Novel benzofuran-chromone and -coumarin derivatives: Synthesis and biological activity in K562 human leukemia cells

Article abstract of DOI:10.1039/c3md00241a

Not widely distributed in nature, aurones, (Z)-2-benzylidene-benzofuran- 3(2H)-ones, are one of the less common and lesser-known representatives of a flavonoid subclass. Nevertheless, they exhibit a strong and broad variety of biological activities. We have combined the benzofuranone part of a classical aurone with either a chromone or a coumarin scaffold which proved to feature interesting biological activities including antimicrobial, antiviral, anticancer, anti-inflammatory and antioxidant properties. Herein we present a series of 26 novel benzofuran derivatives with the first biological results in K562 human leukemia cells showing that compounds 21b, 29b and 29c are able to induce around 24% apoptosis.

Full text of DOI:10.1039/c3md00241a

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Medicinal Chemistry Communications
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www.rsc.org/xxxxxx
ꢀ
ARTICLE TYPE
Novel benzofuran-chromone and –coumarin derivatives: synthesis and
biological activity in K562 human leukemia cells
a
a, b
c
a
d
b
Clemens Zwergel , Sergio Valente , Angela Salvato , Zhanjie Xu , Oualid Talhi , Antonello Mai , Artur
d
c,e
a*
Silva , Lucia Altucci and Gilbert Kirsch
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Not widely distributed in nature, aurones, (Z)-2-benzylidene-benzofuran-3(2H)-ones, are one of the less common and lesser-known
representatives of a flavonoid subclass. Nevertheless they exhibit a strong and broad variety of biological activities.
We have combined the benzofuranone part of a classical aurone with either a chromone or a coumarine scaffold which proved to feature
interesting biological activities including antimicrobial, antiviral, anticancer, anti-inflammatory and antioxidant properties. Herein we
present a series of 26 novel benzofuran derivatives with the first biological results in K562 human leukemia cells showing that compound
1
0
2
1b, 29b and 29c are able to induce around 24% apoptosis.
that are often involved in common diseases, such as autoimmune
1
2
Introduction
diseases, diabetes, arthrosclerosis and cancer .
O
OCH3
O
1
2
2
5
0
5
Flavonoids represent a large class of natural products in the plant
1
kingdom, exhibiting multiple biological activities . Not widely
OCH3
OCH3
distributed in nature, aurones, (Z)-2-benzylidene-benzofuran-
O
O
HO
H CO
3
3
(2H)-ones, are one of the less common and lesser-known
2
3
2
representatives of a flavonoid subclass . This is probably the
reason why this class of compounds has received little attention
in comparison to the structurally similar and widely investigated
Cl
O
O
O
H3CO
H3CO
H3CO
H3CO
3
,
4
OH
flavones and isoflavones
.
Nevertheless they exhibit
a
O
OH
OCH3
pronounced and broad variety of biological activities recently
OCH3
OCH3
OCH3
5
reviewed by us . Aurones play an important role in the
4
5
45
pigmentation of some flowers and fruits and contribute especially
Fig.ꢀ2:ꢀAuronesꢀ(2-4)ꢀandꢀtheꢀisomericꢀflavoneꢀ(5)ꢀwithꢀpostulatedꢀ
6
to the bright yellow colour of flowers . Aureusidin, a common
anticancerꢀpropertiesꢀ3,ꢀ17,ꢀ18
ꢀ
aurone (1), is an inhibitor of iodothyronine- deiodinase, an
1
8 17
In recent literature
several aurones such as 2 and 3 have been
enzyme involved in hormone synthesis and regulation of the
3
7
described with anti-cancer properties. Lawrence et al. studied the
aurones isolated from Uvaria hamiltonii for the total synthesis as
well as for their anticancer properties in K562 cells. Among them
compound 4 was the most active one with a growth inhibition
IC50 value of 50 µM.
thyroid .
50
OCH3
O
H3CO
O
H3CO
OH
1
By reaction with potassium cyanide the aurone 4 converted into
OH
3
0
ꢀ
55 the flavone 5 providing a more active compound with an IC50
value of 40 µM.
Fig.ꢀ1:ꢀAureusidin,ꢀanꢀexampleꢀofꢀaꢀcommonꢀaurone.ꢀ
Flavones as well as the aurones are belonging to the class of
flavonoids and are known to possess anticancer activity, besides
other biological activities like anti-oxidative or anti-inflammatory
Some other aurones have been described as antiviral (influenza,
8
,
9
10
hepatitis C) , antiparasitic (malaria) as well as antibacterial
1
1, 12
and antifungal agents
.
1
9, 20
1
3
60 effects
. They might also prevent cardiovascular diseases
3
5
They are also known as inhibitors of tyrosinase and as
2
1
1
4
when they form part of a daily diet . Besides other activities
antioxidants .
2
2
various chromones exhibit anticancer properties . Their
constitutional isomers, the coumarins, show similar biological
Synthetic aurones bind to the nucleotide-binding domain of P-
1
5
glycoprotein , inhibit cyclin-dependent kinases in connection
2
3
1
6
activities, which have been recently reviewed .
with antiproliferative properties , and can act as anticancer
1
7
65 Therefore our idea was to combine the benzofuran structure from
aurones with the chromone motif or the isomeric coumarine
motif, to obtain potential novel anticancer agents.
4
0
agents .
In another study Bandgar et al. showed that certain aurones are
able to inhibit the production of TNF-α and IL-6, two cytokines
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Medicinal Chemistry Communications
Page 2 of 9
ꢀ
In this study we describe the preparation of 26 chromone- and
coumarine-based benzofuran derivatives and their biological
effects in K562 human leukemia cells when tested at 50 µM for
ꢀ
18a:R
8b:R
1
= H
= CH
O
O
O
R
5
1
1
3
View Article Online
6
DOI: 10.1039/C3MD00241A
O
O
O
R
1
O
4
8 h. In particular, the effect of such new derivatives on the K562
R
18a,b
a
7
O
5
8
O
5
cell cycle as well as induction of apoptosis (pre-G1 peak) have
been determined.
6
H
O
8
2
0-28(a-b)
O
R'
7
O
R
O
5
8
1
9
9
-17
a
6
7
O
O
2
0c,22c,24c,25c,27c
Results and Discussion
2
2
2
2
0a: R=H; R'=H
0b: R=H; R'=Me
0c: R=H
24a: R=6-Cl; R'=H
24b: R=6-Cl; R'=Me
24c: R=6-Cl
25a: R=6-F; R'=H
25b: R=6-F; R'=Me
1
0
Chemistry
1a: R=6-Me; R'=H
2
2
2
7c: R=5-OMe
8a: R=7-OMe, 8-OMe; R'=H
8b: R=7-OMe, 8-OMe; R'=Me
Although the standard method to prepare coumarin-4-aldehyde 8
21b: R=6-Me; R'=Me
2
4
is reported using 4-methylcoumarine and SeO
2
, we applied the
2
2a: R=6-Me, 7-Me; R'=H
25c: R=7-F
2
5
2
2
2b: R=6-Me, 7-Me; R'=Me 26a: R=7-OMe; R'=H
2c: R=6-Me, 7-Me
Kröhnke oxidation to the 4-chloromethylcoumarine 6 achieving
the corresponding aldehyde 8 with an improved yield (90%). The
reaction is carried out with p-nitrosodimethylaniline as oxidising
agent at room temperature in basic conditions followed by an
acidic hydrolysis of the intermediate 6 to yield the desired
aldehyde 8 (Scheme 1).
