Effect of flavonol derivatives on the carrageenin-induced paw edema in the rat and inhibition of cyclooxygenase-1 and 5-lipoxygenase in vitro.

Article abstract of DOI:10.1002/1521-4184(20007)333:7<205::AID-ARDP205>3.0.CO;2-Y

Alkoxyflavonols were synthesized by the Algar-Flynn-Oyamada (AFO) cyclization of chalcones. Hydroxyflavonols were prepared by dealkylation of methoxyflavonols by refluxing in hydroiodic acid. The alkoxyflavonols 3-hydroxy-2-(2,3,4-trimethoxyphenyl)-4H-chr

Full text of DOI:10.1002/1521-4184(20007)333:7<205::AID-ARDP205>3.0.CO;2-Y

Flavonol Derivatives
205
Effect of Flavonol Derivatives on the Carrageenin-Induced
Paw Edema in the Rat and Inhibition of Cyclooxygenase-1 and
5-Lipoxygenase in Vitro
a, b)
b)
b)
c)
c)
c)
Andrea M. Sobottka
, Wolfgang Werner , Gottfried Blaschke , Werner Kiefer , Ulrike Nowe , Gerd Dannhardt ,
a)
a)
d)
Elfrides E. S. Schapoval , Eloir P. Schenkel , and Gerhard K.E. Scriba *
a) Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, 90610-000 Porto Alegre-RS, Brazil
b) Department of Pharmaceutical Chemistry, University of Münster, Hittorfstrasse 58–62, D-48149 Münster, Germany
c) Department of Pharmaceutical Chemistry, University of Mainz, Staudingerweg 5, D-55099 Mainz, Germany
d) Department of Pharmaceutical Chemistry, University of Jena, Philosophenweg 14, D-07743 Jena, Germany
Key Words: Flavonols; anti-inflammatory activity; rat paw edema; cyclooxygenase-1; 5-lipoxygenase
Chemical-biological relationship studies of flavonols (3-
Summary
hydroxyflavones) are of great interest. However, most studies
of the biological activities have been limited to the naturally
Alkoxyflavonols were synthesized by the Algar-Flynn-Oyamada
(AFO) cyclization of chalcones. Hydroxyflavonols were prepared
by dealkylation of methoxyflavonols by refluxing in hydroiodic
acid. The alkoxyflavonols 3-hydroxy-2-(2,3,4-trimethoxy-
phenyl)-4H-chromen-4-one (6), 2-(4-ethoxyphenyl)-3-hydroxy-
4H-chromen-4-one (7), 2-(4-butoxyphenyl)-3-hydroxy-
4H-chromen-4-one (10), and 2-(3-n-butoxyphenyl)-3-hydroxy-
4H-chromen-4-one (11) as well as the trihydroxy derivative 3-hy-
occurring derivatives such as quercetin, kaempferol,
[11–15]
galangin, fisetin, morin, and myricetin
. This may be
due to the fact that flavonols are more difficult to synthesize
than flavones.
The aim of the present study was the investigation of the
anti-inflammatory activity of alkoxy flavonols. Thus, several
methoxy, ethoxy, butoxy, and benzyloxy derivatives have
been synthesized together with the respective hydroxy fla-
vonols in order to compare their anti-inflammatory activity
in vivo and in vitro. Six new flavonol derivatives were inves-
tigated along with 13 known compounds including quercetin.
droxy-2-(3,4,5-trihydroxyphenyl)-4H-chromen-4-one
(18)
displayed high anti-inflammatory activity in carrageenin-induced
rat paw edema. Additionally, the inhibition of enzymes of the
arachidonic acid cascade by the derivatives was investigated in
vitro. In contrast to the natural compound quercetin, the com-
pounds were more potent inhibiting cyclooxygenase-1 than 5-
lipoxygenase except for 3-hydroxy-7-methoxy-2-(4-methoxy-
phenyl)-4H-chromen-4-one (5). No correlation between the anti-
inflammatory activity in the rat paw edema test and the inhibition
of 5-lipoxygenase or cyclooxygenase-1 could be observed. In
conclusion, the present results suggest that other effects than
inhibition of these enzymes of the arachidonic acid cascade are
important for the anti-inflammatory activity of the investigated
alkoxyflavonols.
Results and Discussion
The general synthetic procedure is outlined in Figure 1.
