Design, synthesis and biological evaluation of new inhibitors of Bax/Bcl-xL interaction in cancer cells

Article abstract of DOI:10.1016/j.bmcl.2014.02.035

We describe the synthesis of a series of new molecules containing phenol and triazoles moieties, compounds which have been evaluated for their ability to inhibit Bax/Bcl-xL interactions in cancer cells, by using BRET assays, and to induce cell death. Several derivatives exhibit a very promising activity, being more potent than the reference compounds acylpyrogallol A and ABT-737. These preliminary results demonstrate that derivatives of this family can be attractive to develop new molecules with potent anticancer activity.

Full text of DOI:10.1016/j.bmcl.2014.02.035

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1758–1761
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of new inhibitors
of Bax/Bcl-xL interaction in cancer cells
Duc Duy Vo a, Fabien Gautier b,c,d, Sophie Barillé-Nion b, Philippe Juin b,c, Nicolas Levoin e, René Grée a,
⇑
a Université de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France
b UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 ‘‘Cell survival and tumor escape in breast cancer’’, Institut de Recherche Thérapeutique de l’Université de Nantes, 8 quai
Moncousu, BP 70721, 44007 Nantes Cedex 1, France
c Institut de Cancérologie de l’Ouest, Centre de Lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, 44805 Saint Herblain-Nantes Cedex, France
d Plateforme IMPACTÒ, Biogenouest Institut de Recherche Thérapeutique de l’Université de Nantes, 8 quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France
e Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint Grégoire, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the synthesis of a series of new molecules containing phenol and triazoles moieties, com-
pounds which have been evaluated for their ability to inhibit Bax/Bcl-xL interactions in cancer cells, by
using BRET assays, and to induce cell death. Several derivatives exhibit a very promising activity, being
more potent than the reference compounds acylpyrogallol A and ABT-737. These preliminary results
demonstrate that derivatives of this family can be attractive to develop new molecules with potent anti-
cancer activity.
Received 26 December 2013
Revised 11 February 2014
Accepted 13 February 2014
Available online 24 February 2014
Keywords:
Triazoles
Cancer
Ó 2014 Elsevier Ltd. All rights reserved.
Apoptosis
Bcl-xL
Bax
Polyphenol
BRET
Protein protein interactions (PPIs) play critical roles in numer-
ous biological processes. Life death decisions are, in particular, reg-
ulated by a network of PPIs among Bcl-2 family members, with
individual anti-apoptotic Bcl-2 homologues (such as Bcl-2, Bcl-xL,
Mcl-1. . .) binding to, and inhibiting, pro-apoptotic counterparts
(the effector multi-domain proteins Bax/Bak and their upstream
regulators, BH3-only proteins such as Bim, Bid, Puma, Bad,
Noxa. . .). This so called Bcl-2 network is often dysregulated in can-
cer cells, leading to aberrant survival. Developing small molecule
inhibitors of PPIs engaged by Bcl-2 homologues is thus of major
therapeutic interest, as their use may help override cancer cell out-
growth by promoting apoptosis. Numerous compounds have been
developed on that basis and some have entered clinical trials.1
As part of our programme towards the research of new pro-
apoptotic anti cancer agents,2 we became interested in acylpyrro-
gallol A, which has been reported by the group of Wang as a potent
inhibitor of Bcl-2.3 Based on this core structure, we have first dem-
onstrated that it is also an inhibitor of Bcl-xL and that the phenol
group in position 3 played a key role for the biological activities
in these series. Further, introduction of a p-fluorobenzyl group on
the right part of the molecule resulted in a significant improve-
ment of activity (triazole B)4 Then, we explored the possibility of
replacing the aromatic group by 6-membered heteroaromatic
structures (series C) or 5-membered derivatives (triazoles series
D). In latter case in particular, some potent derivatives have been
discovered.5 An important point to notice is that most of the active
compounds in these series of molecules (such as TW 37, TM
179,. . .) have, like first model A, a carbonyl group vicinal to the
phenolic core. Further, molecular docking studies have identified
relevant interactions of latter carbonyl group inside the binding
pockets of the proteins.3,6 On the other hand, it is known that
sp2-hybridized nitrogen atoms are able to make stronger hydrogen
bond (HB) interactions that oxygen.7 Therefore, we tried to exploit
this advantage by designing new target molecules (Fig. 1) where
the benzophenone carbonyl group has been replaced by a nitrogen
isostere. As first representative examples, we selected triazole
derivatives (series E) since this type of heterocycle has proved
already to be very versatile in bioorganic and medicinal chemistry.
