Synthesis and biological activities of a series of 4,5-diaryl-3-hydroxy-2(5H)-furanones

Article abstract of DOI:10.1016/j.ejmech.2007.08.005

A series of thirteen 4,5-diaryl-3-hydroxy-2(5H)-furanones were synthesized. They were evaluated for their antioxidant potencies and inhibitory properties of 5-lipoxygenase, cyclooxygenases, HIV-1 integrase and PC3 cell proliferation. New hits were discove

Full text of DOI:10.1016/j.ejmech.2007.08.005

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1222e1229
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological activities of a series of
4,5-diaryl-3-hydroxy-2(5H )-furanones
a
b
b
Fabrice Bailly a, , Clemence Queffelec , Gladys Mbemba , Jean-Franc¸ois Mouscadet ,
*
Nicole Pommery , Jean Pommery , Jean-Pierre Henichart , Philippe Cotelle
´
´
c
c
c
a
´
a Laboratoire de Chimie Organique et Macromole´culaire, UMR CNRS 8009, Baˆtiment C3, Universite´ de Lille 1,
59655 Villeneuve d’Ascq Cedex, France
b Laboratoire de Biotechnologies et Pharmacologie Ge´ne´tique Applique´e, UMR CNRS 8113, ENS Cachan, 61 Avenue du Pre´sident Wilson,
94235 Cachan, France
c Institut de Chimie Pharmaceutique Albert Lespagnol, 3 rue du Professeur Laguesse, EA 2692, BP83, 59006 Lille, France
Received 18 June 2007; received in revised form 16 July 2007; accepted 9 August 2007
Available online 11 September 2007
Abstract
A series of thirteen 4,5-diaryl-3-hydroxy-2(5H )-furanones were synthesized. They were evaluated for their antioxidant potencies and inhib-
itory properties of 5-lipoxygenase, cyclooxygenases, HIV-1 integrase and PC3 cell proliferation. New hits were discovered either in the anti-
proliferation test or in the HIV anti-integrase test.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 3-Hydroxy-2-(5H )-furanones; Antioxidant; 5-Lipoxygenase; Cyclooxygenases; HIV-1 integrase; PC3 proliferation
1. Introduction
and are also involved in numerous inflammatory diseases
and allergic disorders, such as allergy, asthma, arthritis, and
psoriasis [10,11]. Several polyphenols display anti-inflamma-
tory properties by different ways: they may inhibit 5-lipoxyge-
nase by interfering with the redox catalytic cycle of the
enzyme [12e14], and their antioxidant properties may also
modulate cellular signalling inflammatory pathways [15]. In
this field, two series of 4,5-diaryl-3-hydroxy-2(5H )-furanones
with interesting antioxidant and anti-inflammatory properties
were elaborated [16,17] and we previously reported the syn-
thesis of a lipophilic analogue of vitamin C, a 4-(4-hydroxy-
phenyl)-3-hydroxyfuran-2-one [18], which was also found to
be a good inhibitor of HIV-1 integrase (IC50 ¼ 3.6 mM; unpub-
lished data).
On the basis of these results, we elaborated a novel series of
3-hydroxy-2(5H )-furanones substituted at 4- and 5- positions
by aryl groups. The 4-hydroxyphenyl group at position 4
was maintained in the major part of the series to keep antiox-
idant potencies as in the lipophilic analogue of vitamin C and
we decided to investigate their possible anti-inflammatory
Oxidative stress is common in inflammatory processes of
many diseases, including the Chaga’s disease [1], heart failure
[2], autoimmune rheumatic disease [3], Alzheimer disease [4],
asthma, chronic obstructive pulmonary disease [5], and AIDS
[6,7]. Reactive oxygen species, either directly or via the for-
mation of lipid peroxidation products, may play a role in en-
hancing inflammation through the activation of stress kinases
(c-jun, p38) and redox-sensitive transcription factors, such as
nuclear factor NF-kappaB and activator protein-1. In other re-
spects, lipoxygenases (LOX) constitute a heterogeneous fam-
ily of lipid-peroxidizing enzymes, widely distributed not
only in plants and mammals but also in fungi and invertebrates
[8,9]. Leukotrienes are potent mediators of inflammation de-
rived from arachidonic acid through the action of 5-LOX
* Corresponding author. Tel.: þ 33 320337231; fax: þ 33 320336309.
E-mail address: fabrice.bailly@univ-lille1.fr (F. Bailly).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.08.005

F. Bailly et al. / European Journal of Medicinal Chemistry 43 (2008) 1222e1229
1223
properties in association with their antioxidant abilities. Keep-
ing in mind the potential anti-integrase properties of these
compounds, 4-benzyloxyphenyl, 3,4-dibenzyloxyphenyl and
3,5-dibenzyloxyphenyl groups (as in the HIV-1 integrase in-
hibitor L-708,906 from Merck Company, Scheme 1) [19]
were chosen for position 5. The 4-fluorophenyl group present
in the structures of the HIV-1 integrase inhibitors S-1360 from
Shionogi Company, L-870,810 (Scheme 1) and L-870,812
from Merck Company [19], was also introduced at positions
4 and 5.
Thirteen molecules were synthesized and herein we present
their large physicochemical and pharmacological evaluation.
