Synthesis and in vitro protein tyrosine kinase inhibitory activity of furan-2-yl(phenyl)methanone derivatives

Article abstract of DOI:10.3390/molecules16064897

A series of novel furan-2-yl(phenyl)methanone derivatives were synthesized, and their structures were established on the basis of ¹H-NMR, ¹³C-NMR and mass spectral data. All the prepared compounds were screened for their in vitro protein tyrosine kinase inhibitory activity and several new derivatives exhibited promising activity, which, in some cases, was identical to, or even better than that of genistein, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and are discussed.

Full text of DOI:10.3390/molecules16064897

Molecules 2011, 16, 4897-4911; doi:10.3390/molecules16064897
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and In Vitro Protein Tyrosine Kinase Inhibitory
Activity of Furan-2-yl(phenyl)methanone Derivatives
Fei Lang Zheng 1, Shu Rong Ban 1, Xiu E Feng 1, Cheng Xiao Zhao 1, Wenhan Lin 2 and
Qing Shan Li 1,2,
*
1
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, Shanxi, China
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China
2
* Author to whom correspondence should be addressed; E-Mail:qingshanl@yahoo.com;
Tel.: +86-351-4690322; Fax: +86-351-4690114.
Received: 27 April 2011; in revised form: 1 June 2011 / Accepted: 7 June 2011 /
Published: 14 June 2011
Abstract: A series of novel furan-2-yl(phenyl)methanone derivatives were synthesized,
and their structures were established on the basis of 1H-NMR, 13C-NMR and mass spectral
data. All the prepared compounds were screened for their in vitro protein tyrosine kinase
inhibitory activity and several new derivatives exhibited promising activity, which, in some
cases, was identical to, or even better than that of genistein, a positive reference compound.
The preliminary structure-activity relationships of these compounds were investigated and
are discussed.
Keywords: halophenols; furan-2-yl(phenyl)methanone; protein tyrosine kinases inhibitor;
structure-activity relationships (SAR)
1. Introduction
Bromophenols isolated from various marine algae, ascidians and sponges have recently attracted
much attention due to their unique structures and varied pharmacological activities, which include
antioxidative [1], protein tyrosine kinase (PTK) inhibitory [2], anticancer [3], protein tyrosine
phosphatase 1B inhibitory [2], antithrombotic [4], antimicrobial [5], anti-inflammatory [6], enzyme
inhibitory [7], cytotoxic [8] and appetite suppressant [9] effects. The core structures of these
bromophenols are two benzene rings connected by a methylene or carbonyl group. However, studies

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on their structure optimization and their corresponding structure-activity relationship (SAR) with PTK
inhibitors have been rarely reported, despite the fact that several natural bromophenol compounds [10]
and some new derivatives with antimicrobial activities were prepared [5,11].
Protein kinases play an important role as cell function regulators in signal transduction pathways
that regulate a number of cellular functions, such as proliferation, growth, differentiation, death and
various regulatory mechanisms. A variety of tumor types have dysfunctional growth factor receptor
tyrosine kinases, which result in inappropriate mitogenic signaling. PTKs are, therefore, attractive targets
in the search for therapeutic agents, not only against cancer, but also in many other diseases [12,13].
A wide range of heterocyclic ring systems has been studied for the development of novel chemical
entities as lead molecules in drug discovery. Introduction of appropriate heterocycles into a lead
compound is a common strategy during the drug discovery process. It has been found that many
common rings, including different heterocyclic and simplified aromatic structures, are important as
PTK inhibitors [14]. The encouraging activities of our previously prepared bromophenols [15]
prompted us to investigate new analogs involving further modification of five-membered heterocyclic
rings, to optimize the SAR that might lead to potent and selective biological activity. The furan ring is
a very important bioactive structure that is considered to be a basic building block in the design and
synthesis of new drugs. Furan rings are electron-rich systems that are amenable to act as good ligands
for metal ions. Furan derivatives that are substituted at the 2- and 5- positions are frequently found in
nature. These derivatives show broad-spectrum pharmacological properties [16]. Hence, in this study,
we modified the structures of bromophenols by replacement of one benzene ring with a furan ring.
The introduction of new substituents and functional groups at various positions on aromatic or
heteroaromatic fragments of a potential drug might lead to changes in its molecular shape that allows
optimum binding to the receptor, as well as its physicochemical properties that affect drug distribution
and metabolism [17,18]. The scaffold was designed in such a way that the benzene ring was connected
with heteroaryl system by a carbonyl group, with the hope of attaining superior biological activity.
A series of new furan-2-yl(phenyl) methanone derivatives was synthesized by convenient methods to
evaluate their biological and PTK inhibitory activities. Finally, the preliminary SARs were investigated.
2. Results and Discussion
Two strategies were adopted to prepare the target compounds. One strategy was Friedel-Crafts
acylation of substituted benzene derivatives with the furoyl chloride (Schemes 1–3), and the other was
Friedel-Crafts acylation of furan with substituted benzoyl chloride derivatives (Schemes 4 and 5).
The synthetic routes of compounds 3a–3d and 4a–4d are shown in Scheme 1. The starting material,
furan-2-carboxylic acid, was reacted with dry SOCl2 in the presence of a catalytic amount of
N,N-dimethylformamide (DMF) to yield furan-2-carbonyl chloride, which was reacted further with
substituted benzene derivatives to yield compound 3. Compound 4 was obtained by treating compound
3 with BBr3.
5-Bromofuran-2-carboxylic acid (5) and 4,5-dibromofuran-2-carboxylic acid (11) were prepared
according to the previously described procedures [19,20], which were also used to prepare compounds
7a–7c, 8a–8c, 13 and 14 (Schemes 2 and 3).