Base-catalyzed condensation of 2-hydroxyacetophenone and
benzaldehyde derivatives yielded the respective 2-hydroxy-
chalcones. Without extensive purification cyclization of the
chalcones was obtained by the AFO (Algar-Flynn-Oyamada)
[16]
[17]
reaction according to Algar and Flynn
and Oyamada
with alkaline hydrogen peroxide to yield the target com-
pounds 1–13. While the methoxy derivatives reacted readily
at room temperature or below, the ethoxy-, butoxy-, and
Introduction
Flavonoids are ubiquitously distributed throughout higher benzyloxychalcones had to be refluxed to achieve the cycli-
plants. They share the 2,3-dihydro-2-phenyl-4H-chromen-4- zation. The hydroxyflavonols 14–18 were prepared by de-
one structure and are classified according to the substitution alkylation of the respective alkoxyflavonols in refluxing hy-
pattern and degree of ring saturation in flavonols, flavones, droiodic acid [18]. Especially the dihydroxy and trihydroxy
flavanones, flavanonols.
derivatives required long reaction times. The lipophilicity of
The compounds display a wide range of biological activities the compounds (Table 1) was estimated by calculation using
[1–4]
[19]
which have been the subject of many reviews
. Worth the CLogP program
.
[5, 6]
[7]
mentioning is the antiviral
, antimicrobial , anti-inflam- The anti-inflammatory activity of the flavonols 1–18 in the
activity. Moreover, the fla- rat paw edema test
[8]
[9]
[20, 21]
matory , and spasmolytic
at a dose of 25 mg/kg injected
vonoids affect numerous enzymes and are able to modulate intraperitoneally is summarized in Table 1. The minus sign
[10]
the functional activity of several types of cells
. The of the percent inhibition in some cases denotes that the size
anti-inflammatory activity of flavonoids has been studied of the edema exceeded the size of the respective control
[10]
extensively in several in vitro and in vivo models . Various series. Compounds 6, 7, 10, 11, and 18 displayed high activity
stages of inflammations are affected by the compounds in- over the entire period of time. The activity was comparable
cluding the formation of granulose tissue, chronic arthritis as to quercetin, a known anti-inflammatory flavonol [10]. Com-
[8]
well as the permeability of capillaries in the early stages
.
pounds 8, 15, and 16 moderately suppressed the edema 2 h
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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206
Scriba and co-workers
and 4 h after the injection of carrigeenin while flavonols 4, 5,
12, and 13 displayed only low activity. Derivatives 1, 2, 3, 9,
14, and 17 were inactive. Except for the trihydroxy derivative
18, the butoxyflavonols 10 and 11 were amoung the most
effective compounds. Moreover, most alkoxy derivatives
displayed at least some activity.
No general correlation could be observed between the cal-
culated lipophilicity and the activity of the compounds. An
earlier study by Reddy et al. about methoxyflavonols demon-
strated a correlation between the anti-inflammatory activity
[22]
and the lipophilicity
. Quercetin pentamethyl ether dis-
played a greater inhibitory effect than quercetin itself. On the
other hand, Arivudai Nambe et al. described a higher activity
of hydroxyflavonols compared to the corresponding methoxy
[23]
derivatives
.
The experiments by Gábor and Rázga demonstrated that
derivatives containing the o-dihydroxy substitution of ring B
such as myricetin, fisetin, and quercetin were among the most
effective flavonols inhibiting the carrageenin-induced rat
[12]
paw edema . The present study showed that the o-diphenol
pattern is not necessary. In our hands, application of 3,4-di-
hydroxyflavonol (17) did not effect the edema significantly.
In contrast, alkoxyflavonols were very potent anti-inflamma-
tory agents.
Additionally, the flavonols were screened for their ability
to inhibit cyclooxygenase-1, 5-lipoxygenase, and 12-lipoxy-
Figure 1. Structures of the flavonols.
Table 1. Effect of flavonols on the carrageenin-induced paw edema in the rat upon i.p. administration of a dose of 25 mg/kg and IC50 values of the inhibition
of cyclooxygenase-1 and 5-lipoxygenase in vitro.