The synthesis of these new molecules has been performed by using
simple and efficient methods. We then used the BRET (Biolumines-
cence Resonance Energy Transfer) technique to monitor the
⇑
Corresponding author. Tel.: +33 02 23 23 57 15; fax: +33 02 23 23 69 78.
E-mail address: Rene.Gree@univ-rennes1.fr (R. Grée).
http://dx.doi.org/10.1016/j.bmcl.2014.02.035
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

D. D. Vo et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1758–1761
1759
R1
OH
HO
OH
and/or
OH
F
F
N
N
X
(OH)n
F
OH
R2
O
HO
OH
R'
ref 5
this
O
C
3
O
N
work
N
N
OH
R'
R
O
HO
N
E
N
"
R
A : R=R'=Me (Wang)
B : R=H, R'=pFPh
O
D
Figure 1. Previous studies and design of our target molecules.
NO2
O
S
N
NH
HN
N
N
O
O
S
Cl
ABT-737
Figure 2. Structure of ABT-737.
incidence of these molecules on Bax/Bcl-xL interactions.4 This
technique allows detection and quantification of protein–protein
interactions in whole living cells by measuring energy transfer be-
tween a donor fusion protein (Rluciferase-Bax in this work) and an
acceptor fusion protein (eYFP-Bcl-xL in this work). Thus we dem-
onstrated that some of these derivatives are significantly more po-
tent inhibitors of the interaction between Bax and Bcl-xL than
molecule A and than the classical reference ABT-7378 (Fig. 2).
The structure activity relationship has been analyzed in light of
molecular docking experiments.
Figure 3. BRET activity regarding disruption of Bax/Bcl-xL interaction, for the new
triazoles E series (10
A.
lM each, 24 h treatment). Unt. is untreated and Ref. is model
The synthesis of the triazoles is reported in Scheme 1. The reac-
tion of known4 aldehydes 1a–1c with Ohira–Bestmann reagent9
gave in 64–78% yield the alkynes 2a–2c.
previously described,4 and the corresponding results are reported
in Figure 3.
Then Huisgen’s 1,3 dipolar cycloaddition10 of appropriate
azides, under click chemistry conditions,11 afforded in good to
excellent yields the desired triazoles 3a–5c. A final deprotection
step using BBr3 in CH2Cl2 afforded, in fair to excellent yields after
purification by chromatography on silica gel, the target molecules
6–13. All these new molecules have been fully characterized by
their spectral and analytical data.