26b: R=7-OMe; R'=Me
27a: R=5-OMe; R'=H
27b: R=5-OMe; R'=Me
23a: R=7-Cl; R'=H
23b: R=7-Cl; R'=Me
1
5
O
R
1
O
1
8a:R
1
= H
O
O
18b:R1= CH3
29a:R = H
1
O
H
The compounds 9-17, 18b, 19 and 30 have been prepared by
R
1
O
1 3
29b:R = CH
1
8a,b
a
2
,3, 17, 18, 26-36
2
0
known literature methods.
H3CO
O
O
29a-b
H
3
CO
O
O
O
8
O
N
N
1
9
a
O
O
O
H
CH2Cl
O
O
H
3
CO
O
a
b
29c
ꢀ
2 3
Schemeꢀ 2:ꢀ Syntheticꢀ routeꢀ a acidꢀ Al O ,ꢀ anhydrousꢀ DCM,ꢀ roomꢀ
H3CO
O
O
H3CO
O
H3CO
O
O
6
7
8
temperature,ꢀ2-6ꢀdꢀ
Schemeꢀ 1:ꢀ Synthesisꢀ ofꢀ coumarine-4-aldehydeꢀ aꢀ p-
50
nitrosodimethylaniline,ꢀ sodiumꢀ ethanolate,ꢀ ethanol,ꢀ roomꢀ
2
3
3
4
4
5
0
5
0
5
2
temperature,ꢀ 20ꢀ mins,ꢀ 95%;ꢀ bꢀ hydrolysisꢀ 5Nꢀ H SO4ꢀ roomꢀ
Biology
temperature,ꢀ30ꢀmins,ꢀ95%ꢀ
Effect of compounds 20-29 on cell cycle distribution and
apoptosis induction in human K562 cells.
The described compounds 20-29 were tested at 50 µM for 48 h in
A common way to prepare aurones is based on the method of an
aldol–like condensation of benzofuran-3(2H)-ones with
benzaldehydes. These aldol reactions are usually carried out with
catalytic amounts of acid (hydrochloric acid) or base (pyrrolidine)
5
6
6
5
0
5
K562 human leukemia cells to determine their effects on cell
cycle and apoptosis induction (Fig. 2 A and B). The HDAC
inhibitor SAHA was included as a positive control.
Analysing the results, we could observe that compound 21b and,
to a lesser extent, 22c, 27c and 29b displayed slight cell cycle
arrest in the G1 phase, whereas with some other derivatives (20b,
2
in ethanol or THF under reflux . Firstly we used these conditions
to synthesize the desired compounds in very low yields (about 5-
1
0%). Then we decided to perform the aldolic condensation
3
7
2 3
through the use of acidic Al O (Brockmann I) . The desired
2
1a, 23b, 24b, 25a and 25b) a block in the S phase occurred.
compounds were obtained at room temperature within 2 to 6 days
in acceptable yields. No purification was necessary or in some
cases recrystallization from ethanol was suffcient to obtain the
pure compounds 20-29 (Scheme 2).
Only one among the new described compounds, 29c, was able to
arrest the cell cycle in G2 phase.
Taking in account the pre-G1 peak in Fig. 2B as an index of pro-
apoptotic properties of the compounds, it results that 20a, 20c,
Although an unambiguous assignment of the isomeric structures
of our series of compounds was not carried out, the values are
consistent with those present in the literature for known (Z)-
2
2c, 24c, 26a and 27c exhibit 17 to 22% of apoptosis induction in
this assay, while 21b, 29b and 29c showed the strongest effect
3
8, 39
with around 24%.
aurones
.
1
70
The synthetic yields, melting points, elemental analyses, H and
1
3
C NMR spectra of all compounds are described in the
experimental section.
2
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ꢀ
ARTICLE TYPE
100ꢀ
G1ꢀ
Sꢀ
G2ꢀ
A
80ꢀ
60ꢀ
40ꢀ
20ꢀ
0ꢀ
5
0ꢀ
0ꢀ
0ꢀ
0ꢀ
0ꢀ
B 4
Pre-G1ꢀ
3
2
1
0ꢀ
ꢀ
ꢀꢀꢀꢀꢀꢀꢀFig.ꢀ2ꢀ(A)ꢀCell-cycleꢀphaseꢀdistributionꢀinꢀK562ꢀcellsꢀandꢀ(B)ꢀapoptosisꢀinductionꢀinꢀK562ꢀcellsꢀtreatedꢀwithꢀ20aꢀ-29cꢀꢀatꢀ50ꢀμMꢀforꢀ48ꢀh.ꢀ
Structure-activity relationship analysis highlighted that the
more efficient than 8 and 30. These data suggest that combination
5
0
5
0
5
different substitutions (halogen, methyl and methoxy) on the 30 of an aurone-like template with a chromome or coumarine
chromone (20-28) do not influence the potency of the
compounds. Instead, exchanging the benzofuranone or
methylbenzofuranone moiety with a napthofuranone seems to
exert a more powerful effect toward apoptosis with the exception
of 20a, 21b and 29b.
scaffold can lead to new compounds endowed with interesting
apoptotic effect in K562 leukemia cells.
48 h
72 h
1
1
2
2
The replacement of the chromone moiety (20-28) with the
isomeric coumarin (29) afforded the only one compound able to
block the cell cylce in G2 (29c).
O
O
3
H C
3
0
OMe
Fig.ꢀ3ꢀDose-dependentꢀapoptosisꢀinductionꢀinꢀK562ꢀcellsꢀtreatedꢀwithꢀ
29b,ꢀ8ꢀandꢀ30ꢀforꢀ48ꢀ(A)ꢀandꢀ72ꢀ(B)ꢀh.ꢀ
35
To better ascertain the pro-apoptotic property of these
oxobenzofuran-chromone and –coumarine derivatives, we
selected 29b as lead compound, and we tested it in K562 cells at
doses ranging from 5 to 100 µM, in comparison with 8, the
comarin-4-aldheyde used for the synthesis of 29b, and with the
(Z)-2-(4-methoxybenzylidene)-6-methylbenzofuran-3(2H)-one
Experimental
Chemistry
Melting points were determined with a Stuart SMP3 apparatus
1
(
30), a compound showing a simple, classic aurone structure (Fig.