—————————————————————————————————————————————————————————————
Rat paw edema test [20]
In vitro inhibition [24]
paw edema mean ± SEM in mm (% inhibition of control)
IC50 [µM]
————————————————————————
————————————————
CompoundC log Pa
N
1 h
2 h
4 h
5-lipoxygenase
cyclooxygenase-1
—————————————————————————————————————————————————————————————
1
2
2.97
2.42
3.07
2.49
3.00
1.91
3.50
3.50
3.55
4.56
4.56
5.67
4.74
2.41
2.32
2.41
1.82
1.16
4
5
5
4
8
4
8
4
5
5
5
5
5
4
4
6
4
8
4
–
14.0 ± 4.9 (11)
14.8 ± 7.4 (6)
18.6 ± 7.6 (–17)
15.5 ± 2.1 (–26)
9.8 ± 4.2 (38)
17.5 ± 3.8 (39)
22.4 ± 9.8 (22)
30.6 ± 10.0 (–6)
16.8 ± 3.1* (52)
18.7 ± 3.0* (35)
24.6 ± 4.7 (32)
43.7 ± 11.4 (–20)
34.6 ± 7.7 (5)
20 %b
inactivec
n.d.d
7.2
3.3
n.d.d
3
4
15.0 ± 2.6* (43)
25.6 ± 3.4 (30)
6.5 ± 5.5** (83)
19.2 ± 4.9** (47)
14.0 ± 1.4* (47)
30.0 ± 7.5 (–12)
6.8 ± 2.8*** (74)
inactivec
22 %b
25 %b
inactivec
inactivec
6.2
5
8.7
6
2.0 ± 0.8*** (113) 4.0 ± 2.1** (86)
1.4 ± 3.1*** (109) 4.8 ± 2.1** (83)
inactivec
35 %b
inactivec
n.d.d
7
8
15.7 ± 2.1 (–28)
10.6 ± 2.8 (14)
13.3 ± 3.0** (52)
19.6 ± 2.0 (–3)
9
n.d.d
10
11
12
13
14
15
16
17
18
1.3 ± 2.1*** (110) 1.0 ± 1.2*** (96)
n.d.d
n.d.d
1.0 ± 3.6*** (108) 0.6 ± 4.7*** (102) 10.6 ± 5.5** (60)
n.d.d
n.d.d
8.8 ± 6.4 (29)
12.1 ± 5.3 (23)
23.8 ± 4.8 (–93)
9.1 ± 3.0 (26)
14.4 ± 5.2 (–28)
27.8 ± 6.8 (–109)
2.4 ± 3.6** (81)
3.5 ± 3.1** (72)
n.d.d
16.6 ± 5.8* (40)
12.7 ± 7.5* (35)
18.3 ± 4.0 (34)
13.3 ± 4.0** (52)
12.0 ± 3.2** (56)
28.3 ± 4.5 (–3)
35.3 ± 10.2 (–33)
40.2 ± 8.3 (–11)
23.5 ± 4.7 (12)
15.3 ± 4.0* (43)
11.1±2.3** (58)
30.0 ± 7.5 (–12)
n.d.d
n.d.d
n.d.d
n.d.d
inactivec
inactivec
inactivec
43 %b
inactivec
0.54
7.3
20 %b
41 %b
7.1
4.2 ± 2.6*** (84) 11.5 ± 3.3** (57)
6.0 ± 2.7*** (78) 1.0 ± 4.5*** (96)
n.d.d n.d.d
46 %b
15 %b
0.004
quercetin 0.68
indo-
–
inactivec
methacin
ibuprofen –
–
n.d.d
n.d.d n.d.d
inactivec
0.6
—————————————————————————————————————————————————————————————
The minus sign denotes that the size of the edema exceeded the size of the respective control series.
a calculated log P using C log P 2.0; b percent inhibition at 10 µM; c no inhibition at 10 µM; d not determined;
* P < 0.05; ** P < 0.01; *** P < 0.001.
Arch. Pharm. Pharm. Med. Chem. 333, 205–210 (2000)

Flavonol Derivatives
[24]
207
chalcone was suspended in 100 ml ethanol, cooled to 0–5 °C and 45 g
(0.4 mol) 30% H2O2 was slowly added. After stirring for 2–5 h at room
temperature the crude product was precipitated by the addition of 2 N acetic
acid and recrystallized from hot ethanol.