The first basic designed structure, triazole 6, showed a moder-
ate activity, slightly above reference model A. Removal of one phe-
nolic group led to some improvement in the case of 8 and better
activity for 11 which is now as potent as ABT-737. However, most
fruitful was the introduction of substituents on the diphenyl ether
terminal aromatic ring. Addition of a t-butyl group in ortho posi-
tion gave a triazole 7 which was now significantly more active than
ABT 737 (p value: 0.0007). The analogues with only two OH group
9 and 12 gave also excellent results with the former being the most
The biological activity of these new type E analogues was eval-
uated using a BRET assay in whole living HeLa cancer cells, as
O
O
B
P(OMe)2
B
RN3, CuSO4 5%
A
C
F
A
C
F
N2
Na ascorbate 10%
MeOH, rt
overnight
64-78%
toluene, 110°C
24-36h, 79-96%
O
2a A=B=C=OMe
1a A=B=C=OMe
2b A=B=OMe, C=H
2c A=H, B=C=OMe
1b A=B=OMe, C=H
1c A=H, B=C=OMe
B
B
A
N
C
F
A
C
F
R'
R'
BBr3, DCM
O
O
N
N
-78°C-rt
47-95%
N
N
N
6: A=B=C=OH, R' = H
3a A=B=C=OMe, R'=H
7: A=B=C=OH, R' = o-tBu
8: A=B=OH, C=H, R'= H
9: A=B=OH, C=H, R'= o-tBu
10: A=B=OH, C=H, R'= p-F
11: A=H, B=C=OH, R'=H
12: A=H, B=C=OH, R'=o-tBu
13: A=H, B=C=OH, R'= p-F
4a A=B=C=OMe, R'=o-tBu
3b A=B=OMe, C=H, R'=H
4b A=B=OMe, C=H, R'=o-tBu
5b A=B=OMe, C=H, R'=p-F
3c A=H, B=C=OMe, R'=H
4c A=H, B=C=OMe, R'=o-tBu
5c A=H, B=C=OMe, R'=p-F
Scheme 1. Synthesis of the triazoles 6–13.

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D. D. Vo et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1758–1761
active of the series (p value: 0.0002). The introduction of a fluoro
substituent in para position appeared to be also a good option since
corresponding analogues 10 and 13 also demonstrated a good
activity.
Cell death experiments have been then performed on HeLa can-
cer cells (Fig. 4). They establish that these compounds used as
single agents for 48 h could induce significant cell death. Interest-
ingly, 7–13 analogues were more efficient to trigger cell death than
reference molecule A or analogue 6, which were both poorly able
to disrupt Bax/Bcl-xL interaction. In addition, analogues 7 and 9 in-
duced cell death as efficiently as ABT-737 did, in good correlation
with BRET assay. Noteworthy is the triazole 12 which exhibited a
very high activity as compared to ABT-737, despite an equal
disruptive activity in BRET assay, suggesting that this compound
triggered cell death through additional signalling pathways.
All together, these preliminary data show that this novel
scaffold bearing a triazole is very promising.
Molecular simulations confirmed that the binding pocket and li-
gand orientation of the novel triazole series are very close to those
described for previous phenol-derived structures.5,12 As compared
with reference molecule B, triazole 6 occupies the same crevice
lined with Glu96, Tyr195, Trp137 and Glu92. The key interactions
are conserved, with hydrogen bond (HB) between the polyphenol,
Glu96 and Arg100 (Fig. 5). A weak HB (with suboptimal geometry)
previously observed between Tyr101 and the ketone is however
lost with this triazole. This could explain the moderate lowering
of affinity. The position of diphenyl-ether is slightly shifted, but
HB with Asn136 is maintained through a change in the rotameric
state of the residue.
Figure 6. Triazoles 7, 9 and 12 docked into the Bcl-xL binding site. The Connolly
surface of the protein is colored according to electrostatic potential.
Substitutions of the terminal phenyl, either by t-Bu in ortho-
position or fluorine in para-position, have a twofold advantage:
they increase the van der Waals interactions between the ligands
and the receptor, and they facilitate the desolvation of ligands. Fur-
ther, since the triazoles have two and strong HB possibilities, they
can easily compensate for the lack of one hydroxyl function for cat-
echols (compounds 9–13). Hence, a HB with Tyr101 is gained
through a small displacement of the ligand (Fig. 6).
In conclusion, efficient strategies allowed the preparation of the
mixed triazole–phenol target molecules13 which were found as
attractive new structures for Bax/Bcl-xL inhibition in cancer cells.
The triazoles 7, 9 and 12 especially, which are much more potent
than ABT-737 and previous model derivatives A and B, are promis-
ing hits for extended studies. Molecular docking gave a rationale
for the interactions of these molecules with Bcl-xL and will be of
much use for optimisation of their biological properties. Corre-
sponding studies are under development in our groups and will
be reported in due course.