and are uncorrected. H NMR spectra were recorded on a Bruker
3
3
). After 48 h as well as 72 h of treatment, 29b showed at higher 40 AC 250 MHz spectrometer in CDCl or DMSO. Chemical shifts
doses (50 and 100 µM) the strongest apoptosis induction, it being
are reported in δ (ppm) units relative to the internal standard
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ꢀ
tetramethylsilane (Me
4
Si). Mass spectra were recorded with a 60 MHz, CDCl
3
) d 55.81, 110.10, 108.17, 113.27, 122.17, 127.37,
2
4
MicroTof-Q 98. All reactions were routinely monitored by TLC
Merck DC, Alufolien Kieselgel 60 F254) with spots visualized by
143.75, 156.51, 160.75, 163.35, 191.75
View Article Online
DOI: 10.1039/C3MD00241A
(
UV light. Column chromatography was performed on silica gel
LC 60A (70-200 micron, SigmaAldrich). All solvents were
reagent grade and, when necessary, were purified and dried by
standard methods. Concentration of solutions after reactions and
extractions involved the use of a rotary evaporator operating at
reduced pressure of approx. 20 Torr. Organic solutions were
dried over anhydrous magnesium sulfate. Elemental analysis has
been used to determine purity of the described compounds, that is
Synthesis of the benzofuran-chromone and –coumarin
derivatives:
5
6
7
7
5
0
5
A mixture of the chromone-3 aldehydes or coumarine-4-
aldehydes (5 mmol) and different benzofuranone derivatives (5
mmol) were stirred at room temperature in dichloromethane (5
2 3
mL) with acidic Al O (Beckmann I, 1g) for 2 to 6 days. The
suspension was filtered through celite and washed with
dichloromethane/THF to remove all traces of aluminium oxide.
After distillation of the solvent in vacuo the obtained solid was
recrystallized from ethanol.
1
0
>
95%. The solvents used were purchased from Carlo Erba
(
France) and the reactives from Sigma Aldrich (France) or Acros
Organics (France).
2
0a) (Z)-3-[(6-methyl-3-oxobenzofuran-2(3H)-ylidene)methyl)]-
chromone
mp: 233-234; yellow solid; yield: 36%; H NMR (250 MHz,
CDCl ) d 7.23-7.33 (d, 2H, J= 10.0 Hz, aromatic protons), 7.38
1
5
General procedure for the synthesis of 3-formylchromones (9-
1
1
7):
To a stirred solution of corresponding o-hydroxy-acetophenone
30 mmol) in dimethylformamide (40 mL), phosphorous
oxychloride (60 mmol) was added dropwise at 0°C over 20-30
3
(
(s, 1H =C-CH=C), 7.44–7.54 (m, 2H, aromatic protons), 7.64–
7.77 (m, 2H, aromatic protons), 7.81–7.84 (d, 1H, J= 7.5 Hz,
2
0
minutes. The mixture was stirred on ice for further 30 minutes 80 aromatic proton), 8.29-8.33 (d, 1H, J=10.0 Hz, aromatic proton),
1
3
and then continued at room temperature for 3-5 hrs. The mixture
was treated with ice-cold water (100 mL). The resulting solid was
filtered, washed with water and purified if necessary by
recrystallization from ethanol. † The experimental data of these
starting materials are provided in the supporting information.
3
9.09 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl ) d
102.25, 112.75, 118.13, 118.27, 121.75, 123.62, 123.83, 124.87,
125.84, 126.53, 134.15, 136.92, 147.15, 155.90, 158.77, 165.58,
2
5
175.13, 183.57 HRMS (ESI) [M+H]+ C18
85 291.0652 found: 291.0663.
11 4
H O calculated:
Elemental Analysis: calculated: C: 74.48%; H: 3.47%; O: 22.05%
found: C: 74.48%; H: 3.47%
Synthesis of 7-methoxy-coumarin-4-aldehyde (8)
Synthesis of 7 (E)-N-[4-(dimethylamino)phenyl)-1-(7-methoxy-2-
oxo-2H-chromen-4-yl]methanimine oxide
3
0
2
0b) (Z)-3-[(6-methyl-3-oxobenzofuran-2(3H)-ylidene)methyl]-
chromone
mp: 210-212; yellow solid; yield: 66%; H NMR (250 MHz,
CDCl ) d 2.51 (s, 3H, –CH ), 7.04-7.08 (d, 1H, J= 10.0 Hz,
A mixture of 7-methoxy-4(chloromethyl)coumarine (1 mmol)
and p-nitrosodimethylaniline (3 mmol) in ethanol is added
dropwise to sodium ethanolate (1 mmol) in ethanol at room
temperature. An orange nitrone salt is almost immediately
precipitating. After 20 minutes the solid was filtered and washed
with an excess of ethanol. The product was used without further
purification for the next step.
9
0
1
3
3
aromatic proton), 7.11 (s, 1H, aromatic proton), 7.33 (s, 1H =C-
CH=C), 7.43–7.54 (m, 2H, aromatic protons), 7.68–7.76 (m, 2H,
aromatic protons), 8.29-8.33 (d, 1H, J= 10.0 Hz, aromatic
3
4
4
5
5
5
0
5
0
5
95
13
proton), 9.06 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz,
1
mp: 207-209; orange-red solid; yield: 95%; H NMR (250 MHz,
CDCl
3
) d 22.66, 101.70, 112.91, 118.18, 118.27, 119.39, 123.60,
24.50, 125.17, 125.80, 126.51, 134.12, 147.62, 149.13, 155.89,
58.61, 166.14, 175.17, 183.17 HRMS (ESI) [M+H]+ C19
3 3 3
CDCl ) d 3.06 (s, 6H, 2 –CH ), 3.88 (s, 3H, –OCH ), 6.67-6.70
1
1
(d, 2H, J=7.5 Hz, ), 6.85–6.89 (m, 2H,), 7.53–7.56 (d, 1H, J=7.5
Hz,), 7.66–7.69 (d, 2H, J=15.0 Hz, ), 8.26 (s, 1H, ), 8.46 (s, 1H, ),
13 4
H O
1
1
1
1
00 calculated: 305.0808 found: 305.0811.
1
3
ppm; C NMR (62.5 MHz, CDCl
3
) d 40.28, 55.76, 101.62,
09.73, 110.40, 111.16, 111.35, 122.64, 123.34, 123.46, 138.62,
39.09, 151.96, 155.51, 162.22, 162.29 HRMS (ESI) [M+Na]+
calculated: 339.1339, found 339.1338.