genase
. The IC values of the inhibition of cyclooxy-
50
genase-1 and 5-lipoxygenase are summarized in Table 1
along with the data of the known drugs indometacin and
ibuprofen. Compounds 9–13 could not be evaluated due to
their insolubility in the assay medium. None of the flavonols
affected 12-lipoxygenase. Most flavonols investigated were
more effective inhibiting cyclooxygenase-1 than 5-lipoxy-
genase except for 5 and quercetin although the cyclooxy-
genase-1 activity was less potent than the activity of the
known NSAIDs ibuprofen and indomethacin. Several studies
have indicated that the selectivity towards 5-lipoxygenase of
Method B
0.05 mol of the 2-hydroxyacetophenone and 0.05 mol benzaldehyde
derivative were added to a solution of 2.3 g (0.1 mol) sodium in 80 ml ethanol
and stirred at room temperature or refluxed overnight. The resulting chalcone
was processed further without isolation or precipitated by acidification. No
attempt was made to characterize this intermediate. 45 g (0.4 mol) 30% H2O2
was added slowly to a sodium ethoxide solution of the chalcone derivative
at 0–5 °C and maintained at this temperature for 2 h. After warming to room
temperature the mixture was kept at room temperature or refluxed for 1–5 h.
The crude product was precipitated by the addition of 2 N acetic acid and
recrystallized from hot ethanol.
cyclooxygenase-1 may depend on the lipophilicity of fla-
vones and flavonols
[25–27]
. Highly hydroxylated compounds
displayed 5-lipoxygenase selectivity while derivatives with 3
or less hydroxy groups were more potent inhibitors of cyclo-
oxygenase-1. Thus, the selectivity for cyclooxygenase-1 ob-
served in our experiments may be related to the lipophilicity
of the compounds. Interestingly, the methoxy derivative 5
was selective for 5-lipoxygenase though the compound was
about 15-fold less potent compared to quercetin.
No correlation between the activity in the rat paw edema
model and the in vitro inhibition of cyclooxygenase-1 and
5-lipoxygenase was observed in the present study. For exam-
ple, compounds 6 and 7 which were very active in the paw
edema test were essentially inactive inhibiting both enzymes.
Thus, other factors than inhibition of these enzymes of the
arachidonic acid cascade seem to contribute to the anti-in-
flammatory activity of the investigated flavonols. Radical
3-Hydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (1)
Method A; yield: 3.1 g (12%); mp 236–239 °C (236–237 °C [18]). 1H-NMR
(200 MHz, CDCl3): δ 3.86 (s, 3H, OCH3), 7.14 (d, 2H, J = 9,0 Hz, 3′/5′-H
aromat.), 7.47 (ddd, 1H, J = 7.7 Hz, 6.2 Hz, 1.6 Hz, 6-H aromat.), 7.79 (d,
1H, J = 8.5 Hz, 8-H aromat.), 7.88 (ddd, 1H, J = 8.5 Hz, 6.2 Hz, 1.6 Hz, 7-H
aromat.), 8.12 (d, 1H, J = 7.7 Hz, 5-H aromat.), 8.22 (d, 2H, J = 9.0 Hz,
2′/6′-H aromat.). 13C-NMR (50.3 MHz, CDCl3): δ 55.3 (OCH3), 114.0
(C-3′/5′), 118.2 (C-8), 121.3 (C-10), 123.5 (C-1′), 124.4 (C-6), 124.6 (C-5),
129.3 (C-2′/6′), 133.4 (C-7), 138.1 (C-3), 145.6 (C-2), 154.4 (C-9), 160.4
(C-4′), 172.5 (C-4). MS (70eV): m/z (%) 268 (100) [M+], 253 (21) [M+
–CH3], 225 (16) [253–CO], 197 (23), 92 (20) [C7H8], 77 (33) [C6H5+], 63
(22), 51 (26).
3-Hydroxy-2-(2-methoxyphenyl)-4H-chromen-4-one (2)