We investigated: (i) their antioxidant properties in the 1,1-
diphenyl-2-picryl-hydrazyl (DPPH) radical and peroxynitrite
anion scavenging tests, (ii) their ability to inhibit the 5-
lipoxygenase (5-LOX), (iii) their cyclooxygenases (COX-1
and COX-2) inhibitory activities since some cyclooxygenase-
2 (COX-2) selective inhibitors like Rofecoxib (Scheme 1) con-
tain a furan-2-one moiety, (iv) their effects on human PC3 cell
proliferation since recent data have demonstrated the involve-
ment of COX-2 in both in vitro and in vivo prostate tumor
growth rate [20e22] and (v) their inhibitory activities against
the catalyzed 30-processing reaction of wild-type HIV-1
integrase.
corresponding 4,5-diaryl-3-hydroxy-2(5H ) furanones 4aeh.
Compounds 4iem were then obtained by hydrogenolysis of
their precursors over Pd/C. We failed to obtain by this method
the catechol compound resulting from 4f.
The antioxidant properties were first expressed by the clas-
sical ECR50 parameter describing the global reactivity of the
tested compound towards the 1,1-diphenyl-2-picryl-hydrazyl
(DPPH) radical. Table 1 shows that the 4-hydroxyphenyl
group in position 4 is necessary to confer radical scavenging
activity since compounds 4def and 4l,m bearing a 4-fluoro-
phenyl group on the same position were inactive. Compounds
4b, 4c, 4j and 4k had antioxidant profiles similar to those of
reference compounds Trolox (6-hydroxy-2,5,7,8-tetramethyl-
chromane-2-carboxylic acid) and ascorbate (ECR50 ¼ 0.26)
with a total stoichiometry (1/2ECR50), which is about 2. The
addition of phenolic or catechol moieties at position 5 did
not improve the DPPH scavenging abilities. Furanones effec-
tively protected Evans Blue dye against peroxynitrite-induced
oxidation (Table 1). Here again the protecting molecules were
the same as in the DPPH test and the substitution by a 4-fluo-
rophenyl group on position 4 was unfavourable (except sur-
prisingly for 4m). In contrast to the DPPH test, it seems that
the presence of (poly)phenolic moieties at position 5 led to in-
creased protective effects when comparing the bleaching inhi-
bitions of compounds 4c, 4g and 4h to those of the respective
deprotected homologues 4k, 4i and 4j. The protective effects
at 50 mM were in the range 30e45% and largely inferior to
those of reference compounds, Trolox (90% bleaching inhibi-
tion at 50 mM) and ascorbate (83.6% bleaching inhibition at
50 mM). Only compound 4j (92%) was as effective as Trolox.
HPLC analysis of calcium ionophore A-stimulated 5-HETE
production made assessment of 5-LOX activity in human
whole blood samples possible. Only compounds 4g, 4h and
4j inhibited 5-LOX at a 10 mM dose (Table 1) and the exper-
imental results were strongly limited at 100 mM, due to solu-
bility problems. Compounds 4a, 4b, 4i, 4k and 4m exhibited
2. Results and discussion
4-Benzylideneoxazol-5(4H )-ones 1a,b obtained from 4-hy-
droxybenzaldehyde and 4-fluorobenzaldehyde by a previously
reported Erlenmeyer synthesis [23] were hydrolysed by 3 M
HCl to give the corresponding (Z )-3-aryl-2-hydroxypropenoic
acids 2a,b (Scheme 2) [23]. Methylation in the presence of
1,5-diazabicyclo[5.4.0]undecene (DBU) and methyl iodide ac-
cording to the method described by Namicki et al. [24] gave
the methylarylpyruvates 3a,b. Condensation with the appropri-
ate benzaldehydes in presence of DBU [16,17] gave the
R1
R2
O
H
N
F
O
O
O
R3
N
N
OH
O
OH
H3CO2S
O
R
S-1360
3-Hydroxy-2(5H)-furanones
Rofecoxib
O
OH
COOH
BnO
O
S
N
O
F
N
H
N
OBn
N
L-708,906
O
L-870,810
OH
Scheme 1.

1224
F. Bailly et al. / European Journal of Medicinal Chemistry 43 (2008) 1222e1229
O
COOH
3 M HCl
reflux, 4 h
O
N
OH
R
R
CH3
1a: R = OAc
1b: R = F
2a: R = OH
2b: R = F
R1
DBU, CH3I
0 °C, 3 h
rt, 15 h
R1
DMF
R2
R2
CHO
O
O
R3
CO2CH3
R3
OH
DBU, DMF
R
OH
0 °C, 3 h
rt, 15 h
3a: R = OH
3b: R = F
4a-h
R
Scheme 2.
poor 5-LOX inhibitory activities (10e30%) even at 100 mM
and the most potent inhibitor was compound 4j (79.5% inhibi-
tion). These activities were very modest in regard to that of
reference compound, Zileuton (50% inhibition at 0.7 mM).
No compounds displayed COX-2 inhibition and only com-
pounds 4a and 4b at 100 mM (32.9% and 16.4% inhibition,
respectively) inhibited COX-1 to a lesser extent than reference
compound, Celecoxib (50% inhibition at 13.1 mM).
The antiproliferative activity of furanones was evaluated
against the human prostate carcinoma PC3 cell line.