Elemental Analysis: calculated: C: 74.99%; H: 3.97%; O: 21.03%
found: C: 74.42 H: 4.22
1
1
19 19 2 4
C H N O
2
0c)
(Z)-2-[(chromon-3-yl)methylene]naphtho[2,3-b]furan-
Elemental Analysis: calculated: C: 67.44%; H: 5.36%; N: 8.28%;
O: 18.91% found: C: 67.22%; H: 5.49%
05 3(2H)-one
1
mp: 243-245; yellow solid; yield: 21%; H NMR (250 MHz,
3
CDCl ) d 7.37 (s, 1H =C-CH=C), 7.43-7.55 (m, 3H, aromatic
Compound 7 is added slowly into vigorously stirring diluted
sulfuric acid (5M). After 30 minutes of stirring the reaction is
quenched with water and extracted with DCM. The organic
phased is washed with diluted HCl (2M), dried with magnesium
sulfate and the evaporated giving pure 7-methoxycoumarine-4-
aldehyde.
proton), 7.59–7.65 (m, 2H, aromatic protons), 7.70–7.76 (t, 1H,
J=7.5 Hz, aromatic proton), 7.87–7.90 (d, 1H, J=7.5 Hz, aromatic
10 proton), 7.98–8.01 (d, 1H, J=7.5 Hz, aromatic proton), 8.30–8.33
(
d, 1H, J=7.5 Hz, aromatic proton), 8.40 (s, 1H, aromatic proton),
13
9
1
1
3
.16 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl ) d
01.07, 107.74, 118.29, 121.75, 123.61, 125.53, 126.54, 126.64,
27.84, 129.69, 130.05, 130.73, 130.90, 134.12, 138.26, 147.84,
1
mp: 194-196; yellow solid; yield: 95%; H NMR (250 MHz,
15 155.92, 158.58, 159.44, 175.19, 183.95 HRMS (ESI) [M+H]+
calculated: 341.0808 found: 341.0803.
CDCl
3 3
) d 3.89 (s, 3H, –OCH ), 6.72 (s, 1H, -CHCOO-), 6.88–
22 13 4
C H O
6
.95 (m, 2H, aromatic protons) 7.48-7.52 (d, 1H, J=10.0 Hz,
Elemental Analysis: calculated: C: 77.64%; H: 3.55%; O: 18.80%
found: C: 77,78%; H: 3.11%
1
3
aromatic proton), 10.08 (s, 1H -CHO) ppm; C NMR (62.5
4
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Medicinal Chemistry Communications
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1
44.71, 147.42, 148.97, 154.45, 158.43, 166.09, 175.07, 183.16
2
1a) (Z)-6-methyl-3-[3-oxobenzofuran-2((3H)-ylidene)methyl]- 60 HRMS (ESI) [M+H]+ C21
H
17
O
4
calculated: 333.1121 found:
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chromone
mp: 218-220; pale yellow solid; yield: 37%; H NMR (250 MHz,
CDCl ) d 2.48 (s, 3H, –CH ), 7.21-7.28 (m, 1H, aromatic proton),
.32 (s, 1H =C-CH=C), 7.37 (s, 1H, aromatic proton), 7.33–7.34
d, 1H, J= 10.0 Hz, aromatic proton), 7.50–7.54 (d, 1H, J=10.0 65 22c) (Z)-2-[(6,7-dimethylchromon-3-yl)methylene]naphtho[2,3-
333.1120.
DOI: 10.1039/C3MD00241A
1
Elemental Analysis: calculated: C: 75.89%; H: 4.85%; O: 19.26%
5
0
5
0
5
0
5
0
5
0
5
3
3
found C: 75.80%; H: 4.74%
7
(
Hz, aromatic proton), 7.63–7.70 (t, 1H, J=7.5 Hz, aromatic
proton), 7.80–7.83 (d, 1H, J=7.5 Hz, aromatic proton), 8.07 (s,
b]furan-3(2H)-one
mp: 207-209; yellow solid; yield: 41%; H NMR (250 MHz,
CDCl ) d 2.38-2.42 (d, 6H, J=10.0 Hz, 2 –CH ), 7.30 (s, 1H =C-
1
13
1
1
2
2
3
3
4
4
5
5
1H, aromatic proton), 9.06 (s, 1H –O-CH=C-) ppm; C NMR
62.5 MHz, CDCl ) d 20.98, 102.54, 112.75, 117.87, 118.03,
3
3
(
3
CH=C), 7.39 (s, 1H, aromatic proton), 7.45–7.51 (m, 1H,
1
1
21.77, 123.25, 123.78, 124.84, 125.81, 135.97, 136.88, 147.02, 70 aromatic proton), 7.59–7.63 (m, 2H, aromatic protons), 7.87–7.90
54.18, 158.74, 165.55, 175.21, 183.59 HRMS (ESI) [M+H]+
calculated: 305.0808, found: 305.0820.
(d, 1H, J=7.5 Hz, aromatic proton) 7.98–8.04 (m, 2H, aromatic
protons), 8.41 (s, 1H, aromatic proton), 9.12 (s, 1H –O-CH=C-)
19 13 4
C H O
1
3
Elemental Analysis: calculated: C: 74.99%; H: 3.97%; O: 21.03%
found: C: 75.24%; H: 4.03%
3
ppm; C NMR (62.5 MHz, CDCl ) d 18.82, 19.15, 113.96,
114.03, 115.58, 119.52, 120.88, 124.53, 124.95, 126.07, 129.03,
129.29, 129.34, 130.71, 130.90, 131.55, 133.46, 149.02, 149.37,
151.05, 153.39, 154.13, 177.51, 182.66 HRMS (ESI) [M+Na]+
7
5
2
1b)
ylidene)methyl]-chromone
mp: 255-257; pale orange solid; yield: 37%; H NMR (250 MHz,
CDCl ) d 2.48 (s, 3H, –CH ), 2.50 (s, 3H, –CH ), 7.03-7.06 (d,
H, J= 7.5 Hz, aromatic proton), 7.10 (s, 1H, aromatic proton),
.33 (s, 1H =C-CH=C), 7.39–7.43 (d, 1H, J=10.0 Hz, aromatic
(Z)-6-methyl-3-[(6-methyl-3-oxobenzofuran-2(3H)-
24 17 4
C H O calculated: 369.1121, found 369.1117.
1
Elemental Analysis: calculated: C: 78.25%; H: 4.38%; O: 17.37%
found: C: 78.34%; H: 4.36%;
3
3
3
1
7
80
23a)
chromone
mp: 253-255; pale yellow solid; yield: 45%; H NMR (250 MHz,
CDCl ) d 7.23 (s, 1H =C-CH=C), 7.29–7.33 (m, 2H, aromatic
0.98, 22.64, 101.99, 112.89, 117.95, 118.01, 119.44, 123.31, 85 proton), 7.40-7.45 (d, 1H, J=12.5Hz, aromatic protons), 7.65–
(Z)-7-chloro-3-[(3-oxobenzofuran-2(3H)-ylidene)methyl]
proton), 7.50–7.53 (d, 1H, J=7.5 Hz, aromatic proton), 7.67–7.70
1
(d, 1H, J=7.5 Hz, aromatic proton), 8.08 (s, 1H, aromatic proton),
1
3
9
2
1
1
.03 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl
3
) d
3
24.48, 125.13, 125.82, 135.33, 135.90, 147.51, 149.05, 154.18,
58.57, 166.22, 175.31, 183.32 HRMS (ESI) [M+H]+ C20
7.72(m, 2H, aromatic protons), 7.80–7.84 (d, 1H, J=10.5 Hz,
aromatic proton) 8.22-8.26 (d, 1H, J=10.0 Hz, aromatic proton),
15 4
H O
1
3
calculated: 319.0965, found: 319.0961.