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Scheme 1. Syntheis of compounds 3a–3d and 4a–4d.
O
4
O
O
O
O
O
a
b
c
COOH
COCl
R2
R1
R
3
2
1
R2= 4-OH
R2= 3,4-OH
R2= 5-Br-2-OH
R2= 2,3,4-OH
R= -OCH3
R1= 4-OCH3
R1= 3,4-OCH3
R1= 5-Br-2-OCH3
R= 1,2-OCH3
R= 1-Br-4-OCH3
R= 1,2,3-OCH3
R1= 2,4-OCH3-3-OH
Reagents and conditions: (a) SOCl2, DMF, reflux, 5 h, 95%; (b) AlCl3, CH2Cl2, reflux, 8 h,
70%–80%; (c) BBr3 (10 equiv.), CH2Cl2, −78 °C to room temperature, 4 h, 90%–95%.
Scheme 2. Syntheis of compounds 7a–7c and 8a–8c.
Reagents and conditions: (a) Br2, CCl4, reflux, 10 h, 70%; (b) SOCl2, DMF, reflux, 5 h, 90%–95%;
(c) AlCl3, CH2Cl2, reflux, 8 h, 70%–80%; (d) BBr3 (10 equiv.), CH2Cl2, −78 °C to room
temperature, 4 h, 90%–95%.
Scheme 3. Syntheis of compounds 13 and 14.
O
O
O
Br
Br
Br
Br
a
c
CHO
COOH
CHO
b
9
11
10
O
O
O
O
O
HO
O
HO
HO
Br
Br
COCl
d
e
Br
Br
O
O
Br
Br
12
14
13
Reagents and conditions: (a) Br2, AlCl3, 0 °C, 5 h, 60%; (b) AgNO3, NaOH, 3 h, 90%; (c) SOCl2,
DMF, reflux, 5 h, 95%; (d) AlCl3, CH2Cl2, reflux, 8 h, 60%; (e) BBr3 (10 equiv.), CH2Cl2, −78 °C
to room temperature, 4 h, 91%.
The synthetic routes to compounds 17a/17b and 18a/18b are illustrated in Scheme 4. Variously
substituted benzoic acids 15 (Figure 1) were refluxed in anhydrous SOCl2 to yield acyl chlorides 16,
which were reacted with furfural catalyzed by AlCl3. The product was purified by silica gel column
chromatography (ligarine/EtOAc 80:20, v/v) to give compound 17, which were treated with BBr3 to
give compound 18.

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Figure 1. Structures of starting materials 15.
Scheme 4. Syntheis of compounds 17a–17b and 18a–18b.
O
O
O
O
c
a
b
O
O
OH
Cl
R
R'
R
R
O
16
17
18
15
R=OCH3
R'=OH
Reagents and conditions: (a) SOCl2, DMF, reflux, 5 h, 90%–95%; (b)AlCl3, CH2Cl2, 0 °C to room
temperature, 20 h, 80%–85%; (c) BBr3 (10 equiv.), CH2Cl2, −78 °C to room temperature, 4 h,
90%–95%.
Scheme 5. Syntheis of compounds 21a–21d and 21a–21d.
O
O
O
O
a
c
b
O
Cl
OH
OH
15
R
R
X
R
R
O
21
X
X
20
19
X
O
O
d
R=OCH3
X=Br or Cl
R'=OH
R'
22
Reagents and conditions: (a) Br2, CCl4, 50 °C, 24 h, 90%–95% or SO2Cl2, CH2Cl2, 40 °C, 20 h,
90%–95%; (b) SOCl2, DMF, reflux, 5 h, 95%; (c) AlCl3, CH2Cl2, 0 °C to room temperature, 20 h,
80%–85%; (d) BBr3 (10 equiv.), CH2Cl2, −78 °C to room temperature, 4 h, 90%–95%.
To examine the influence of the number and position of halogen atoms on their bioactivites,
chlorination of 15 (Figure 1) with SO2Cl2 or bromination with Br2 provided a good yield of 19.
Chloro- and bromo-substituted compounds 21 and 22 were then synthesized according to the second
route (Scheme 5). The structures of target compounds are shown in Table 1.
Table 1. Structures of the target new compounds.

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Table 1. Cont.
Compounds
Compounds
Substituent Group
3,4-OCH3
Substituent Group
3,4-OH
3a
3b
4a
4b
2,4-OCH3, 3-OH
2-OCH3, 5-Br
2,3,4- OH
3c
4c
2-OH, 5-Br
3d
4-OCH3
4d
4-OH
7a
2,3-OH, 4-OCH3, 5’-Br
2-OCH3, 5-Br, 5’-Br
3-OH, 4-OCH3, 5’-Br
3-OH, 4-OCH3,4’,5’-Br
2,3-OCH3
8a
2,3,4-OH, 5’-Br
2-OH, 5-Br, 5’-Br
3,4-OH, 5’-Br
3,4-OH, 4’,5’-Br
2,3-OH
7b
8b
7c
8c
13
14
17a
17b
21a
21b
21c
21d
18a
18b
22a
22b
22c
22d
2,6-OCH3
2,6-OH
3-Br, 4-OCH3
3-Br, 4-OH
2,6-Br, 3,4,5-OCH3
2-Cl, 3,4,5-OCH3
2-OH, 3-OCH3, 4,5-Br
2,6-Br, 3,4,5-OH
2-Cl, 3,4,5-OH
2,3-OH, 4,5-Br
2.1. Results
As shown in Table 2, all of the furan-2-yl(phenyl)methanone derivatives were subjected to the
in vitro PTK inhibitory activity testing using the PTK assay, as previously reported [13]. Some of the
new derivatives exhibited promising activity, which in some cases, was identical to, or even better than
that of genistein, a positive reference compound in the same model. Thus, compounds 4a, 4b, 8a, 8c
and 22c exhibited PTK inhibitory activity (IC50 values 4.66, 6.42, 5.31, 2.72 and 4.62 μM, respectively),
which was more potent than that of the genistein (IC50 13.65 μM). Compounds 18a, 18b and 22d also
displayed moderate PTK inhibitory activity (IC50 values 13.23, 12.65 and 9.56 μM, respectively).
Table 2. PTK inhibitory activity.
Protein Tyrosine Kinase
Protein Tyrosine Kinase
Compounds
Compounds
(PTK) inhibition activity a
(PTK) inhibition activity a
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
3a
3b
4a
4b
4.66
6.42
NA
3c
4c
NA
3d
4d
7a
8a
5.31
NA
7b
8b
7c
8c
2.72
NA
13
14
17a
17b
21a
21b
21c
21d
18a
18b
22a
22b
22c
22d
13.23
12.65
NA
NA
4.62
9.56
a IC50 (μM). Values are means of three experiments; NA, not active at 5 μg/mL. Genistein 13.65 μM.