Compounds bearing benzyloxy or fluorophenyl groups on
position 5 were inactive. Compounds 4i, 4j and 4l showed
Table 1
Antioxidant and enzymatic inhibitory activities for test compounds 4aem
O
O
Ar2
OH
R1
Entry
R1
Ar2
DPPHa ECR50
Peroxynitrite %
scavengingb
5-LOXc (10 mM)
5-LOXd (100 mM)
HIV-1 Integrasef
IC50 (mM)
4a
4b
4c
4d
4e
4f
eOH
eOH
eOH
eF
eF
eF
eC6H5
4-FeC6H4
0.49
0.27
0.30
0
29.4
46.5
0
0
0
18.6
16.4
nde
nde
nde
nde
nde
nde
11.6
79.5
27.8
0
>300
>300
>300
>300
30
4-OBneC6H4
4-OBneC6H4
3,5-diOBneC6H4
3,4-diOBneC6H4
3,5-diOBneC6H4
3,4-diOBn-C6H4
3,5-diOHeC6H4
3,4-diOHeC6H4
4-OHeC6H4
0
0
0
0
0
0
0
0
0
10
4g
4h
4i
eOH
eOH
eOH
eOH
eOH
eF
0.65
0.71
0.47
0.25
0.32
0
10.4
4.90
33.1
92.0
44.9
0
32.0
12.7
0
>300
1
22
4j
35.4
0
9.2
4k
4l
220
300
92
4-OHeC6H4
3,5-diOHeC6H4
0
4m
a
eF
0
40.9
0
10.7
Ratio of antioxidant concentration to DPPH concentration producing a 50% decrease in DPPH after 5 min.
Inhibition produced by 50 mM test compound on ONOꢀ2 induced Blue Evans bleaching.
Inhibition by 10 mM test compound of 5-HETE generation from human whole blood.
Inhibition by 100 mM test compound of 5-HETE generation from human whole blood.
nd ¼ not determined, due to solubility problems.
b
c
d
e
f
Inhibition of HIV-1 integrase activity.

F. Bailly et al. / European Journal of Medicinal Chemistry 43 (2008) 1222e1229
1225
Table 2
Activity of compounds 4iem on the proliferation of PC3 cancer cell linea
4. Experimental
Compd
IC50 (mM) or % inhibitionb
4.1. Pharmacological assays
Celecoxib
48.0
39%
20%
0%
4i
4j
4k
4l
4m
a
4.1.1. HPLC analysis of arachidonic acid
metabolites in whole blood [28]
Fresh blood was collected in heparinized tubes from normal
volunteers. Then 1 mL aliquots were transferred to heparin-
ized tubes preloaded with either 4 mL of vehicle (DMSO) or
4 mL of test compounds and incubated for 15 min at 37 ꢁC.
Then, 40 mM calcium ionophore A 23187 alone or in combi-
nation with LPS (500 mg) was added. Incubation was carried
out at 37 ꢁC for 30 min and 20 h at 37 ꢁC to stimulate 5-
LOX and COX-1 pathways, respectively. For the COX-2 path-
way, samples stimulated with A 23187 þ LPS were incubated
for 20 h. Eicosanoids were extracted from the samples into
ethyl acetate. Samples were then evaporated to dryness under
nitrogen, re-suspended in the mobile phase to precipitate pro-
teins and then centrifuged. The supernatant was directly ana-
lysed by HPLC using Hypersil ODS 3 mM columns (12.5 mm ꢂ
0.46 mm), a methanol/water/acetic acid (80:20:0.08) mobile
phase at a flow rate of 1 mL/min and UV detection firstly at
270 nm and 12 min later at 245 nm.
31%
0%
Activity determined with the MTT method.
Compounds tested at a concentration of 10 mM.
b
antiproliferative activities ranging between 20 and 30% inhibi-
tion at a 10 mM dose (Table 2). These were noticeable poten-
cies when compared to that of reference compound, Celecoxib
(50% inhibition at 48 mM).
Inhibition of HIV-1 activity by furanones was very weak
with IC50 values around 200e300 mM (Table 1) except for
compounds 4f, 4h and 4j (IC50 ¼ 10.0, 1.0 and 9.2 mM, re-
spectively). The good activity of 4j was expected to be due
to its structural similarities with the previously published bis-
catechols [25] but the presence of a catechol moiety is not re-
quired in this series since compound 4f has a similar
micromolar inhibitory activity and compound 4h is even 10-
fold more active than compound 4j. The structures of 4f and
4h may be related to that of a 4-keto-3-hydroxy-furan-2-one,
a 3D model pharmacophore discovered by Barreca et al. as
a closed structural analogue of the 1,3-diketo acid potent
anti-integrase moiety [26]. However compounds 4f and 4h
lack a second keto group on position 4 and may not be consid-
ered as strict diketoacid analogues. We may expect that an
additional keto function on position 4 may increase the anti-
integrase activities of our compounds although this hypothesis
did not recently give potent integrase inhibitors [27]. Further-
more we present the inhibition of the 30-processing integrase
activity but not of the strand transfer one, which is character-
istic of the selective inhibition by diketo acids. The inhibition
of this strand transfer activity will have to be evaluated.
4.1.2. Cell culture and cell proliferation assay
Human prostate PC3 cancer cells were grown at 37 ꢁC in
RPMI 1640 medium supplemented with 10% fetal calf serum,
in a humidified incubator containing 5% CO2. In the cell
proliferation assay, cells were plated (1.8 ꢂ 104 cells/well)
on 24-well plates. After 3 days, the cell medium was changed
to serum-free medium, and the cells were starved for 24 h for
culture synchronization. Cells were then incubated in culture
medium that contained various concentrations of test com-
pounds, each dissolved in less than 0.1% DMSO. After
incubating for 72 h, cell growth was estimated by the colori-
metric MTT test.