Elemental Analysis: C: 75.46%; H: 4.43%; O: 20.10% found: C:
3
9.06 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl ) d
101.57, 112.76, 118.36, 118.50, 121.65, 122.08, 123.95, 124.93,
90 126.72, 127.91, 137.05, 140.35, 147.33, 155.94, 158.59, 165.59,
7
5.64% H: 4.50%
1
74.36, 183.54 HRMS (ESI) [M+H]+ C18
4
H10ClO calculated:
2
2a)
(Z)-6,7-dimethyl-3-[(3-oxobenzofuran-2(3H)-
325.0262 found: 325.0286.
ylidene)methyl]chromone
mp: 238-240; pale yellow solid; yield: 42%; H NMR (250 MHz,
CDCl ) d 2.38-2.41 (d, 6H, J=7.5 Hz, 2 –CH ), 7.21-7.29 (m, 2H,
Elemental Analysis: calculated: C: 66.58%; H: 2.79%; Cl:
10.92%; O: 19.71% found: C: 66.65%, H: 2.83%
1
3
3
95
aromatic protons), 7.31 (s, 1H =C-CH=C), 7.38 (s, 1H, aromatic
proton), 7.63–7.69 (t, 1H, J=7.5 Hz, aromatic proton), 7.79–7.82
(d, 1H, J=7.5 Hz, aromatic proton), 8.01 (s, 1H, aromatic proton),
23b)
ylidene)methyl]chromone
mp: 267-269; pale yellow solid; yield: 55%; H NMR (250 MHz,
CDCl ) d 2.51 (s, 3H, –CH ), 7.04 (s, 1H =C-CH=C), 7.07-7.11
9.34, 20.46, 102.77, 112.73, 117.80, 118.35, 121.42, 121.81, 100 (d, 1H, J=10.0 Hz, aromatic protons), 7.40–7.44 (d, 1H, J=10.0
(Z)-7-chloro-3-[(6-methyl-3-oxobenzofuran-2(3H)-
1
1
3
9
1
1
1
.02 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl
3
) d
3
3
23.73, 124.81, 126.06, 135.26, 136.81, 144.78, 146.94, 154.45,
58.61, 165.53, 175.04, 183.57 HRMS (ESI) [M+H]+ C20
Hz, aromatic proton), 7.54 (s, 1H, aromatic proton), 7.68–7.70 (d,
H
15
O
4
1H, J=5.0Hz, aromatic proton) 8.21-8.25 (d, 1H, J=10.0 Hz,
1
3
calculated: 319.0965 found: 319.0977.
aromatic proton), 9.01 (s, 1H –O-CH=C-) ppm; C NMR (62.5
MHz, CDCl ) d 22.68, 101.01, 112.92, 118.34, 118.57, 119.31,
105 122.09, 124.55, 125.28, 126.66, 127.90, 140.28, 147.82, 149.28,
55.94, 158.41, 166.15, 174.38, 183.10 HRMS (ESI) [M+H]+
calculated: 339.0419 found: 339.0428.
Elemental Analysis: calculated: C: 75.46%; H: 4.43%; O: 20.10%
found: C: 75.40%; H: 4.40%
3
1
2
2b)
ylidene)methyl]chromone
mp: 286-288; pale yellow solid; yield: 44%; H NMR (250 MHz,
CDCl ) d 2.37-2.40 (d, 6H, J=7.5 Hz, 2 –CH ), 2.50 (s, 3H, – 110
CH ), 7.03-7.06 (d, 1H, J= 7.5 Hz, aromatic proton), 7.10 (s, 1H,
(Z)-6,7-dimethyl-3-[(6-methyl-3-oxobenzofuran-2(3H)-
19 4
C H12ClO
Elemental Analysis: calculated: C: 67.37%; H: 3.27%; Cl:
10.47%; O: 18.89% found: C: 67.55%, H: 3.26%
1
3
3
3
24a)
chromone
mp: 250-252; pale yellow solid; yield: 42%; H NMR (250 MHz,
CDCl ) d 7.23 (s, 1H =C-CH=C), 7.29–7.32 (d, 2H, J=7.5 Hz,
3
) d 19.34, 20.45, 22.63, 102.20, 112.88, 115 aromatic proton), 7.47-7.51 (d, 1H, J=10.0Hz, aromatic protons),
(Z)-6-chloro-3-[(3-oxobenzofuran-2(3H)-ylidene)methyl]
aromatic proton), 7.28 (s, 1H =C-CH=C), 7.33 (s, 1H, aromatic
proton), 7.67–7.70 (d, 1H, J=7.5 Hz, aromatic proton), 8.02 (s,
1
13
1
H, aromatic proton), 8.99 (s, 1H –O-CH=C-) ppm; C NMR
3
(
62.5 MHz, CDCl
1
17.87, 118.34, 119.47, 121.43, 124.44, 125.07, 126.05, 135.20,
7.64–7.71 (m, 2H, aromatic protons), 7.80–7.83 (d, 1H, J=7.5 Hz,
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Medicinal Chemistry Communications
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aromatic proton) 8.26-8.27 (d, 1H, J=2.5 Hz, aromatic proton),
ylidene)methyl]chromone
1
3
1
9
1
1
.07 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl ) d 60 mp: 230-232; pale yellow solid; yield: 38%; H NMR (250 MHz,
3
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01.60, 112.75, 118.21, 120.03, 121.64, 123.95, 124.46, 124.93,
25.90, 131.88, 134.39, 137.04, 147.29, 154.20, 158.66, 165.59,
CDCl ) d 2.51 (s, 3H, –CH ), 7.05–7.11 (t, 2H, J=7.5 Hz,
3 3
DOI: 10.1039/C3MD00241A
aromatic proton), 7.28 (s, 1H =C-CH=C), 7.44-7.48 (m, 1H,
aromatic proton), 7.52–7.57 (m, 1H, aromatic proton), 7.68–7.71
(d, 1H, J=7.5 Hz, aromatic proton) 7.92-7.95 (d, 1H, J=7.5 Hz,
5
0
5
0
5
0
5
0
5
0
5
9 4
174.06, 183.52 HRMS (ESI) [M+Na]+ C18H ClNaO calculated:
3
47.0082 found: 347.0092.