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2.2. SAR Analysis
The results indicated that the number of hydroxyl groups had a great effect on the PTK inhibitory
activity. More than one hydroxyl group was essential for the activity, as none of the compounds that
had only one hydroxyl group in the phenyl ring showed any activity, whereas those with more than one
exhibited high to moderate activity, although the activities did not increase directly with the number of
hydroxyl groups. For example, when three hydroxyl groups were present in the phenyl ring, the
corresponding activity was lower than that with two hydroxyl groups. Among the hydroxyl substituted
derivatives, the three compounds 4a, 18a and 18b with a similar structure that had two hydroxyl
groups in the benzene ring had strong to moderate activity. However, they did not show equal activity,
which suggested that two substituent hydroxyl groups at appropriate positions in the benzene ring were
important to the PTK inhibitory activity of these compounds.
Comparison of the activities of the halogen-substituted derivatives indicated that the halogen atoms
in the phenyl ring (22b and 22c) contributed to the PTK inhibitory activity in the order of Cl > Br.
However, compound 22b with a fully-substituted phenyl ring showed no activity.
We can conclude that hydroxyl groups on the furan-2-yl(phenyl)methanone backbone are essential
for the in vitro PTK inhibitory activity of these compounds, and introduction of a methoxyl group can
lead to the disappearance of activity, as all the methoxyl derivatives were inactive. The presence of one
or more halogen atoms on the phenyl ring also increases the activity. The number and position of the
hydroxyl groups and halogen atoms in the phenyl ring could influence the activity potency.
By comparison of the activity of compounds 4a, 4b, 8a and 8c, we found that the introduction of a
Br atom at the C-5 position in the furan ring could increase activity. However, compound 14 showed
no activity due to the introduction of another Br atom at the C-4 position in the furan ring of 8c which
showed the strongest activity. The results suggest that a Br atom substituted at the C-5 position in the
furan ring could enhance the PTK inhibitory activity, but Br atoms substituted at the C-4 position in
are inhibitory for such activity.
3. Experimental
3.1. General
Melting points were determined on a XT4A microscopic stage melting point apparatus with an
aromatic temperature control system. NMR spectra were recorded on a Bruker-AV400 spectrometer
with TMS as an internal standard and DMSO-d6 or CDCl3 as the solvent. Chemical shifts (d values)
and coupling constants (J values) were given in ppm and Hz, respectively. ESI mass spectra were
obtained on an API QTRAP 3200 LC-MS spectrometer，the high-resolution mass spectra were
obtained on a Bruker Daltonics Apex IV 70e FTICR-MS (Varian 7.0T). TLC analysis was carried out
on silica gel plates GF254 (Qingdao Haiyang Chemical, China). Silica gel column chromatography was
performed with silica gel 60 G (Qingdao Haiyang Chemical). Commercial solvents were used without
any pretreatment, whereas dichloromethane was dried by refluxing and distilling over calcium hydride.

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3.2. Chemistry
3.2.1. Procedure for the synthesis of 5-bromofuran-2-carboxylic acid 5
Br2 (8 mL) was slowly added to a solution of 2-furancarboxylic acid (1, 14.0 g) in CCl4 (60 mL).
The reaction mixture was stirred at 45–50 °C for 24 h. The solvent was then removed under reduced
pressure to yield a red solid which was recrystallized from boiling water to give the compound 5.
3.2.2. Procedure for the synthesis of 4,5-dibromofuran-2-carboxylic acid 11
Freshly distilled furfural (10.0 g) was added dropwise with mechanical stirring at 0 °C to aluminum
chloride (32.0 g) over a two hour period. Bromine (37.0 g) was then added dropwise at 0 °C over a two
hours period, after which stirring was discontinued and the reaction mixture allowed to stand overnight.
The reaction was quenched by carefully pouring the mixture into ice (800 mL) and then extracting the
aqueous layer three times with ether. The combined organics were washed twice with saturated sodium
bicarbonate, once with brine, and dried with anhydrous MgSO4. The solvent was removed under
reduced pressure to yield a red oil. Purification using column chromatography on silica (hexanes/ethyl
acetate V/V = 1:1 as eluent) yielded compound 10 (13.2 g, Rf = 0.45, 20% ethyl acetate in hexanes) as
an orange oil. Next compound 10 (13.2 g), H2O (40.0 mL) and AgNO3 (8.0 g) were added into a flask
and the mixture was stirred at room temperature for 4 h. Then the reaction was completed, 6 M
hydrochloric acid adjusted to PH to 2~3, and extracting the aqueous layer three times with ethyl
acetate. The combined organics were dried with Na2SO4. The solvent was removed under reduced
pressure, the solid separated was recrystallized from boiling water to give compound 11.
3.2.3. General procedure for synthesis of compounds 3a–3d, 7a–7c and 13
A solution of 2-furancarboxylic acid (1, 1.0 g) and a catalytic amount of DMF in thionyl chloride
(5 mL) was stirred at 80–90 °C for 5 h. After concentration under reduced pressure, furoyl chloride 2
was dissolved in dried CH2Cl2 and reacted with 1,2-dimethoxybenzene (1 mL) catalyzed by AlCl3. The
reaction mixture was heated to 50–60 °C for 12 h. After the reaction was completed, the reaction was
quenched by carefully pouring the mixture into iced water (100 mL), extracting the aqueous layer three
times with CH2Cl2, and drying with anhydrous Na2SO4. The solvent was removed under reduced
pressure to yield a yellow oil. The residue was purified by silica gel column chromatography
(petroleum ether/EtOAc 80:20, v/v) to give compound 3a as a light yellow solid (1.66 g, 80% yield).
(3,4-Dimethoxyphenyl)(furan-2-yl)methanone (3a). Mol. formula (MW): C13H12O4 (232 g/mol); mp:
1
98–100 °C; H-NMR (CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H, Ph-6-H), 7.67(s, 1H, Ph-2-H), 7.55 (d,
J = 1.6 Hz, 1H, 5’-H), 7.22 (d, J = 3.6 Hz, 1H, 3’-H), 6.92 (d, J = 8.4 Hz, 1H, Ph-5-H), 6.57 (d,
13
J = 2.0 Hz, 1H, 4’-H), 3.94 (s, 6H, CH3); C-NMR (CDCl3) δ 56.2, 56.2, 110.1, 111.8, 112.0, 119.6,
124.1, 129.9, 146.6, 148.6, 152.6, 153.1, 181.0; ESI-MS (%): m/z = 233 (100) [M+H]+, 255 (100)
[M+Na]; HRMS (ESI): Calcd. for [M+H]+: 233.0808; Found: 233.0811.
Furan-2-yl(3-hydroxy-2,4-dimethoxyphenyl)methanone (3b). Mol. formula (MW): C13H12O5 (248 g/mol);
1
light yellow solid; Yield: 75%; mp: 168–170 °C; H-NMR (DMSO-d6) δ 8.13 (d, J = 9.2 Hz, 1H,