4.1.3. HIV-1 integrase assay
Oligonucleotides were purchased from Eurogentec and fur-
ther purified on 18% acrylamide/urea denaturing gel. U5B:
GTGTGGAAAATCTCTAGCA; U5A: 59-ACTGCTAGA
GATTTTCCACAC. Wild-type HIV-1 integrase was purified
as described previously [29]. 30-Processing assay was per-
formed in a reaction volume of 20 mL containing 0.025 pmol
of labelled U5A/U5B double-stranded DNA substrate and
1 pmol of integrase in buffer [20 mM Hepes (pH 7.2),
10 mM MgCl2, 25 mM NaCl, and 1 mM DTT]. Products
were separated on an 18% acrylamide/urea denaturing gel
and quantified on a phosphoimager using ImageQuant soft-
ware (Amersham Pharmacia Biotech).
3. Conclusion
We synthesized and investigated the pharmacological prop-
erties of a series of 4,5-diaryl-3-hydroxy-2(5H )-furanones.
Compounds with a 4-hydroxyphenyl group on position 4,
and particularly compound 4j, displayed vitamin C-like anti-
oxidant behaviours like the original lipophilic analogue of
vitamin C [18]. They did not inhibit COX-1 and COX-2 cyclo-
oxygenases because they lack a phenyl group at position 2 and
an alkylsulfonyl(or sulfonamido)phenyl group at position 4
present in the COX-2 selective Rofecoxib. They had no or
low potency as 5-LOX inhibitors, when compared to Zileuton.
Three compounds were found to be moderate inhibitors of
HIV-1 integrase activity. New hits like 4h in the HIV anti-in-
tegrase test and 4i (or 4l) in the antiproliferation test were dis-
covered and are worth being pharmacologically evaluated in
more detail.
4.2. Antioxidant assays
4.2.1. Reaction with DPPH
All spectrophotometric measurements were performed with
a Kontron Uvikon 932 spectrophotometer. Calibration curves
for 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical were

1226
F. Bailly et al. / European Journal of Medicinal Chemistry 43 (2008) 1222e1229
carried out in triplicate and the DPPH concentration (mM) was
calculated from the following equation:
Compound 1a: 95% yield (lit. [31] 90%); yellow solid; mp
134e135 ꢁC (lit. [31] 134e136 ꢁC); 1H NMR (DMSO-d6,
200 MHz) 2.26 (s, 3H), 2.37 (s, 3H), 7.10 (s, 1H), 7.23 (d,
3
3
A515 ¼ 0:0087 ꢂ CDPPH ꢀ 0:0097
2H, J ¼ 8.80 Hz), 8.23 (d, 2H, J ¼ 8.80 Hz); 1b: 88% yield;
yellow solid; mp 150e152 ꢁC (lit. [32] 154 ꢁC); 1H NMR
(DMSO-d6, 200 MHz) 2.38 (s, 3H), 7.24 (s, 1H), 7.35 (t, 2H,
Stock solutions (0.01 M) of antioxidants were prepared in
N,N-dimethylformamide (DMF) and rapidly mixed (volumes
from 1.5 to 270 mL) with an ethanol solution of DPPH (final
volume 3.0 mL). Initial concentrations of DPPH were around
50 mM. The decrease in absorbance at 515 nm was recorded
every 0.02 min. The effective concentration ratio (ECR50) is
the ratio of antioxidant concentration to DPPH concentration
producing a 50% decrease in DPPH after 6 min of reaction.
Antioxidant reference compounds like Trolox (6-hydroxy-
2,5,7,8-tetramethylchromane-2-carboxylic acid) and ascorbic
acid were used.
3
3JHeH¼3JHeF ¼ 8.90 Hz), 8.21 (dd, 1H, JHeH ¼ 8.90 Hz,
4JHeF ¼ 6.10 Hz); 13C NMR (DMSO-d6, 50 MHz) 15.3,
116.2 (2JCeF ¼ 21.60 Hz), 128.5, 129.8 (4JCeF ¼ 3.35 Hz),
132.2 (5JCeF ¼ 2.60 Hz), 134.4 (3JCeF ¼ 8.90 Hz), 163.4
(1JCeF ¼ 251.20 Hz), 166.8 (6JCeF ¼ 1.50 Hz), 167.3.
4.3.2. Synthesis of (Z )-3-aryl-2-hydroxypropenoic acids
2a,b: general procedure
A
solution of the 4-benzylideneoxazol-5-one 1a,b
(10 mmol) in 3 N HCl (60 mL) was refluxed for 4 h. After fil-
tration of the hot mixture, cooling at room temperature and fil-
tration gave the pyruvic acids 2a,b.
4.2.2. Prevention of peroxynitrite-mediated oxidation
Peroxynitrite synthesis was carried out as previously re-
ported [30]. Experiments were conducted at room temperature
in a 50 mM phosphate-buffered saline containing 0.1 mM di-
ethylenetriaminepentaacetic acid, 90 mM NaCl and 5 mM
KCl, pH 7.4. Blanks using DMF alone in the absence of test
compound and peroxynitrite allowed to degrade for 5 min in
phosphate-buffered saline, pH 7.4, were also run. There was
no interference of DMF and degraded peroxynitrite with the
oxidative modification of Evans Blue dye. Test compound,
Evans Blue (17.5 mM) and peroxynitrite (335 mM) were rap-
idly mixed and the peroxynitrite-induced bleaching of Evans
Blue dye was measured at 608 nm (e ¼ 70000 Mꢀ1 cmꢀ1).