1
3
Elemental Analysis: calculated: C: 66.58%; H: 2.79%; Cl: 65 aromatic proton), 9.05 (s, 1H –O-CH=C-) ppm; C NMR (62.5
0.92%; O: 19.71% found: C: 66.78%; H: 2.80% MHz, CDCl ) d 22.66, 101.20, 111.60, 112.90, 117.62, 119.35,
20.38, 124.47, 124.55, 124.55, 124.83, 125.25, 147.79, 149.22,
152.13, 157.86, 166.15, 174.50, 183.09 HRMS (ESI) [M+H]+
calculated: 323.0714 found: 323.0715.
mp: 253-255; pale yellow solid; yield: 37%; H NMR (250 MHz, 70 Elemental Analysis: calculated: C: 70.81%; H: 3.44%; F: 5.89%;
CDCl ) d 2.51 (s, 3H, –CH ), 7.04–7.07 (d, 2H, J=7.5 Hz, O: 19.86% found: C: 69.81%; H: 3.44%
1
3
1
1
1
2
2
3
3
4
4
5
5
24b)
(Z)-6-chloro-3-[(6-methyl-3-oxobenzofuran-2(3H)-
ylidene)methyl]chromone
19 4
C H12FO
1
3
3
aromatic proton), 7.13 (s, 1H =C-CH=C), 7.26 (s, 1H, aromatic
proton), 7.47-7.50 (d, 1H, J=7.5Hz, aromatic protons), 7.63–7.64
25c)
(Z)-2-[(6-fluoro-chromon-3-yl)methylene]naphtho[2,3-
(
d, 1H, J=2.5 Hz, aromatic proton), 7.67–7.70 (m, 1H, aromatic
b]furan-3(2H)-one
1
proton) 8.25-8.26 (d, 1H, J=2.5 Hz, aromatic proton), 9.03 (s, 1H 75 mp: 303-305; yellow solid; yield: 38%; H NMR (250 MHz,
1
3
–
1
O-CH=C-) ppm; C NMR (62.5 MHz, CDCl
3
) d 22.76, 101.04,
CDCl
3
) d 7.32 (s, 1H =C-CH=C), 7.41–7.67 (m, 5H, aromatic
12.91, 118.28, 119.31, 120.01, 124.47, 124.55, 125.28, 125.89,
protons), 7.87–8.01 (m, 3H, aromatic protons), 8.41 (s, 1H,
1
3
131.34, 134.34, 147.78, 149.27, 154.20, 158.49, 166.51, 174.08,
83.08 HRMS (ESI) [M+H]+ C19 calculated: 339.0419
found: 339.0422.
Elemental Analysis: calculated: C: 67.37%; H: 3.27%; Cl:
aromatic proton), 9.16 (s, 1H –O-CH=C-) ppm; C NMR (62.5
MHz, CDCl ) d 100.60, 107.77, 120.43, 120.56, 121.66, 122.61,
1
H
12ClO
4
3
80 125.61, 126.75, 127.85, 129.78, 130.08, 130.94, 131.83, 134.34,
138.28, 142.61, 148.01, 157.99, 158.56, 159.43, 174.26,
1
0.47%; O: 18.89% found: C: 67.37%; H: 3.29%
184.89HRMS (ESI) [M+H]+ C22
found: 359.0710.
4
H12FO calculated: 359.0714
2
4c) (Z)-2-[(6-chloro-chromon-3-yl)methylene]naphtho[2,3-
Elemental Analysis: calculated: C: 73.74%; H: 3.09%; F: 5.30%;
85 O: 17.86% found: C: 73.75%, H: 3.14%
b]furan-3(2H)-one
mp: 310-312; yellow solid; yield: 25%; H NMR (250 MHz,
CDCl ) d 7.32 (s, 1H =C-CH=C), 7.46–7.52 (m, 2H, aromatic
1
3
26a)
ylidene)methyl]chromone
mp: 233-235; pale yellow solid; yield: 45%; H NMR (250 MHz,
) d 3.93 (s, 3H, –OCH ), 6.88 (s, 1H, aromatic proton),
(Z)-7-methoxy-3-[(3-oxobenzofuran-2(3H)-
protons), 7.60–7.71 (m, 3H, aromatic protons), 7.87–7.90 (d, 1H,
1
J=7.5 Hz, aromatic proton) 7.99–8.03 (d, 1H, J=10.0 Hz,
aromatic proton), 8.29 (s, 1H, aromatic proton), 8.42 (s, 1H, 90 CDCl
3
3
1
3
aromatic proton), 9.15 (s, 1H –O-CH=C-) ppm; C NMR (62.5
MHz, CDCl ) d 100.41, 107.76, 118.39, 120.03, 124.48, 125.61,
125.92, 126.75, 127.85, 129.78, 130.09, 130.93, 131.83, 134.34,
38.28, 148.02, 154.26, 157.99, 158.45, 159.40, 174.21, 183.81
HRMS (ESI) [M+H]+ C22
75.0426.
6.98–7.03 (d, 1H, J=12.5 Hz, aromatic proton), 7.21-7.32 (m, 2H,
aromatic protons), 7.37 (s, 1H =C-CH=C), 7.54 (s, 1H, aromatic
proton), 7.63-7.67 (m, 1H, aromatic protons), 7.80–7.83 (d, 1H,
J=7.5Hz, aromatic proton), 8.18-8.22 (d, 1H, J=10.0 Hz, aromatic
3
1
1
3
H
12ClO
4
calculated: 375.0419 found: 95 proton), 9.00 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz,
CDCl ) d 55.92, 100.57, 102.49, 112.74, 114.98, 117.43, 117.97,
121.78, 123.78, 124.84, 127.94, 136.86, 147.08, 157.64, 158.43,
3
3
Elemental Analysis: calculated: C: 74.48%; H: 3.47%; O: 22.05%
found: C: 74.53%; H: 3.56%
164.44, 165.54, 174.42, 183.56 HRMS (ESI) [M+H]+ C19
calculated: 321.0757 found: 321.0764.
13 5
H O
2
5a)
chromone
mp: 249-251; pale yellow solid; yield: 44%; H NMR (250 MHz,
CDCl ) d 7.23 (s, 1H =C-CH=C), 7.29 (s, 1H, aromatic proton),
.32 (s, 1H, aromatic proton), 7.41-7.48 (m, 1H, aromatic
proton), 7.52–7.58 (m, 1H, aromatic proton), 7.65–7.71 (t, 1H, 105 mp: 222-224; pale yellow solid; yield: 41%; H NMR (250 MHz,
(Z)-6-fluoro-3-[(3-oxobenzofuran-2(3H)-ylidene)methyl] 100 Elemental Analysis: calculated: C: 71.25%; H: 3.78%; O: 24.98%
found: C: 71.13% H: 3.83%
1
3
26b)
(Z)-7-methoxy-3-[(6-methyl-3-oxobenzofuran-2(3H)-
7
ylidene)methyl]chromone
1
J=7.5 Hz, aromatic proton), 7.81–7.84 (d, 1H, J=7.5 Hz, aromatic
proton), 7.92-7.95 (d, 1H, J=7.5 Hz, aromatic proton), 9.09 (s, 1H
3 3 3
CDCl ) d 2.50 (s, 3H, –CH ), 3.93 (s, 3H, –OCH ), 6.88 (s, 1H,
aromatic proton), 6.97-7.09 (m, 3H, aromatic protons), 7.32 (s,
1H =C-CH=C), 7.40–7.44 (d, 1H, J= 10.0 Hz, aromatic proton),
7.54 (s, 1H, aromatic proton), 7.66–7.69 (d, 1H, J= 7.5Hz,
1
3
–O-CH=C-) ppm; C NMR (62.5 MHz, CDCl
3
) d 22.66, 101.76,
1
11.23, 111.61, 112.75, 117.53, 120.41, 120.54, 121.68, 122.62,
1
23.92, 124.92, 136.65, 147.30, 158.72, 165.59, 174.47, 183.52 110 aromatic proton), 8.17-8.21 (d, 1H, J=10.0 Hz, aromatic proton),
1
3
HRMS (ESI) [M+H]+ C18
H
12FO
4
calculated: 309.0558 found:
3
8.97 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl ) d
3
09.0557.