Molecules 2011, 16
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Ph-6-H), 7.73 (d, J =1.6 Hz, 1H, 5’-H), 7.38 (d, J = 3.6 Hz, 1H, 3’-H), 6.64 (dd, J = 3.6 Hz, J = 1.6 Hz,
13
1H, 4’-H), 6.58 (d, J =9.2 Hz, 1H, Ph-5-H), 3.97, (s, 3H, OCH3), 3.93 (s, 3H, OCH3); C-NMR
(DMSO-d6) δ 56.1, 60.7, 103.1, 103.2, 112.4, 120.3, 128.2, 136.6, 146.8, 152.2, 158.3, 158.5, 183.9;
ESI-MS (%): m/z = 249 (100) [M+H]+; HRMS (ESI): Calcd. for [M+H]+: 249.0758; Found: 249.0759.
(5-Bromo-2-methoxyphenyl)(furan-2-yl)methanone (3c). Mol. formula (MW): C12H9BrO3 (281 g/mol); light
yellow solid; Yield: 70%; mp: 66–70 °C; 1H-NMR (CDCl3) δ 7.68 (s, 1H, 5’-H), 7.59 (dd, J = 8.8 Hz,
J = 2.8 Hz, 1H, Ph-4-H), 7.54 (d, J = 2.8 Hz, 1H, Ph-6-H), 7.09 (d, J = 4.0 Hz, 1H, 3’-H), 6.91 (d,
J = 8.8 Hz, 1H, Ph-3-H), 6.58 (dd, J = 4.0 Hz, J = 2.0 Hz, 1H, 4’-H), 3.98 (s, 3H, OCH3); 13C-NMR
(CDCl3) δ 56.1, 112.4, 112.5, 113.4, 120.8, 129.6 , 131.9, 134.7, 147.6, 152.5, 156.5, 181.2; ESI-MS (%):
m/z = 281(100) 283 (98.7) [M+H]+ 303 (100) 305 (98.7%) [M+Na].
Furan-2-yl(4-methoxyphenyl)methanone (3d). Mol. formula (MW): C12H10O3 (202 g/mol); light yellow
solid; Yield: 80%; mp: 58–60 °C; 1H-NMR (CDCl3) δ 8.06 (s, 1H, Ph-2-H), 8.04 (s, 1H, Ph-6-H), 7.70
(s, 1H, 5’-H), 7.25 (d, J = 3.6 Hz, 1H, 3’-H), 7.01 (s, 1H, Ph-3-H), 6.99 (s, 1H, Ph-5-H), 6.61 (d, J = 3.6 Hz,
1H, 4’-H), 3.90 (s, 3H, OCH3); 13C-NMR (CDCl3) δ 55.5, 112.1, 113.7, 114.1, 119.7, 129.8, 131.7, 132.2,
146.6, 152.7, 163.3, 181.2; ESI-MS (%): m/z = 203 (100) [M+H]+ 225 (100) [M+Na].
(5-Bromofuran-2-yl)(2,3-dihydroxy-4-methoxyphenyl)methanone (7a). Mol. formula (MW): C12H9BrO5
(313 g/mol); light yellow solid; Yield: 70%; mp: 128–130 °C; 1H-NMR (DMSO-d6) δ 11.01 (br s, 1H,
OH), 8.83 (br s, 1H, OH), 7.43 (dd, J = 8.8 Hz, J =2.4 Hz, 1H, Ph-6-H), 7.38 (d, J = 3.6 Hz, 1H, 3’-H),
6.93 (d, J = 3.6 Hz, 1H, 4’-H), 6.71 (d, J = 8.8 Hz, 1H, Ph-5-H), 3.88 (s, 3H, OCH3); 13C-NMR
(DMSO-d6) δ 56.4, 104.2, 115.4, 122.4, 122.4, 123.3, 129.2, 134.5, 150.1, 153.3, 153.6, 182.0;
ESI-MS (%): m/z = 313 (100) 315 (99.1) [M+H]+ 335 (100) 337 (99.1%) [M+Na]; HRMS (ESI):
Calcd. for [M + H]+:312.9706; Found: 312.9708.
(5-Bromo-2-methoxyphenyl)(5-bromofuran-2-yl)methanone (7b). Mol. formula (MW): C12H8Br2O3
(360 g/mol); light yellow solid; Yield: 76%; mp: 98–100 °C; 1H-NMR (CDCl3) δ 7.59 (dd, 1H, J = 8.8 Hz,
J = 2.4 Hz, Ph-4-H ), 7.53 (d, J = 2.4 Hz, 1H, Ph-6-H), 7.01 (d, J = 3.6 Hz, 1H, 3’-H ), 6.91 (d, J = 8.8 Hz,
13
1H, Ph-3-H ), 6.53 (d, J =3.6 Hz, 1H, 4’-H ), 3.81 (s, 3H, OCH3 ); C-NMR (CDCl3) δ 56.1, 112.6,
113.6, 114.5, 122.5, 128.9, 129.9, 132.0, 135.1, 154.1, 156.6, 179.8; ESI-MS (%): m/z = 359 (51)
361(100) 363 (50) [M+H]+ 381 (51) 383 (100) 385 (50) [M+Na].
(5-Bromofuran-2-yl)(3-hydroxy-4-methoxyphenyl)methanone (7c). Mol. formula (MW): C12H9BrO4
(297 g/mol); light yellow solid; Yield: 72%; mp: 128–130 °C; 1H-NMR (CDCl3) δ 7.67 (s, 1H, Ph-2-H),
7.62 (d, J = 8.4 Hz, 1H, Ph-6-H), 7.32 (d, J = 3.6 Hz, 1H, 3’-H), 7.12 (d, J = 8.4 Hz, 1H, Ph-5-H), 6.50
(d, J = 3.6 Hz, 1H, 4’-H) 3.90 (s, 3H, OCH3); 13C-NMR (CDCl3) δ 56.2, 111.1, 113.8, 118.0, 119.6, 122.1,
123.4, 127.9, 148.6, 152.6, 155.1, 181.0; ESI-MS (%): m/z = 295 (100) 297 (98.9) [M−H]−; HRMS (ESI):
Calcd. for [M+H]+:296.9757; Found: 296.9768.
(4,5-Dibromofuran-2-yl)(3-hydroxy-4-methoxyphenyl)methanone (13). Mol. formula (MW): C12H8Br2O4
(376 g/mol); light yellow solid; Yield: 60%; mp: 107–109 °C; 1H-NMR (CDCl3) δ 7.66 (d, J = 8.4 Hz,
1H, Ph-5-H), 7.54 (s, 1H, 3’-H), 7.23 (s, 1H, Ph-2-H), 7.02 (d, J = 8.4 Hz, 1H, Ph-6-H), 3.98 (s, 3H,