scavenger properties have been suggested as another mode of
Method B; yield 3.5 g (26%); mp 213–214 °C (213–214 °C [18]). 1H-NMR
(200 MHz, CDCl3): δ 3.88 (s, 3H, OCH3), 6.48 (s, 1H, OH), 7.07 (d, 1H, J
= 8.3 Hz, 3′-H aromat.), 7.11 (ddd, 1H, J = 7.5 Hz, 1.0 Hz, 5′-H aromat.),
7.41 (ddd, 1H, J = 8.0 Hz, 6.9 Hz, 1.2 Hz, 6-H aromat.), 7.48 (ddd, 1H, J =
8.3 Hz, 7.5 Hz, 1.8 Hz, 4′-H aromat.), 7.52 (d, 1H, J = 8.1 Hz, 8-H aromat.),
7.59 (dd, 1H, J = 7.5 Hz, 1.8 Hz, 6′-H aromat.), 7.68 (ddd, 1H, J = 8.6 Hz,
6.9 Hz, 1.7 Hz, 7-H aromat.), 8.28 (dd, 1H, J = 8.0 Hz, 1.7 Hz, 5-H aromat.).
13C-NMR (50.3 MHz, CDCl3): δ 56.0 (OCH3), 112.0 (C-3′), 118.5 (C-8),
119.9 (C-1′), 120.7 (C-5′), 121.5 (C-10), 124.3 (C-6), 125.6 (C-5), 131.0
(C-4′), 132.0(C-6′), 133.3(C-7), 138.9 (C-3), 145.9 (C-2), 156.1 (C-9), 157.6
(C-2′), 173.3 (C-4). MS (70 eV): m/z (%) 268 (49) [M+], 237 (20) [M+
–OCH3], 147 (12), 121 (100) [C7H5O2+], 91 (12) [C7H7+], 77 (13) [C6H5+],
65 (13).
[28, 29]
action for flavonols
. However, none of the alkoxyfla-
vonols displayed any radical scavenger activity (data not
shown). Recently, flavonoids have been described as inhibi-
tors of cytokine-induced endothelial cell adhesion protein
[30]
expression
.
Acknowledgement
The financial support of A.M. Sobottka by the Deutscher Akademischer
Austauschdienst (DAAD) is gratefully acknowledged.
Experimental
3-Hydroxy-7-methoxy-2-phenyl-4H-chromen-4-one (3)
Chemistry
Method A; yield 1.9 (12%); mp 177–178 °C (178–179 °C [18]). 1H-NMR
(200 MHz, CDCl3): δ (ppm) = 3.90 (s, 3H, OCH3), 6.90–6.98 (m, 2H, H
aromat.), 7.19 (s, 1H, OH), 7.43–7.55 (m, 3H, H aromat.), 8.11 (d, 1H, J =
8.9 Hz, 5-H aromat.), 8.19–8.23 (m, 2H, H aromat.). 13C-NMR (50.3 MHz,
CDCl3): δ (ppm) = 55.8 (OCH3), 99.9 (C-8), 114.7 (C-10), 114.8 (C-6), 126.8
(C-5), 127.5 (C-2′/6′), 128.6 (C-3′/5′), 129.9 (C-4′), 131.3 (C-1′), 138.2
(C-3), 144.2 (C-2), 157.4 (C-9), 164.3 (C-7), 172.9 (C-4). MS (70 eV): m/z
(%) 268 (100) [M+], 240 (6) [M+ –CO], 225 (14) [240–CH3], 105 (30), 77
(18) [C6H5+], 63 (17), 51 (10).
Melting points were determined on a Reichert melting point apparatus and
are uncorrected. NMR spectra were recorded on a Varian Gemini 200
(Varian, Bremen, Germany). Chemical shifts are reported in ppm relative to
tetramethylsilane. EI mass spectra were obtained on a Finnigan MAT 44S,
with an ionization voltage of 70 eV. Elemental analyses were performed at
the Elemental Analytical Laboratory, Department of Chemistry, University
of Münster, and were within ±0.4% of the theoretical values. TLC was
performed on silica gel 60 F254 plates from Merck (Darmstadt, Germany).
The starting materials were obtained from commercial sources and used
without purification. The lipophilicity of the compounds was estimated by
calculation of log P values on a Macintosh Power PC using the ClogP 2.0
program (Biobyte Corp., Claremont, CA, USA).