The effects are expressed as the concentration giving 50% in-
hibition of the oxidation of Evans Blue (IC50).
Compound 2a: 87% yield; red solid; mp 207 ꢁC dec (lit.
1
[31] 207 ꢁC dec); H NMR (DMSO-d6, 200 MHz) 6.35 (s,
3
3
1H), 6.75 (d, 2H, J ¼ 8.20 Hz), 7.21 (d, 2H, J ¼ 8.20 Hz),
8.81 (s, 1H), 9.60 (s, 1H). 2b: 78% yield; yellow solid; mp
1
163e164 ꢁC; H NMR (DMSO-d6, 200 MHz) 6.42 (s, 1H),
7.20 (t, 2H, JHeH¼3JHeF ¼ 8.90 Hz), 7.82 (dd, 2H, JHeH
3
3
¼ 8.90 Hz, JHeF ¼ 5.80 Hz), 9.30 (s, 1H); 13C NMR
4
(DMSO-d6, 50 MHz) 109.8 (5JCeF ¼ 1.10 Hz), 116.0 (2JCeF
¼ 21.40 Hz), 130.1 (4JCeF ¼ 3.30 Hz), 132.5 (3JCeF ¼ 8.40 Hz),
141.2 (6JCeF ¼ 2.50 Hz), 162.8 (1JCeF ¼ 246.0 Hz), 167.0.
4.3.3. Synthesis of methyl (Z)-3-aryl-2-hydroxypropenoate
3a,b: general procedure
The pyruvic acid 2a,b (13.7 mmol) was dissolved in dry
DMF (80 mL) at 0 ꢁC. DBU (2.28 mL, 15.2 mmol) and methyl
iodide (4.75 mL, 76.3 mmol) were successively added and the
solution was stirred at 0 ꢁC for 3 h and then overnight at room
temperature. The solution was poured into a mixture of AcOEt
(10 mL) and 1 M HCl (50 mL). The organic layer was sepa-
rated and the aqueous layer was extracted four times with
AcOEt (15 mL). The combined organic layers were washed
with H2O (20 mL) and dried over Na2SO4. Evaporation of
the volatiles in vacuo afforded the methyl pyruvates 3a,b.
4.3. Chemistry
All reagents and solvents were purchased from Aldrich-
Chimie (Saint-Quentin-Fallavier, France) of ACS reagent
grade and were used as provided. TLC analyses were per-
formed on plastic sheets precoated with silica gel 60F254
(Merck). SiO2, 200e400 mesh (Merck) was used for column
chromatography. NMR spectra were obtained on an AC 200
Bruker spectrometer in the appropriate solvent with TMS as
internal reference. Melting points were obtained on a Reichert
Thermopan melting point apparatus, equipped with a micro-
scope and are uncorrected. Mass spectra were recorded on
a Voyager DE STR mass spectrometer (Applied Biosystems)
(MALDI-TOF). HRMS were obtained on an APEX Qe 9.4
T Bruker Deltonics spectrometer.
1
Compound 3a: 92% yield; red solid; mp 115e116 ꢁC; H
NMR (DMSO-d6, 200 MHz) 3.77 (s, 3H), 6.75 (d, 2H,
3
3J ¼ 8.60 Hz), 7.62 (d, 2H, J ¼ 8.60 Hz), 9.10 (s, 1H), 9.65
(s, 1H). 3b: 83% yield; beige solid; mp 138e140 ꢁC; 1H
NMR (DMSO-d6, 200 MHz) 3.80 (s, 3H), 6.45 (s, 1H), 7.19
3
3
(t, 2H, JHeH¼3JHeF ¼ 8.90 Hz), 7.85 (dd, 2H, JHeH
¼
4
8.90 Hz, JHeF ¼ 5.80 Hz), 9.61 (s, 1H); 13C NMR (DMSO-
4.3.1. Synthesis of (Z)-4-benzylideneoxazol-5(4H)-ones
1a,b: general procedure
d6, 50 MHz) 52.8, 109.7 (5JCeF ¼ 0.70 Hz), 115.6 (2JCeF
¼
21.10 Hz), 130.2 (4JCeF ¼ 3.20 Hz), 131.5 (3JCeF ¼ 7.90 Hz),
4-Hydroxybenzaldehyde or 4-fluorobenzaldehyde (100 mmol),
N-acetylglycine (14.04 g; 120 mmol), anhydrous NaOAc
(10.66 g; 130 mmol) and Ac2O (51 g; 500 mmol) were mixed
and stirred at 100 ꢁC for 5 h. The mixture was allowed to cool
at room temperature. Then ice water (50 mL) was added. The
resulting precipitate was filtered, washed with 50% aq EtOH
(4 ꢂ 20 mL) and dried at 60 ꢁC to give 1a or 1b.
140.9 (6JCeF ¼ 2.60 Hz), 158.8 (1JCeF ¼ 244.4 Hz), 165.2.