Acknowledgments
We thank Laboratoires Servier and Société de Chimie Thérapeu-
tique for a Fellowship to V.D.D. We thank the Ligue contre le Can-
cer for support to this research. We thank CNRS, INSERM,
University of Rennes 1 and University of Nantes for financial
support.
Supplementary data
Supplementary data (detailed experimental procedures and
complete characterization data) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.bmcl.2014.02.035.
Figure 4. Cell death experiments. Hela cells were treated with the series of
compounds as indicated (10 lM) or DMSO (Unt) for 48 h, then stained with
AnnexinV, and analyzed by flow cytometry. Data are presented as% of AnnexinV-
positive cells (corresponding to dead cells).
References and notes
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O.; Raimbaud, E.; Hickman, J. A. Biochim. Biophys. Acta 2004, 1644, 251; (c)
Walensky, L. D. Cell. Death Diff. 2006, 13, 1339; (d) Verdine, G. L.; Walensky, L.
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Updat. 2007, 10, 207; (f) Zeitlin, B. D.; Zeitlin, I. J.; Nör, J. E. J. Clin. Oncol. 2008,
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Mohammad, R. M. J. Cell. Physiol. 2009, 218, 13; (j) Chonghaile, T. N.; Letai, A.
Oncogene 2009, 27, S149; (k) Vogler, M.; Dinsdale, D.; Dyer, M. J. S.; Cohen, G.
M. Cell. Death Diff. 2009, 16, 360; (l) Leber, B.; Geng, F.; Kale, J.; Andrews, D. W.
Expert Rev. Mol. Med. 2010, 12, e28. and references cited therein.
2. (a) Manero, F.; Gautier, F.; Gallenne, T.; Cauquil, N.; Grée, D.; Cartron, P.-F.;
Geneste, O.; Grée, R.; Vallette, F. M.; Juin, P. Cancer Res. 2006, 66, 2757; (b)
Oliver, L.; Mahé, B.; Grée, R.; Vallette, F. M.; Juin, P. Leukemia Res. 2007, 31, 859;
(c) Grée, D.; Vorin, S.; Manthati, V. L.; Caijo, F.; Viault, G.; Manero, F.; Juin, P.;
Grée, R. Tetrahedron Lett. 2008, 49, 3276; (d) Viault, G.; Grée, D.; Roisnel, T.;
Chandrasekhar, S.; Grée, R. Tetrahedron 2009, 65, 10149.
Figure 5. Superimposition of reference B (carbon atoms in green) and triazole 6
(carbon atoms in grey) docked in the Bcl-xL binding site. Key residues are labeled.

D. D. Vo et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1758–1761
1761
3. Tang, G.; Closka, Z. N.; Qiu, S.; Yang, C.-Y.; Guo, J.; Wang, S. J. Med. Chem. 2008,
51, 717.
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2014, 70, 301.
6. (a) Wang, G.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Wang, R.; Tang, G.; Guo, J.;
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Gao, W.; Wang, G.; Stuckey, J.; Hrajewski, K.; Jiang, S.; Roller, P. P.; Wang, S. J.
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13. Representative synthetic procedures and spectral characterizations:—General
procedure for preparation of alkyne derivatives, example: preparation of
terminal alkyne 2a: To a stirred solution of aldehyde 1a (526 mg, 1.73 mmol)
in MeOH (10 ml) at 0 °C, was added K2CO3 (955 mg, 4 equiv), and Bestmann’s
reagent dimethyl-1-diazo-2-oxopropylphosphonate (443 mg, 1.3 equiv). The
reaction mixture was allowed to warm up to rt and stirred under nitrogen for
overnight. After evaporation of MeOH, the residue was purified on a silica gel
column chromatography using the mixture pentane/Et2O 8:2 as eluent to
afford the desired product 2a (332 mg, 64%) as
(300 MHz, CDCl3) d (ppm): 7.14 (dd, J = 5.4, 8.8 Hz, 2H), 6.96 (t, J = 8.7 Hz, 2H),
6.95 (s, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.85 (s, 2H), 3.75 (s, 3H), 3.21 (s, 1H). 13
a
colorless oil. 1H NMR
C
7. Gilli, P.; Pretto, L.; Bertolasi, V.; Gilli, G. Acc. Chem. Res. 2009, 42, 33. and
references cited therein.
