, J ¼ 8.7 Hz, 2H), 6.46 (d,
J ¼ 4.3 Hz, 1H), 6.10 (br s, 1H), 5.71 (br s, 1H), 3.94 (s, 2H). 13C NMR
(100 MHz, CDCl3)
d
(ppm): 188.7, 170.7, 161.4 (d, J ¼ 243.9 Hz), 157.1,
149.0, 147.6, 135.8 (d, J ¼ 3.2 Hz), 134.1, 131.2, 130.9, 130.2 (d,
(k) B. Leber, F. Geng, J. Kale, D.W. Andrews, Expert Rev. Mol. Medecine 12
(2010) e28 (and references cited therein).
J ¼ 7.9 Hz), 130.1125.5, 124.1, 119.5, 119.0, 115.2 (d, J ¼ 21.2 Hz), 112.5,
111.6, 34.3. 19F NMR (282.4 MHz, CDCl3)
d
(ppm): ꢁ117.1. HRMS [ESI
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4.1.4. Synthesis of (5-(4-Fluorobenzyl)-2,4-dihydroxyphenyl)(4-phe-
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A solution of 10 (100 mg, 0.17 mmol), Pd on C (20 mg, 7%) in
EtOH (5 ml) was stirred under hydrogen atmosphere overnight at
rt. The reaction mixture was then filtered on celite. The residue was
purified by flash chromatography using a pentane/EA 7/3 mixture
to afford 15 (34 mg, 49%) as a light green solid. Mp: 84e86 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
(ppm): 12.50 (br, 1H), 7.57 (d, J ¼ 8.7 Hz,
2H), 7.43 (dd, J ¼ 7.6, 8.3 Hz, 2H), 7.30 (s, 1H), 7.22 (tt, J ¼ 1.1, 7.4 Hz,
1H), 7.15e7.06 (m, 4H), 7.05 (d, J ¼ 8.7 Hz, 2H), 6.95 (t, J ¼ 8.7 Hz,
2H), 6.43 (s, 1H), 6.39 (br, 1H), 3.85 (s, 2H). 13C NMR (100 MHz,
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