4.3.4. Synthesis of the 4,5-diaryl-3-hydroxy-2(5H)
furanones 4aeh: general procedure
To a cold solution of methyl pyruvate (5.27 mmol) and ap-
propriate benzaldehyde (1.3 equiv) in dry DMF (25 mL) was
added DBU (0.8 mL, 5.35 mmol). The mixture was stirred

F. Bailly et al. / European Journal of Medicinal Chemistry 43 (2008) 1222e1229
1227
for 3 h at 0 ꢁC and then overnight at room temperature. The
solution was poured into a mixture of AcOEt (10 mL) and
1 M HCl (50 mL). The organic layer was separated and the
aqueous layer was extracted several times with AcOEt. The
combined organic layers were dried over Na2SO4 and evapo-
rated in vacuo. The oily residue was then purified by column
chromatography (AcOEt/hexane, 30:70) for compounds 4b,
4d, 4e and 4f. For the other ones 4a, 4c, 4g and 4h, the oily
residue was dissolved in aqueous 2 M NaOH and, after filtra-
tion of the insoluble, the solution was acidified to pH 1.0 with
6 M HCl. The precipitate was filtered and dried at room
temperature.
HRMS (nanoESI-FR-ICR) calcd for C23H17FO4 376.11109,
found 376.11113.
4.3.4.5.
5-(3,5-Dibenzyloxyphenyl)-4-(4-fluorophenyl)-3-hy-
droxy-2(5H)-furanone 4e. Yield 12%; white solid; mp 159e
1
160 ꢁC; H NMR (DMSO-d6, 200 MHz) 4.98 (s, 4H), 6.06
4
4
(s, 1H), 6.57 (d, 2H, JHeH ¼ 2.20 Hz), 6.63 (t, 1H, JHe
¼ 2.20 Hz), 6.99 (t, 2H, JHeH¼3JHeF ¼ 8.90 Hz), 7.36 (m,
3
H
10H), 7.56 (dd, 2H, JHeH ¼ 8.90 Hz, JHeF ¼ 5.40 Hz); 13C
NMR (DMSO-d6, 50 MHz) 70.2 (CH2), 81.6 (C5), 103.2,
107.4, 115.7 (2JCeF ¼ 21.60 Hz), 126.1 (4JCeF ¼ 3.30 Hz),
3
4
5
127.4 (C4, JCeF ¼ 1.10 Hz), 127.5, 128.1, 128.5, 129.7
(3JCeF ¼ 8.20 Hz), 136.3, 137.2, 137.5 (C3, 6JCe
4.3.4.1. 3-Hydroxy-4-(4-hydroxyphenyl)-5-phenyl-2(5H)-fura-
none 4a. Yield 30% (lit. [16] 21%); brown solid; mp 253e
255 ꢁC (lit. [16] 258 ꢁC); 1H NMR (DMSO-d6, 200 MHz)
¼ 2.20 Hz), 160.4 (CeOBn), 162.6 (1JCeF ¼ 250.90 Hz),
F
170.2 (C2); MS (MALDI-TOF): m/z (%) ¼ 483 ([MHþ],
100), 309 (11), 287 (9), 231 (8); HRMS (nanoESI-FR-ICR)
calcd for C30H23FO5 482.15295, found 482.15304.
3
6.46 (s, 1H), 6.71 (d, 2H, J ¼ 8.90 Hz), 7.35e7.37 (m, 5H),
3
7.46 (d, 2H, J ¼ 8.90 Hz), 9.79 (s, 1H), 10.61 (s, 1H).
4.3.4.6.
5-(3,4-Dibenzyloxyphenyl)-4-(4-fluorophenyl)-3-hy-
4.3.4.2. 5-(4-Fluorophenyl)-3-hydroxy-4-(4-hydroxyphenyl)-
droxy-2(5H)-furanone 4f. Yield 10%; white solid; mp 155e
1
2(5H)-furanone 4b. Yield 17%; yellow solid; mp 270e
157 ꢁC; H NMR (DMSO-d6, 200 MHz) 5.08 (s, 4H), 6.41
1
3
4
271 ꢁC; H NMR (DMSO-d6, 200 MHz) 6.49 (s, 1H), 6.71
(s, 1H), 6.89 (dd, 1H, JHeH ¼ 8.20 Hz, JHeH ¼ 1.80 Hz),
3
3
3
4
(d, 2H, JHeH ¼ 8.90 Hz), 7.19 (t, 2H, JHeH¼3JHeF
¼ 8.60 Hz), 7.40 (m, 4H), 9.79 (s, 1H), 10.64 (s, 1H); 13C
NMR (DMSO-d6, 50 MHz) 78.6 (C5), 115.3, 115.8
(2JCeF ¼ 21.60 Hz), 121.3, 128.91 (C4), 128.92, 129.5
(3JCeF ¼ 8.60 Hz), 133.2 (4JCeF ¼ 3.00 Hz), 136.5 (C3),
157.7(CeOH), 162.3, 169.4 (C2); MS (MALDI-TOF): m/z
(%) ¼ 287 ([MHþ], 78), 269 (100), 257 (11), 241 (20), 229
(16); HRMS (nanoESI-FR-ICR) calcd for C16H11FO4
286.06414, found 286.06475.
7.03 (d, 1H, JHeH ¼ 8.20 Hz), 7.08 (d, 1H, JHeH
¼ 1.80 Hz), 7.16 (t, 2H, 3JHeH¼3JHeF ¼ 8.90 Hz),
3
4
7.30e7.40 (m, 10H), 7.60 (dd, 2H, JHeH ¼ 8.90 Hz, JHeF
¼ 5.50 Hz); 13C NMR (DMSO-d6, 50 MHz) 69.3 (CH2),
70.2 (CH2), 79.6 (C5), 114.19, 114.25, 115.5 (2JCeF
¼ 21.50 Hz), 121.0, 126.7 (C4), 127.2 (3JCeF ¼ 3.30 Hz),
127.5, 127.6, 127.76, 127.79, 128.30, 128.36, 128.9, 129.5
(3JCeF ¼ 7.80 Hz), 137.0, 138.5 (C3, JCeF ¼ 1.50 Hz), 148.1
6
(CeOBn), 149.1 (CeOBn), 161.5 (1JCeF ¼ 246.20 Hz),
169.0 (C2); HRMS (nanoESI-FR-ICR) calcd for C30H23FO5
482.15295, found 482.15374.