NMR (75 MHz, CDCl3) d (ppm): 161.3 (d, J = 243.9 Hz), 154.5, 152.9, 146.2,
136.2 (d, J = 3.2 Hz), 130.1 (d, J = 7.8 Hz), 129.1, 115.1 (d, J = 21.2 Hz), 111.5,
80.4, 79.6, 61.3, 60.9, 60.8, 35.0. 19F NMR (282.4 MHz, CDCl3) d (ppm): À117.3.
HRMS (ESI+): C18H17FO3Na [M+Na]+ m/z, calcd 323.1059 found. 323.1061.
General procedure for click chemistry, example: preparation of triazole 3a: A
solution of alkyne 2a (105 mg, 0.35 mmol), p-phenoxyphenylazide (81.2 mg,
8. ABT-737 is a highly representative small molecule that binds to the BH3-
binding site of Bcl-2/Bcl-xL proteins at nanomolar concentrations and inhibits
their survival activity. Further, it induces apoptosis in some cancer cells both
in vitro and in vivo. See for instance: (a) Oltersdorf, T.; Elmore, S. W.;
Shoemaker, A. R.; Armstrong, R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.;
Deckwerth, T. L.; Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S.
J.; Kunzer, A. R.; Letai, A.; Li, C.; Mitten, M. J.; Nettesheim, D. G.; Ng, S.; Nimmer,
P. M.; O’Connor, J. M.; Oleksijew, A.; Petros, A. M.; Reed, J. C.; Shen, W.; Tahir, S.
K.; Thompson, C. B.; Tomaselli, K. J.; Wang, B.; Wendt, M. D.; Zhang, H.; Fesik, S.
W.; Rosenberg, S. H. Nature 2005, 435, 677; (b) Moore, V. D. G.; Brown, J. R.;
Certo, M.; Love, T. M.; Novina, C. D.; Letai, A. J. Clin. Invest. 2007, 117, 112; (c)
Deng, J.; Carlson, N.; Takeyama, K.; Cin, P. D.; Shipp, M.; Letai, A. Cancer Cell
2007, 12, 171; (d) Konopleva, M.; Contractor, R.; Tsao, T.; Samudio, I.; Ruvolo, P.
P.; Kitada, S.; Deng, X.; Zhai, D.; Shi, Y.-X.; Sneed, T.; Verhaegen, M.; Soengas,
M.; Ruvolo, V. R.; McQueen, T.; Schober, W. D.; Watt, J. C.; Jiffar, T.; Ling, X.;
Marini, F. C.; Harris, D. D.; Dietrich, M.; Estrov, Z.; McCubrey, J.; May, W. S.;
Reed, J. C.; Andreeff, M. Cancer Cell 2006, 10, 375.
1.1 equiv), copper(II) sulfate (6.13 mg, 0.07 equiv), sodium ascorbate (49 ll,
0.14 equiv, 1 M in H2O) in toluene (5 ml) was stirred under reflux for 24 h.
After cooling down to rt, a NH4OH solution was added to the mixture and then
it was extracted with ethyl acetate. 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/EA 8:2 as eluent to
afford triazole 3a (152 mg, 85%) as a colorless viscous oil. 1H NMR (300 MHz,
CDCl3) d (ppm): 8.50 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.52 (t,
J = 7.9 Hz, 2H), 7.39–7.25 (m, 5H), 7.22–7.18 (m, 2H), 7.08 (t, J = 8.7 Hz, 2H),
4.10 (s, 2H), 4.07 (s, 3H), 4.04 (s, 3H), 3.88 (s, 3H). 13C NMR (75 MHz, CDCl3) d
(ppm): 161.3 (d, J = 243.5 Hz), 157.7, 156.3, 152.0, 149.4, 146.6, 143.6, 136.8 (d,
J = 3.2 Hz), 132.3, 130.7, 130.1 (d, J = 7.8 Hz), 130.0, 124.0, 123.2, 122.2, 120.2,
119.4, 119.3, 115.0 (d, J = 21.2 Hz), 60.7, 60.6, 60.3, 35.5. 19F NMR (282.4 MHz,
CDCl3) d (ppm): À117.2. HRMS (ESI+): C30H26FN3O4Na [M+Na]+ m/z, calcd
534.1805 found. 534.1804.