22.64, 55.90, 100.54, 101.90, 112.89, 114.93, 117.43, 118.03,
119.43, 124.45, 125.11, 127.91, 147.54, 149.04, 157.62, 158.24,
Elemental Analysis: calculated: C: 70.13%; H: 2.94%; F: 6.16%;
O: 20.76% found: C: 70.39%; H: 2.76%
164.40, 166.09, 174.44, 183.13 HRMS (ESI) [M+H]+ C20
15 calculated: 335.0914 found: 335.0924.
15 5
H O
1
2
5b)
(Z)-6-fluoro-3-[(6-methyl-3-oxobenzofuran-2(3H)-
Elemental Analysis: C: 71.85%; H: 4.22%; O: 23.93% found: C:
6
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1
3
7
1.60%; H: 4.31%
3
ppm; C NMR (62.5 MHz, CDCl ) d 56.49, 61.73, 102.31,
60
110.51, 112.74, 117.58, 118.20, 121.76, 121.98, 123.81, 124.86,
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2
7a)
(Z)-5-methoxy-3-[(3-oxobenzofuran-2(3H)-
147.17, 150.23, 156.92, 158.55, 165.55, 174.61, 183.57 HRMS
DOI: 10.1039/C3MD00241A
ylidene)methyl]chromone
mp: 236-238; pale yellow solid; yield: 33%; H NMR (250 MHz,
CDCl ) d) 4.01 (s, 3H, –OCH ), 6.84–6.88 (d, 1H, J=10.0 Hz,
aromatic proton), 7.04–7.08 (d, 1H, J=10.0 Hz, aromatic proton),
.21-7.31 (m, 3H, aromatic protons), 7.37 (s, 1H =C-CH=C), 7.54
s, 1H, aromatic proton), 7.56–7.69 (m, 2H, aromatic protons),
7.80-7.83 (d, 1H, J=7.5 Hz, aromatic proton), 8.90 (s, 1H –O-
15 6
(ESI) [M+H]+ C20H O calculated: 351.0863 found: 351.0853.
1
5
0
5
0
5
0
5
0
5
0
5
Elemental Analysis: calculated: C: 68.57%; H: 4.03%; O: 27.40%
found: C: 68.90%; H: 4.14%
3
3
65
7
28b)
ylidene)methyl]chromone
mp: 214-216; pale yellow solid; yield: 34%; H NMR (250 MHz,
CDCl ) d 2.51 (s, 3H, –CH ), 4.03 (s, 6H, 2 –OCH ), 7.04-7.10
07.05, 110.16, 112.71, 114.24, 119.13, 121.84, 123.72, 124.82, 70 (m, 3H, aromatic protons), 7.31 (s, 1H =C-CH=C), 7.68–7.71 (d,
34.28, 136.80, 147.10, 157.10, 157.80, 160.28, 165.48, 174.41, 1H, J= 7.5Hz, aromatic proton), 8.02-8.05 (d, 1H, J=7.5 Hz,
83.55 HRMS (ESI) [M+H]+ C19 calculated: 321.0757
(Z)-7,8-dimethoxy-3-[(6-methyl-3-oxobenzofuran-2(3H)-
(
1
1
1
2
2
3
3
4
4
5
5
1
3
CH=C-) ppm; C NMR (62.5 MHz, CDCl
3
) d 56.53, 102.66,
3
3
3
1
1
1
1
3
H
13
O
5
aromatic proton), 9.07 (s, 1H –O-CH=C-) ppm; C NMR (62.5
MHz, CDCl ) d 22.66, 56.48, 61.72, 101.75, 110.46, 112.87,
found: 321.0762.
Elemental Analysis: calculated: C: 71.25%; H: 3.78%; O: 24.98%
found: C: 71.03%; H: 3.78%
3
117.65, 118.23, 119.43, 121.98, 124.49, 125.16, 136.77, 147.65,
75 149.11, 150.23, 156.87, 158.36, 166.12, 174.64, 183.16 HRMS
(
17 6
ESI) [M+H]+ C21H O calculated: 365.1020 found: 365.1006.
2
7b)
ylidene)methyl]chromone
mp: 260-262; pale yellow solid; yield: 43%; H NMR (250 MHz,
CDCl ) d 2.51 (s, 3H, –CH ), 4.00 (s, 3H, –OCH ), 6.83–6.87 (d, 80 29a) (Z)-7-methoxy-4-[(3-oxobenzofuran-2(3H)-ylidene)methyl]-
H, J=10.0 Hz, aromatic proton), 7.02-7.08 (m, 3H, aromatic 2H-coumarine
mp: 225-227; yellow solid; yield: 36%; H NMR (250 MHz,
CDCl ) d 3.91 (s, 3H, –OCH ), 6.88-6.95 (m, 2H, aromatic
protons), 7.03 (s, 1H, =CHCOO–), 7.17 (s, 1H, =C-CH=C), 7.33–
proton), 8.90 (s, 1H –O-CH=C-) ppm; C NMR (62.5 MHz, 85 7.38 (m, 2H, aromatic protons), 7.71–7.76 (m, 2H, aromatic
(Z)-5-methoxy-3-[(6-methyl-3-oxobenzofuran-2(3H)-
Elemental Analysis: C: 69.23%; H: 4.43%; O: 26.35% found: C:
69.47%, H: 4,49%
1
3
3
3
1
1
protons), 7.32 (s, 1H =C-CH=C), 7.40–7.44 (d, 1H, J=10.0 Hz,
aromatic proton), 7.54 (s, 1H, aromatic proton), 7.55–7.62 (m,
3
3
1
H, aromatic proton), 7.66-7.69 (d, 1H, J=7.5 Hz, aromatic
1
3
1
3
CDCl
19.20, 119.49, 124.43, 125.06, 134.22, 147.57, 148.94, 156.90,
157.80, 160.27, 166.03, 174.44, 183.12 HRMS (ESI) [M+H]+
calculated: 335.0914 found: 335.0914.
3
) d 22.64, 56.52, 102.08, 106.99, 110.15, 112.86, 114.24,
protons), 7.82–7.85 (d, 1H, J=7.5 Hz, aromatic proton) ppm;
C
1
NMR (62.5 MHz, CDCl ) d 55.84, 101.46, 102.00, 111.72,
3
112.64, 113.28, 114.73, 120.67, 124.54, 125.15, 125.18, 138.18,
143.68, 151.00, 155.64, 161.29, 162.95, 166.66, 184.19 HRMS
20 15 5
C H O
5
Elemental Analysis: C: 71.85%; H: 4.22%; O: 23.93% found: C: 90 (ESI) [M+Na]+ C19H12NaO calculated: 343.057 found: 343.059.