4.3.4.3. 5-(4-Benzyloxyphenyl)-3-hydroxy-4-(4-hydroxyphenyl)-
2(5H)-furanone 4c. Yield 21%; pink solid; mp 268e270 ꢁC;
1H NMR (DMSO-d6, 200 MHz) 5.06 (s, 2H), 6.40 (s, 1H),
4.3.4.7. 5-(3,5-Dibenzyloxyphenyl)-3-hydroxy-4-(4-hydroxy-
3
3
6.72 (d, 2H, J ¼ 8.50 Hz), 6.99 (d, 2H, J ¼ 8.20 Hz), 7.28
phenyl)-2(5H)-furanone 4g. Yield 20%; beige solid; mp
(d, 2H, J ¼ 8.50 Hz), 7.41 (m, 7H); 13C NMR (DMSO-d6,
216e217 ꢁC; H NMR (DMSO-d6, 200 MHz) 5.04 (s, 4H),
3
1
50 MHz) 69.2 (CH2), 79.2 (C5), 115.0, 115.3, 121.6, 122.7,
127.8, 128.4, 128.96, 128.99 (C4), 129.1, 129.2, 136.4 (C3),
136.8, 157.7 (CeOH), 158.9 (CeOBn), 169.3 (C2); MS
(MALDI-TOF): m/z (%) ¼ 375 ([MHþ], 30), 309 (100), 231
(50); HRMS (nanoESI-FR-ICR) calcd for C23H18O5
374.11543, found 374.11517.
6.34 (s, 1H), 6.67 (d, 2H, 4J ¼ 2.20 Hz), 6.74 (t, 2H,
3J ¼ 8.60 Hz), 7.35 (m, 10H), 9.80 (s, 1H), 10.58 (s, 1H);
13C NMR (DMSO-d6, 50 MHz) 69.4 (CH2), 79.3 (C5),
102.2, 106.9, 115.3, 121.5 (C4), 127.8, 127.9, 128.9, 129.0,
136.4, 136.6 (C3), 139.2 (CeOBn), 159.7 (CeOH), 169.2
(C2); MS (MALDI-TOF): m/z (%) ¼ 481 ([MHþ], 100), 423
(18), 287 (5); HRMS (nanoESI-FR-ICR) calcd for C30H24O6
480.15729, found 480.15813.
4.3.4.4. 5-(4-Benzyloxyphenyl)-4-(4-fluorophenyl)-3-hydroxy-
2(5H)-furanone 4d. Yield 16%; white solid; mp 198e
1
199 ꢁC; H NMR (DMSO-d6, 200 MHz) 5.06 (s, 2H), 6.50
4.3.4.8. 5-(3,4-Dibenzyloxyphenyl)-3-hydroxy-4-(4-hydroxy-
3
3
(s, 1H), 6.99 (d, 2H, JHeH ¼ 8.60 Hz), 7.19 (t, 2H, JHe
phenyl)-2(5H)-furanone 4h. Yield 29%; brown solid; mp
¼3JHeF ¼ 8.60 Hz), 7.30 (d, 2H, JHeH ¼ 8.60 Hz), 7.40
218e220 ꢁC; H NMR (DMSO-d6, 200 MHz) 5.08 (s, 2H),
3
1
H
3
4
(m, 5H), 7.64 (dd, 2H, JHeH ¼ 8.90 Hz, JHeF ¼ 5.40 Hz),
6.33 (s, 1H), 6.71 (d, 2H, 3J ¼ 8.20 Hz), 6.88 (d, 1H,
11.07 (s, 1H); 13C NMR (DMSO-d6, 50 MHz) 69.3 (CH2),
3J ¼ 8.20 Hz, J ¼ 1.80 Hz), 7.03 (d, 1H, J ¼ 8.20 Hz), 7.10
(d, 1H, 4J ¼ 1.80 Hz), 7.25e7.30 (m, 12H), 7.80 (s, 1H),
9.82 (s, 1H); 13C NMR (DMSO-d6, 50 MHz) 69.9 (CH2),
70.2 (CH2), 79.5 (C5), 114.2, 114.4, 115.3, 120.8, 121.5,
127.5, 127.71, 127.73, 128.3, 128.8 (C4), 129.0, 129.5, 136.4
(C3), 136.9, 137.0, 148.0 (CeOBn), 148.9 (CeOBn), 157.6
(CeOH), 169.3(C2); MS (MALDI-TOF): m/z (%) ¼ 481
4
3
79.4 (C5), 115.1, 115.5 (2JCeF ¼ 21.60 Hz), 126.9 (C4, JCe
5
¼ 0.80 Hz), 127.2 (4JCeF ¼ 3.30 Hz), 127.7, 127.9, 128.4,
F
129.3, 129.6 (3JCeF ¼ 8.20 Hz), 136.8, 138.5 (C3, JCe
6
¼ 1.90 Hz), 159.0 (CeOBn), 161.5 (1JCeF ¼ 249.50 Hz),
F
169.0 (C2); MS (MALDI-TOF): m/z (%) ¼ 377 ([MHþ],
100), 359 (18), 331 (20), 313 (13), 263 (14), 232 (17);

1228
F. Bailly et al. / European Journal of Medicinal Chemistry 43 (2008) 1222e1229
([MHþ], 100), 463 (43), 439 (38), 423 (33), 407 (21), 362
(15), 335 (28), 287 (19), 229 (18); HRMS (nanoESI-FR-
ICR) calcd for C30H24O6 480.15729, found 480.15668.
m/z (%) ¼ 287 ([MHþ], 100), 269 (10), 231 (18); HRMS
(nanoESI-FR-ICR) calcd for C16H11FO4 286.06414, found
286.06430.