Molecules 2011, 16
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OCH3); 13C-NMR (CDCl3) δ 56.2, 104.3, 111.5, 114.1, 123.2, 124.9, 128.4, 129.0, 146.8, 150.9, 153.6,
180.0; ESI-MS (%): m/z = 373 (51) 375 (100) 377 (50) [M−H]−; HRMS (ESI): Calcd. for [M+H]+:
374.8865; Found: 374.8867.
3.2.4. General procedure for the synthesis of compounds 17a and 17b
A solution of 2,3-dimethoxybenzoic acid (2.0 g) and a catalytic amount of DMF in thionyl chloride
(5 mL) was stirred at 80–90 °C for 3 h. After concentration under reduced pressure, the acid chloride
16 was dissolved in dried CH2Cl2 and reacted with furan (3 mL) catalyzed by AlCl3. The reaction
mixture was stirred at 0 °C for 2 h and then warmed to room temperature and stirred for additional 12 h.
After the reaction was completed, the reaction was quenched by carefully pouring the mixture into iced
water (100 mL) and the resultant compound was collected by filtration. Then, the filtrate was extracted
with CH2Cl2 (3 × 20 mL), and dried with anhydrous Na2SO4. The solvent was removed under reduced
pressure to yield a brown oil that was purified by silica gel column chromatography (petroleum
ether/EtOAc 80:20, v/v) to give (2,3-dimethoxyphenyl)(furan-2-yl)methanone (17a) as light yellow oil
(1.78 g, 70% yield). Molecular formula (MW): C13H12O4 (232 g/mol); 1H-NMR (CDCl3) δ 7.67 (d, 1H,
J = 1.0 Hz, 5’-H), 7.15 (dd, 1H, J = 8.0 Hz, J = 7.6 Hz, Ph-5-H), 7.08 (dd, 1H, J = 8.4 Hz, J =1.6 Hz,
Ph-4-H), 7.06 (d, J = 3.6 Hz, 1H, 3’-H), 7.02 (dd, 1H, J = 7.6 Hz, J = 1.6 Hz, Ph-6-H), 6.55 (dd, J = 3.6 Hz,
J = 2.0 Hz, 1H, 4’-H), 3.92 (s, 3H, OCH3), 3.83 (s, 3H, OCH3); 13C-NMR (CDCl3) δ 56.0, 62.1, 112.3,
114.7, 120.5, 121.1, 123.9, 133.4, 147.1, 147.5, 152.7, 152.8, 182.8; ESI-MS (%): m/z = 233 (100)
[M+H]+ 255 (100) ([M+Na].
(2,6-Dimethoxyphenyl)(furan-2-yl)methanone (17b). Mol. formula (MW): C13H12O4 (232 g/mol); light
1
yellow solid; Yield: 85%; mp: 64–66 °C; H-NMR (CDCl3) δ 7.87 (d, 1H, J = 1.0 Hz, 5’-H) 7.42
(dd, 1H, J = 8.0 Hz, J = 8.0 Hz, Ph-4-H), 7.08 (d, 1H, J = 8.0 Hz, J = 1.6 Hz, Ph-3-H), 7.06 (d, J = 3.6 Hz,
1H, 3’-H), 7.02 (dd, 1H, J = 8.0 Hz, J = 1.2 Hz, Ph-5-H), 6.55 (dd, J = 3.6 Hz, J = 1.0 Hz, 1H, 4’-H), 3.91
13
(s, 3H, OCH3), 3.83 (s, 3H, OCH3); C-NMR (CDCl3) δ 56.0, 62.5, 112.3, 114.7, 120.5, 121.1, 123.9,
133.3, 147.1, 147.5, 152.7, 152.8, 182.8; ESI-MS (%): m/z = 233 (100) [M+H]+ 255 (100) [M+Na].
3.2.5. General procedure for the synthesis of compounds 21a–21d
Br2 (2 mL) was slowly added to a solution of 4-methoxybenzoic acid (5.0 g) in CCl4 (20 mL).
The reaction mixture was stirred at 40–45 °C for 24 h. After concentration under reduced pressure,
the residue was re-crystallized from boiling water to give 3-bromo-4-methoxybenzoic acid (19) as
white needles. To chlorinate the methoxybenzoic acid, we used SO2Cl2. A solution of 19 (2.0 g) and
a catalytic amount of DMF in thionyl chloride (5 mL) was stirred at 80–90 °C for 3 h. After
concentration under reduced pressure, the acid chloride 20 was dissolved in dried CH2Cl2 and reacted
with furan (3 mL) catalyzed by AlCl3. The reaction mixture was stirred at 0 °C for 2 h and then
warmed to room temperature and stirred for an additional 12 h. After the reaction was completed, it
was quenched by carefully pouring the mixture into iced water (100 mL) and the resultant compound
was collected by filtration. The filtrate was then extracted with CH2Cl2 (3 × 20 mL) and dried with
anhydrous Na2SO4. The solvent was removed under reduced pressure to yield a brown oil that