7
1.60%; H: 4,26%
Elemental Analysis: calculated: C: 71.25%; H: 3.78%; O: 24.98%
found: C: 70.96%; H: 3.90%
27c)
b]furan-3(2H)-one
mp: 286-288; yellow solid; yield: 37%; H NMR (250 MHz, 95 ylidene)methyl]-2H-coumarine
CDCl ) d 4.02 (s, 3H, –OCH ), 6.85-6.88 (m, 1H, aromatic mp: 238-240; yellow solid; yield: 40%; H NMR (250 MHz,
CDCl ) d 2.53 (s, 3H, –CH ), 3.88 (s, 3H, –OCH ), 6.87-6.95 (m,
(Z)-2-[(5-methoxy-chromon-3-yl)methylene]naphtho[2,3-
29b)
(Z)-7-methoxy-4-[(6-methyl-3-oxobenzofuran-2(3H)-
1
1
3
3
proton), 7.07-7.10 (m, 1H, aromatic proton), 7.37 (s, 1H =C-
CH=C), 7.45–7.49 (m, 1H, aromatic proton), 7.54–7.67 (m, 3H,
aromatic protons), 7.83–7.92 (m, 1H, aromatic proton), 7.95–8.03
3
3
3
2H, aromatic protons), 6.97 (s, 1H, =CHCOO–), 7.09–7.15 (m,
3H, aromatic protons,=C-CH=C), 7.69–7.76 (t, 2H, J=9.5 Hz,
1
3
(
3
m, 1H, aromatic proton), 8.40 (s, 1H, aromatic proton), 9.02 (s, 100 aromatic protons) ppm; C NMR (62.5 MHz, CDCl ) d 22.84
1
3
1
1
H –O-CH=C-) ppm; C NMR (62.5 MHz, CDCl
3
) d 56.52,
55.83, 101.43, 101.52, 111.77, 112.60, 113.41, 114.53, 118.34,
124.82, 125.18, 125.86, 143.83, 150.75,151.57, 155.62, 161.34,
01.47, 107.00, 107.66, 110.18, 114.25, 119.30, 121.88, 125.44,
126.51, 127.81, 129.59, 130.02, 130.86, 134.23, 138.22, 147.79,
56.90, 157.83, 159.40, 160.29, 174.46, 183.89 HRMS (ESI)
M+H]+ C23 calculated: 371.0914 found: 371.0920.
162.90, 167.11, 183.65 HRMS (ESI) [M+Na]+ C20
calculated: 357.0733, found: 357.0742.
H14NaO
5
1
[
H
15
O
5
105 Elemental Analysis: calculated: C: 71.85%; H: 4.22%; O: 23.93%
found: C: 71.67%; H: 4.32%
Elemental Analysis: calculated: C: 74.59%; H: 3.81%; O: 21.60%
found: C: 74.19%; H: 3.44%
29c)
b]furan-3(2H)-one
110 mp: 291-293; orange solid; yield: 38%; H NMR (250 MHz,
CDCl ) d 3.91 (s, 3H, –OCH ), 6.89-6.96 (m, 2H, aromatic
(Z)-2-[(7-methoxycoumarin-yl)methylene]naphtho[2,3-
2
8a)
ylidene)methyl]chromone
mp: 250-252; pale yellow solid; yield: 40%; H NMR (250 MHz,
CDCl ) d 2.51 (s, 3H, –CH ), 4.03 (s, 6H, 2 –OCH ), 7.07–7.10
(Z)-7,8-dimethoxy-3-[(3-oxobenzofuran-2(3H)-
1
1
3
3
3
3
3
protons), 7.01 (s, 1H, =CHCOO–), 7.26 (s, 1H, =C-CH=C), 7.49–
7.54 (m, 1H, aromatic proton), 7.64–7.70 (m, 2H, aromatic
protons), 7.76–7.80 (d, 1H, J=10.0 Hz, aromatic proton) ppm,
(d, 1H, J= 7.5Hz, aromatic proton), 7.22-7.31 (m, 2H, aromatic
protons), 7.36 (s, 1H =C-CH=C), 7.61-7.64 (m, 1H, aromatic
proton), 7.81–7.84 (d, 1H, J= 7.5Hz, aromatic proton), 8.02-8.06 115 7.90–7.94 (d, 1H, J=10.0 Hz, aromatic proton) ppm, 8.00–8.03
(
d, 1H, J=10.0 Hz, aromatic proton), 9.11 (s, 1H –O-CH=C-)
(d, 1H, J=7.5 Hz, aromatic proton) ppm, 8.45 (s, 1H, aromatic
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Medicinal Chemistry Communications
Page 8 of 9
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1
3
c
55
Dipartimento di Biochimica, Biofisica e Patologia generale, Seconda
proton); C NMR (62.5 MHz, CDCl
3
) d 55.83, 100.65, 101.45,
08.47, 111.78, 112.60, 114.43, 120.48, 125.13, 126.03, 127.47,
28.23, 130.27, 130.40, 131.07, 138.70, 143.83, 151.93, 155.65,
59.79, 161.42, 162.90, 184.53 HRMS (ESI) [M+Na]+
calculated: 393.074 found: 393.074.
Università di Napoli, Vico L. De Crecchio 7, 80138, Napoli, Italy
1
1
1
d
Department of Chemistry, University of Aveiro, QOPNA, 3 8V 1i e0 w- 1 A9 r 3t icle Online
DOI: 10.1039/C3MD00241A
Istituto di genetica e Biofisica IGB Via P. Castellino 1111, 80131
60 Naples, Italy
Aveiro, Portugal
e
5
C
23
H
14NaO
5
Elemental Analysis: calculated: C: 74.59%; H: 3.81%; O: 21.60%
found: C: 74.63%; H: 3.82%
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
65
1
0
Biology:
Cell culture :
1. V. Cody, E. Middleton and Meeting Plant Flavonoids in Biology and
K562 (chronic myeloid leukemia) cells were cultured in RPMI
Medicine, Plant flavonoids in biology and medicine
:
(
Invitrogen) with 10% fetal calf serum (Hyclone), 100 U/mL
70
biochemical, pharmacological, and structure-activity
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Cell Cycle Analysis on K562 Cells
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2.5 × 10 treated (containing the tested compound and 0. 1%
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iodide (PI), RNAse A). Cells were incubated in the dark for 30
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3
3
4
0
5
0
In summary, new benzofuran-chromone and –coumarine
derivatives have been synthesized and evaluated against K562
human leukeima cells. Both these chemical structures displayed
anticancer acitivity because they are able to block the K562 cell
cycle in G1 (21b 72%), S (24a 63%) or G2 (29c 46%) phase, and
to induce high (around 24%) apoptosis (21b, 29b and 29c). These
new compounds seem to provide a promising scaffold for
medicinal chemistry bearing in mind the possibility to access
heterocyclic analogues of benzofurans. Complementary
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Biochimie Pharmacologique, Institut Jean Barriol, Université de
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