4.3.5. Synthesis of the 4,5-diaryl-3-hydroxy-2(5H)
furanones 4iem: general procedure
4.3.5.5. 5-(3,5-Dihydroxyphenyl)-4-(4-fluorophenyl)-3-hydroxy-
2(5H)-furanone 4m. Yield 76%; brown solid; mp 92e94 ꢁC;
1H NMR (acetone-d6, 200 MHz) 6.22 (s, 1H), 6.33 (t, 1H,
Pd/C (10%; 0.091 g/mmol OBn group) was added to the
furanone dissolved in THF/EtOH and the solution was submit-
ted to a hydrogen atmosphere for 5 h. After filtration of the
catalyst, the solvent was evaporated in vacuo. Purification by
column chromatography (AcOEt/hexane, 50:50) and crystalli-
zation from ethyl ether afforded the deprotected furanones.
4
4JHeH ¼ 2.05 Hz), 6.40 (d, 2H, JHeH ¼ 2.05 Hz), 7.10 (dd,
2H, 3JHeH¼3JHeF ¼ 9.10 Hz), 7.73 (dd, 2H, 3JHeH
4
¼ 9.10 Hz, JHeF ¼ 5.60 Hz), 8.40 (br s, 2H), 9.52 (s, 1H);
13C NMR (acetone-d6, 50 MHz) 81.5 (C5), 103.2, 104.9,
107.7, 116.7 (2JCeF ¼ 22.00 Hz), 128.2 (C4, 5JCeF
¼ 0.80 Hz), 128.7 (4JCeF ¼ 3.30 Hz), 131.2 (3JCeF
6
4.3.5.1.
5-(3,5-Dihydroxyphenyl)-3-hydroxy-4-(4-hydroxy-
¼ 8.20 Hz), 139.8 (C3, JCeF ¼ 2.20 Hz), 140.2, 160.6
phenyl)-2(5H)-furanone 4i. Yield 82%; brown solid; mp
(CeOH), 163.9 (1JCeF ¼ 248.20 Hz), 170.2 (C2); HRMS
(nanoESI-FR-ICR) calcd for C16H11FO5 302.05905, found
302.05931.
1
270e272 ꢁC; H NMR (acetone-d6, 200 MHz) 6.10 (s, 1H),
3
6.33 (m, 1H), 6.38 (m, 2H), 6.78 (d, 2H, J ¼ 7.90 Hz), 7.53
3
(d, 2H, J ¼ 7.90 Hz); 13C NMR (acetone-d6, 50 MHz) 80.5
(C5), 103.5, 106.5, 115.4, 122.3 (C4), 128.8, 129.5, 136.5,
139.1 (C3), 157.8 (CeOH), 158.8 (CeOH), 169.3 (C2); MS
(MALDI-TOF): m/z (%) ¼ 301 ([MHþ], 28), 265 (9), 231
(17); HRMS (nanoESI-FR-ICR) calcd for C16H12O6
300.06339, found 300.06288.
Acknowledgement
This work was financially supported by grants from le Cen-
tre National de la Recherche Scientifique (CNRS), l’Agence
Nationale de la Recherche contre le SIDA (ANRS) and the Eu-
ropean Commission (LSHB-CT-2003-503480). The Mass
Spectrometry facility used in this study was funded by the Eu-
4.3.5.2.
5-(3,4-Dihydroxyphenyl)-3-hydroxy-4-(4-hydroxy-
phenyl)-2(5H)-furanone 4j. Yield 86%; black solid; mp
´
ropean Community (FEDER), the Region Nord-Pas de Calais
(France), the CNRS and the Universite des Sciences et Tech-
1
273e274 ꢁC; H NMR (acetone-d6, 200 MHz) 6.17 (s, 1H),
´
6.77 (m, 5H), 7.54 (dd, 2H, 3J ¼ 6.75 Hz, 4J ¼ 2.05 Hz),
8.01 (s, 1H), 8.13 (s, 1H), 8.72 (s, 1H), 9.07 (s, 1H); 13C
NMR (acetone-d6, 50 MHz) 80.8 (C5), 114.9, 115.5, 115.7,
120.6, 122.6, 128.7 (C4), 128.8, 129.8, 136.8 (C3), 145.6
(CeOH), 146.4 (CeOH), 158.0 (CeOH), 169.5 (C2);
HRMS (nanoESI-FR-ICR) calcd for C16H12O6 300.06339,
found 300.06386.
nologies de Lille.
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238 ꢁC; H NMR (acetone-d6, 200 MHz) 6.21 (s, 1H), 6.77
3
4
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4
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1
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3
(d, 2H, JHeH ¼ 8.50 Hz), 7.10 (t, 2H, JHeH¼3JHeF
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