Molecules 2011, 16
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was purified by silica gel column chromatography (petroleum ether/EtOAc 80:20, v/v) to give
compound 21a as a light yellow solid (1.85 g, 76% yield).
(3-Bromo-4-methoxyphenyl)(furan-2-yl)methanone (21a). Mol. formula (MW): C12H9BrO3 (281 g/mol);
mp: 112–114 °C; 1H-NMR (CDCl3) δ 8.30 (d, 1H, J = 2.0 Hz, 5’-H), 8.06 (dd, 1H, J = 8.0 Hz, J = 2.0 Hz,
Ph-6-H), 7.93 (s, 1H, Ph-2-H), 7.30 (d, 1H, J = 3.6 Hz, 3’-H), 7.01 (d, 1H, J = 8.0 Hz, Ph-5-H), 6.63
13
(dd, J =3.6 Hz, J = 2.0 Hz, 1H, 4’-H), 4.00 (s, 3H, OCH3); C-NMR (CDCl3) δ 56.5, 111.1, 112.3,
113.7, 120.1, 130.7, 131.7, 134.9, 146.9, 152.3, 159.4, 179.7; ESI-MS (%): m/z = 281(100) 283 (98.7)
[M+H]+ 303 (100) 305 (98.7) [M+Na].
(2,6-Dibromo-3,4,5-trimethoxyphenyl)(furan-2-yl)methanone (21b). Mol. formula (MW): C14H12Br2O5
(420 g/mol); light yellow solid; Yield: 85%; mp: 96–98 °C; 1H-NMR (CDCl3) δ 7.71 (d, J = 1.0 Hz, 1H,
5’-H), 7.13 (d, J = 3.6 Hz, 1H, 3’-H), 6.61 (dd, J = 3.6 Hz, J = 1.6 Hz, 1H, 4’-H), 4.01 (s, 9H, OCH3);
13C-NMR (CDCl3) δ 61.2, 61.4, 61.4, 110.1, 112.9, 121.2, 136.0, 148.3, 148.6, 151.0, 151.1, 180.5;
ESI-MS (%): m/z = 419 (51) 421 (100) 423 (50) [M+H]+ 441 (51) 443 (100) 445 (50) [M+Na] 457 (51)
459 (100) 461 (50) [M+K].
(2-Chloro-3,4,5-trimethoxyphenyl)(furan-2-yl)methanone (21c). Mol. formula (MW): C14H13ClO5
1
(297 g/mol); light yellow solid; Yield: 82%; mp: 80–82 °C; H-NMR (CDCl3) δ 7.74 (s, 1H, 5’-H),
7.12 (d, J = 3.6 Hz, 1H, 3’-H), 6.80 (s, 1H, Ph-6-H), 6.60 (dd, J = 3.6 Hz, J = 2.0 Hz, 1H, 4’-H), 3.97
13
(s, 9H, OCH3); C-NMR (CDCl3) δ 56.3, 61.3, 61.3, 107.0, 107.8, 112.7, 121.4, 132.9, 145.2, 147.9,
150.3, 152.1, 153.0, 181.5; ESI-MS (%): m/z = 297 (100) 299 (34) [M+H]+ 319 (100) 321 (34) [M+Na]
335 (100) 337 (34) [M+K]; HRMS (ESI): Calcd. for [M+Na]: 319.0344; Found: 319.0343.
(4,5-Dibromo-2-hydroxy-3-methoxyphenyl)(furan-2-yl)methanone (21d). Mol. formula (MW):
C12H8Br2O4 (376 g/mol); light yellow solid; Yield: 80%; mp: 102–104 °C; 1H-NMR (DMSO-d6) δ 9.86
(br s, 1H, OH), 8.07 (d, 1H, J = 1.2 Hz, 5’-H), 7.44 (s, 1H, Ph-6-H), 7.20 (d, J = 3.6 Hz, 1H, 3’-H),
6.74 (dd, J = 3.6 Hz, J = 2.0 Hz, 1H, 4’-H), 3.89 (s, 3H, OCH3); 13C-NMR (DMSO-d6) δ 57.0, 111.4,
113.6, 113.6, 117.3, 121.6, 129.6, 144.8, 148.6, 149.5, 151.6, 180.6; ESI-MS (%): m/z = 375 (51) 377
(100) 379 (50) [M+H]+ 397 (51) 399 (100) 401 (50) [M+Na]; HRMS (ESI): Calcd. for [M+Na]:
396.8682; Found: 396.8683.
3.2.6. General procedure for the synthesis of compounds 4a–4d, 8a–8c, 14, 18a–18b and 22a–22d
10% (equiv.) BBr3 (2 mL) was added to a solution of compound 3a (0.5 g) in CH2Cl2 (20 mL). The
reaction mixture was stirred at −78 °C for 30 min and then warmed to room temperature and stirred for
additional 3.5 h. After the reaction was completed, it was quenched by carefully pouring the mixture
into iced water (100 mL), extraction of the aqueous layer three times with EtOAc, washing with 5%
NaHSO3 (40 mL) and water (100 mL), and drying with anhydrous Na2SO4. The solvent was removed
under reduced pressure to yield a light red solid compound 4a (0.403 g, 91.7% yield).
Synthesis of (3,4-Dihydroxyphenyl)(furan-2-yl)methanone (4a). Mol. formula (MW): C11H8O4
(204 g/mol); mp: 132–134 °C; 1H-NMR (CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H, Ph-5-H), 7.53 (s, 1H, 5’-H),
7.40 (s, 1H, Ph-2-H), 7.10 (d, J = 3.2 Hz, 1H, 3’-H), 6.81 (d, J = 8.0 Hz, 1H, Ph-6-H), 6.46 (s, 1H, 4’-H);

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13C-NMR (CDCl3) δ 111.8, 114.9, 116.5, 119.7, 124.0, 129.8, 146.6, 148.9, 152.3, 153.0, 180.1;
ESI-MS (%): m/z = 205 (100) [M+H]+; HRMS (ESI): Calcd. for [M+Na]: 227.0315; Found: 227.0310.
Furan-2-yl(2,3,4-trihydroxyphenyl)methanone (4b). Mol. formula (MW): C11H8O5 (220 g/mol); light
1
red solid; Yield: 95%; mp: 168–170 °C; H-NMR (DMSO-d6) δ 7.73 (d, J = 1.6 Hz, 1H, 5’-H), 7.64
(d, J = 9.2 Hz, 1H, Ph-6-H), 7.44 (d, J = 3.6 Hz, 1H, 3’-H), 6.78 (dd, J = 3.6 Hz, J = 1.6 Hz, 1H, 4’-H),
13
6.53 (d, J = 9.2 Hz, 1H, Ph-5-H); C-NMR (DMSO-d6) δ 108.6, 113.1, 113.2, 120.9, 123.7, 148.5,
148.7, 151.8, 152.9, 153.3, 183.5; ESI-MS (%): m/z = 219 (100) [M−H]−; HRMS (ESI): Calcd. for
[M+Na]: 243.0264; Found: 243.0261.
(5-Bromo-2-hydroxyphenyl)(furan-2-yl)methanone (4c). Mol. formula (MW): C11H7BrO3 (267 g/mol);
1
light red solid; Yield: 94%; mp: 88–90 °C; H-NMR (DMSO-d6) δ 10.50 (br s, 1H, OH), 8.08 (d,
J = 1.0 Hz, 1H, 5’-H), 7.58 (d, J = 2.4 Hz, 1H, Ph-6-H), 7.56 (d, J = 8.4 Hz, 1H, Ph-4-H), 7.26 (d,
J = 3.6 Hz, 1H, 3’-H), 6.95 (d, J = 8.4 Hz, 1H, Ph-3-H), 6.76 (dd, J = 3.6 Hz, J = 2.0 Hz, 1H, 4’-H);
13C-NMR (CDCl3) δ 110.3, 113.4, 119.4, 121.7, 127.5, 131.8, 135.5, 149.1, 152.2, 156.0, 181.7;
ESI-MS (%): m/z = 265 (100) 267 (98.6) [M−H]−; HRMS (ESI): Calcd. for [M+Na]: 288.9471;
Found: 288.9473.
Furan-2-yl(4-hydroxyphenyl)methanone (4d). Mol. formula (MW): C11H8O3 (188 g/mol); light red
1
solid; Yield: 95%; mp: 168–170 °C; H-NMR (DMSO-d6) δ 10.44 (br s, 1H, OH), 8.07 (d, J = 1 Hz,
1H, 5’-H), 7.89 (s, 1H, Ph-2-H), 7.87 (s, 1H, Ph-6-H), 7.33 (d, J = 3.6 Hz, 1H, 3’-H), 6.93 (s, 1H,
13
Ph-5-H), 6.91 (s, 1H, Ph-3-H), 6.76 (dd, J = 3.6 Hz, J = 2.4 Hz, 1H, 4’-H); C-NMR (DMSO-d6)
δ 112.9, 115.8, 115.8, 120.3, 128.3, 132.1, 132.1, 148.1, 152.2, 162.4, 180.4; ESI-MS (%): m/z = 187
(100) [M−H]−; HRMS (ESI): Calcd. for [M+Na]: 211.0366; Found: 211.0368.
(5-Bromofuran-2-yl)(2,3,4-trihydroxyphenyl)methanone (8a). Mol. formula (MW): C11H7BrO5
(299 g/mol); light red solid; Yield: 95%; mp: 132–134 °C; 1H-NMR (DMSO-d6) δ 7.48 (d, J = 8.8 Hz,
1H, Ph-6-H), 7.43 (d, J = 3.6 Hz, 1H, 3’-H), 6.94 (d, J = 3.6 Hz, 1H, 4’-H), 6.50 (d, J = 8.8 Hz, 1H,
Ph-5-H); 13C-NMR (DMSO-d6) δ 182.0, 158.7, 153.3, 153.1, 147.3, 127.2, 123.3, 120.5, 114.8, 112.6,
108.7; ESI-MS (%): m/z = 297 (100) 299 (99) [M−H]−; HRMS (ESI): Calcd. for [M+Na]: 320.9369;
Found: 320.9374.
(5-Bromo-2-hydroxyphenyl)(5-bromofuran-2-yl)methanone (8b). Mol. formula (MW): C11H6Br2O3
(346 g/mol); light red solid; Yield: 95%; mp: 82–84 °C; 1H-NMR (DMSO-d6) δ 10.46 (br s, 1H, OH),
7.57 (d, J = 8.0 Hz, 1H, Ph-4-H), 7.54 (s, J = 8.0 Hz, 1H, Ph-6-H), 7.25 (d, J = 3.6 Hz, 1H, 3’-H), 6.95
13
(d, J = 8.0 Hz, 1H, Ph-3-H), 6.90 (d, J = 3.6 Hz, 1H, 4’-H); C-NMR (DMSO-d6) δ 110.3, 115.6,
119.4, 123.8, 127.1, 130.0, 131.9, 135.6, 153.4, 155.7, 180.3; ESI-MS (%): m/z = 343 (51) 345 (100)
347 (50) [M−H]−; HRMS (ESI): Calcd. for [M+H]+: 344.8736; Found: 344.8742.
(5-Bromofuran-2-yl)(3,4-dihydroxyphenyl)methanone (8c). Mol. formula (MW): C11H7BrO4 (283 g/mol);
1
light red solid; Yield: 95%; mp: 138–140 °C; H-NMR (CDCl3) δ 7.54 (d, J = 2.0 Hz, 1H, Ph-2-H),
7.48 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H, Ph-6-H), 7.12 (d, J = 3.6 Hz, 1H, 3’-H), 6.94 (d, J = 8.4 Hz, 1H,
Ph-5-H), 6.49 (d, J = 3.6 Hz, 1H, 4’-H); 13C-NMR (CDCl3) δ 118.8, 120.0, 121.3, 126.2, 127.6, 132.7,