9. (a) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521; (b) Roth,
G. J.; Liepold, B.; Müller, S.; Bestmann, H. J. Synthesis 2004, 59.
10. (a) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565; (b) Huisgen, R. J. Org. Chem.
1976, 41, 403; (c) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry In Padwa, A.,
Ed.; ; John Wiley & Sons: New York, 1984; Vol. 1,.
11. For a general review on click chemistry see: (a) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Ang. Chem., Int. Ed. 2004, 2001, 40; (b) Rostovtsev, V. V.; Green,
L. G.; Sharpless, K. B. Ang. Chem., Int. Ed. 2002, 41, 2596; (c) Tornoe, C. W.;
Christensen, C.; Medal, M. J. Org. Chem. 2002, 67, 3057; (d) Lutz, J.-F. Ang. Chem.,
Int. Ed. 2008, 47, 2182. and references cited therein.
12. Oltersdorf, T. et al Nature 2005, 435, 677. The crystal structure PDB: 1YSG was
used for all molecular simulations. Docking experiments were performed using
LigandFit, implemented in Discovery Studio v.4.0 (Accelrys Inc, San Diego, CA).
A CFF energy grid was defined with 10 Å extension from the binding site of
1134 Å3, and an energetic penalty of 150 kcal/mol/atom was set outside the
binding site. A softened potential energy was used, with distance dependant
dielectric constant of 1. Ligands conformers were generated before docking
experiments by using both ‘fast’ and ‘best’ protocols, that is, discretized
rotations about the rotatable bonds with 120° search increments between sp3
atoms, with and without energy minimization steps. After docking, each pose
and binding site (ligand–receptor complex) were optimized through energy
minimization (6000 steps of steepest descent with CHARMm force field).
General procedure for demethylation with BBr3, example: preparation of triazole
6: To a stirred solution of triazole 3a (66.5 mg, 0.13 mmol) was added dropwise
BBr3 (1.17 ml, 9 equiv, 1 M in CH2Cl2) in CH2Cl2 (10 ml) at À78 °C under
nitrogen. The reaction mixture was allowed to warm up to rt and stirred for
overnight. The mixture was then cooled again to 0 °C and water was added, the
solution diluted with CH2Cl2, stirred during 1 h before extraction 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/EA 7:3 as eluent to afford mixed phenol-triazole
compound 6 (34 mg, 55%) as a light yellow solid. 1H NMR (300 MHz, CDCl3)
d (ppm): 10.93 (br s, 1H), 8.01 (s, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.40 (dd, J = 7.5,
8.5 Hz, 2H), 7.24–7.16 (m, 3H), 7.15 (d, J = 8.9 Hz, 2H), 7.09–7.06 (m, 2H), 6.97
(d, J = 8.7 Hz, 2H), 6.75 (s, 1H), 5.58 (br s, 2H), 3.95 (s, 2H). 13C NMR (75 MHz,
CDCl3) d (ppm): 161.4 (d, J = 243.6 Hz), 158.5, 156.1, 148.3, 142.7, 142.4, 136.5
(d, J = 3.2 Hz), 132.0, 131.7, 130.1 (d, J = 7.8 Hz), 130.0, 124.4, 122.5, 119.7,
119.6, 119.2, 117.4, 116.2, 115.1 (d, J = 21.1 Hz), 106.1, 34.4. 19F NMR
(282.4 MHz, CDCl3) d (ppm): À117.2. HRMS (ESI+): C27H20FN3O4Na [M+Na]+
m/z, calcd 492.1336 found. 492.1338.