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133.0, 150.0, 155.4, 158.9, 184.4; ESI-MS (%): m/z = 283 (100) 285 (98.8) [M+H]+; HRMS (ESI):
Calcd. for [M+Na]: 304.9420; Found: 304.9420.
(4,5-Dibromofuran-2-yl)(3,4-dihydroxyphenyl)methanone (14). Mol. formula (MW): C11H6Br2O4
1
(362 g/mol); light red solid; Yield: 91%; mp: 184–186 °C; H-NMR (CDCl3) δ 7.53 (s, 1H, Ph-2-H),
7.48 (d, J = 8.0 Hz, 1H, Ph-6-H), 7.18 (s, 1H, 3’-H), 6.95 (d, J = 8.0 Hz, 1H, Ph-5-H); 13C-NMR (CDCl3)
δ 104.0, 115.2, 116.5, 121.3, 122.8, 127.7, 128.6, 145.1, 150.9, 158.4, 179.0; ESI-MS (%): m/z = 359 (51)
361 (100) 363 (50) [M−H]−; HRMS (ESI): Calcd. for [M+Na]: 382.8531; Found: 382.8533.
(2,3-Dihydroxyphenyl)(furan-2-yl)methanone (18a). Mol. formula (MW): C11H8O4 (204 g/mol); light
red solid; Yield: 95%; mp: 64–66 °C; 1H-NMR (DMSO-d6) δ 8.06 (d, 1H, J = 1.0 Hz, 5’-H), 7.30 (d,
J = 3.6 Hz, 1H, 3’-H), 7.10 (dd, 1H, J = 8.0 Hz, J = 1.6 Hz, Ph-6-H), 7.06 (dd, 1H, J = 8.4 Hz, J = 2.0 Hz,
Ph-4-H), 6.91 (dd, 1H, J = 8.4 Hz, J = 8.0 Hz, Ph-5-H), 6.72 (dd, J = 3.6 Hz, J = 2.0 Hz, 1H, 4’-H);
13C-NMR (DMSO-d6) δ 109.4, 113.1, 113.6, 120.1, 121.5, 130.0, 144.3, 146.8, 149.4, 151.8, 180.9;
ESI-MS (%): m/z = 203 (100) [M−H]−; HRMS (ESI): Calcd. for [M+Na]: 227.0315; Found: 227.0313.
(2,6-Dihydroxyphenyl)(furan-2-yl)methanone (18b). Mol. formula (MW): C11H8O4 (204 g/mol); light
red solid; Yield: 95%; mp: 66–68 °C; 1H-NMR (DMSO-d6) δ 8.08 (d, 1H, J = 1.0 Hz, 5’-H), 7.30 (d,
J = 3.6 Hz, 1H, 3’-H), 7.17 (dd, 1H, J = 8.0 Hz, J = 1.6 Hz, Ph-3-H), 7.04 (dd, 1H, J = 8.4 Hz, J = 2.0 Hz,
Ph-5-H), 6.81 (dd, 1H, J = 8.4 Hz, J = 8.0 Hz, Ph-4-H), 6.76 (dd, J = 3.6 Hz, J = 2.0 Hz, 1H, 4’-H);
13C-NMR (DMSO-d6) δ 113.2, 119.4, 119.6, 120.5, 121.6, 123.9, 146.5, 147.4, 148.9, 152.2, 184.0;
ESI-MS (%): m/z = 203 (100) [M−H]−; HRMS (ESI): Calcd. for [M+Na]: 227.0315; Found: 227.0310.
(3-Bromo-4-hydroxyphenyl)(furan-2-yl)methanone (22a). Mol. formula (MW): C11H7BrO3 (267 g/mol);
1
light red solid; Yield: 90%; mp: 100–102 °C; H-NMR (DMSO-d6) δ 11.32 (br s, 1H, OH), 8.10 (d,
1H, J = 2.8 Hz, Ph-2-H), 8.09 (d, 1H, J = 2.0 Hz, 5’-H), 7.90 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz, Ph-6-H),
7.40 (d, J = 3.6 Hz, 1H, 3’-H), 7.12 (d, 1H, J = 8.8 Hz, Ph-5-H), 6.79 (dd, J = 3.6 Hz, J = 2.0 Hz, 1H,
13
4’-H); C-NMR (DMSO-d6) δ 110.0, 113.1, 116.5, 120.9, 129.6, 131.1, 134.7, 148.6, 151.9, 158.9,
179.2; ESI-MS (%): m/z = 265 (100) 267 (98.6) [M−H]−; HRMS(ESI): Calcd. for [M+Na]: 288.9472;
Found: 288.9470.
(2,6-Dibromo-3,4,5-trihydroxyphenyl)(furan-2-yl)methanone (22b). Mol. formula (MW): C11H6Br2O5
(378 g/mol); light red solid; Yield: 93%; mp: 148–150 °C; 1H-NMR (DMSO-d6) δ 9.82 (br s, 2H, OH),
9.58 (br s, 1H, OH), 8.07 (d, J = 1.6 Hz, 1H, 5’-H), 7.13 (d, J = 3.6 Hz, 1H, 3’-H), 6.74 (dd, J = 3.6 Hz,
13
J = 1.6 Hz, 1H, 4’-H); C-NMR (DMSO-d6) δ 99.1, 113.6, 113.7, 121.9, 130.9, 136.9, 143.8, 143.8,
149.7, 151.3, 181.4; ESI-MS (%): m/z = 375 (51) 377 (100) 379 (50) [M−H]−; HRMS (ESI): Calcd. for
[M+H]+: 378.8635; Found: 378.8637.
(2-Chloro-3,4,5-trihydroxyphenyl)(furan-2-yl)methanone (22c). Mol. formula (MW): C11H7ClO5
(255 g/mol); light red solid; Yield: 94%; mp: 150–152 °C; 1H-NMR (DMSO-d6) δ 9.65 (br s, 3H, OH),
9.42 (br s, 3H, OH), 8.07 (s, 1H, 5’-H), 7.14 (d, J = 3.6 Hz, 1H, 3’-H), 6.74 (dd, J = 3.6 Hz, J = 1.6 Hz,
13
1H, 4’-H), 6.25 (s, 1H, Ph-6-H); C-NMR (DMSO-d6) δ 108.1, 113.3, 121.8, 127.8, 137.4, 143.5,
144.5, 146.1, 149.1, 152.2, 181.4; ESI-MS (%): m/z = 253 (100) 255 (33.7) [M−H]−; HRMS (ESI):

Molecules 2011, 16
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Calcd. for [M+Na]: 276.9874; Found: 276.9876.
(4,5-Dibromo-2,3-dihydroxyphenyl)(furan-2-yl)methanone (22d). Mol. formula (MW): C11H6Br2O4
(362 g/mol); light red solid; Yield: 95%; mp: 138–140 °C; 1H-NMR (DMSO-d6) δ 9.66 (br s, 1H, OH),
9.37 (br s, 1H, OH), 8.07 (s, 1H, 5’-H), 7.40 (s, 1H, Ph-6-H), 7.14 (d, J = 3.6 Hz, 1H, 3’-H), 6.74 (dd,
13
J = 3.6 Hz, J = 2.0 Hz, 1H, 4’-H); C-NMR (DMSO-d6) δ 108.1, 109.3, 113.3, 120.0, 121.8, 127.8,
143.5, 144.5, 149.1, 152.2, 181.4; ESI-MS (%): m/z = 359 (51) 361 (100) 363 (50) [M−H]−; HRMS (ESI):
Calcd. for [M+Na]: 382.8526; Found: 382.8528.
4. Biological Evaluation
4.1. PTK Inhibitory Activity
The activities of PTKs were tested using ELISA. The tyrosine kinase was extracted from brain
tissue of rat, and microtiter plates were coated using poly-Glu-Tyr (PGT) as substrates. If the tyrosine
residues of PGT were phosphorylated by PTKs, they bound to phospho-specific monoclonal antibody
that was labeled specifically with HRP. The absorbance was measured to reflect the activity of PTK.
4.2. Tyrosine Kinase Assay
The phosphorylation assays were performed at 37 °C in a final volume of 40 µL tyrosine kinase.
The concentrations of PTKs used to construct calibration curves were as follows: 600, 500, 400, 300,
200 and 100 × 10−7 U/mL for PTK. A concentration of 500 × 10−7/μL was used for each inhibitor.
Phosphorylation reactions were initiated with the addition of 40 mM ATP (10 μL) into each vessel, and
the plate was incubated at 37 °C for 30 min. After completion of reaction, liquid was decanted and the
vessels were washed four times with Tween-PBS. One hundred microliters of blocking solution was
added to the vessels and incubated at 37 °C for 30 min. After washing the plate with Tween-PBS,
anti-phosphotyrosine (50 μL) was added to the vessels and incubated at 37 °C for 30 min. The reaction
liquid was decanted and the remaining solution was removed by rinsing four times with Tween-PBS.
One hundred μL of HRP coloring agent was added and incubated at 37 °C for 15 min. The reaction
was terminated by addition of 1 N sulfuric acid (100 μL /well). The absorbance of the reaction was
measured at 450 nm on a microplate reader.
5. Conclusions
In summary, a number of new furan-2-yl(phenyl) methanone derivatives were synthesized and
evaluated for their in vitro PTK inhibitory activity. Several new derivatives exhibited promising
activity, which in some cases was identical to, or even stronger than, that of genistein, a positive
reference compound.
The results justify further studies on these types of derivatives with significant pharmacological
(PTK inhibitory) value.

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Acknowledgements
This work was financially supported by the State “Innovative Drugs Development” Key and
Technology Major Projects of China (No. 2009ZX09302-003), by the State Key Laboratory of Natural
and Biomimetic Drugs, Peking University (No. 20080210), by the Shanxi Foundation for Returning
Overseas Scientists, by the Program for the Top Science and Technology Innovation Teams of Higher
Learning Institutions of Shanxi, by the Program for the Top Young and Middle-aged Innovative Talents
of Higher Learning Institutions of Shanxi Province and by Shanxi Province Foundation Science for
Youths (No. 2009021041-1).
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Sample Availability: Samples are available from the authors.
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