2-(3,4-Dimethoxyphenyl)-3-hydroxy-4H-chromen-4-one (4)
Method B; yield 6.0 g (40%); mp 199–203 °C (201–202 °C [31]). 1H-NMR
(200 MHz, CDCl3): δ 3.97 (s, 3H, OCH3), 3.99 (s, 3H, .OCH3), 7.01 (d, 1H,
J = 8.4 Hz, 5′-H aromat.), 7.04–7.10 (bs, 1H, OH), 7.40 (ddd, 1H, J = 8.1 Hz,
6.9 Hz, 1.2 Hz, 6-H aromat.), 7.58 (dd, 1H, J = 8.5 Hz, 0.7 Hz, 8-H aromat.),
7.69 (ddd, 1H, J = 8.6 Hz, 6.9 Hz, 1.7 Hz, 7-H aromat.), 7.84–7.92 (m, 2H,
2′/6′-H aromat.), 8.24 (dd, 1H, J = 8.0 Hz, 1.7 Hz, 5-H aromat.). 13C-NMR
(50.3 MHz, CDCl3): δ 56.0 (OCH3, 56.1 (OCH3), 111.1, 111.2 (C-2′; C-5′),
118.2 (C-8), 120.8 (C-10), 121.6 (C-6′), 123.99 (C-1′), 124.5; 125.6 (C-5;
C-6), 133.4 (C-7), 137.8 (C-3), 145.2 (C-2), 149.0 (C-3′), 150.9 (C-4′), 155.3
General Synthetic Procedures for Compounds 1–13
Method A
A solution of 10 g (0.25 mol) NaOH in 10 ml water was added to 0.1 mol
of the 2-hydroxyacetophenone and 0.1 mol of the benzaldehyde derivative
in 100 ml ethanol and stirred at room temperature or refluxed for 1–4 h. The
reaction was monitored by TLC. Without extensive purification the resulting
Arch. Pharm. Pharm. Med. Chem. 333, 205–210 (2000)

208
Scriba and co-workers
(C-9), 173.2 (C-4). MS (70eV): m/z (%) 298 (100) [M+], 283 (77) [M+ –CH3],
269 (23), 255 (86) [283–CO], 227 (34), 212 (31) [227 –CH3], 149 (36), 121
(81) [C7H5O2+], 105 (42), 92 (65) [C7H8+], 77 (51) [C6H5+], 63 (91), 51 /68).
-OCH
2CH3), 6.91 (d, 1H, J = 9.2 Hz, 5′-H aromat.), 7.31 (ddd, 1H, J = 8.0 Hz,
6.9 Hz, 1.3 Hz, 6-H aromat.), 7.48 (d, 1H, J = 8.2 Hz, 8-H aromat.), 7.60
(ddd, 1H, J = 8.5 Hz, 6.9 Hz, 1.2 Hz, 7-H aromat.), 7.76–7.80 (m, 2H, 2′/6′-H
aromat.), 8.15 (dd, 1H, J = 7.8 Hz, 1.2 Hz, 5-H aromat.). 13C-NMR
(50.3 MHz, CDCl3): δ 14.8 (CH3), 14.9 (CH2), 64.5 (CH2), 64.9 (CH2), 112.7
(C-2′), 113.2 (C-5′), 118.2 (C-8), 120.8 (C-10), 121.7 (C-6′), 123.6 (C-1′),
124.5 (C-6), 125.5 (C-5), 133.4 (C-7), 137.9 (C-3), 145.4 (C-2), 148.5 (C-3′),
150.8 (C-4′), 155.3 (C-9), 173.2 (C-4). MS (70 eV): m/z (%) = 326 (100)
[M+], 298 (20) [M+ –C2H4], 269 (47) [298 –C2H5], 241 (14) [269 –CO], 213
(7), 185 (5), 121 (9) [C7H5O2+], 65 (6), 55 (5). Anal. (C19H18O5).
3-Hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (5)
Method A; yield 5.0 g (20%); mp 192–196 °C (193–194 °C [18]). 1H-NMR
(200 MHz, CDCl3: δ 3.88 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.92 (d, 1H,
J = 2.2 Hz, 8-H aromat.), 6.97 (dd, 1H, J = 8.8 Hz, 2.2 Hz, 6-H aromat.), 7.03
(dd, 2H, J = 7.1 Hz, 2.0 Hz, 3′/5′-H aromat.), 8.11 (d, 1H, J = 8.8 Hz, 5-H
aromat.), 8.19 (dd, 2H, J = 7.1 Hz, 2.0 Hz, 2′/6′-H aromat.). 13C-NMR (50.3
MHz, CDCl3): δ 55.4 (OCH3), 55.8 (OCH3), 99.9 (C-8), 112.4 (C-10), 114.1
(C-3′/5′), 114.6 (C-6), 123.8 (C-1′), 126.7 (C-5), 129.2 (C-2′/6′), 137.3 (C-3),
144.6 (C-2), 157.2 (C-9), 160.9 (C-4′), 164.1 (C-7), 172.6 (C-4). MS (70 eV):
m/z (%) 298 (84) [M+], 283 (100) [M+ –CH3], 269 (17) [283 –CH2], 255 (64)
[2883 –CO], 227 (2), 149 (23), 135 (50) [C8H7O2+], 119 (27), 107 (25), 92
(23) [C7H8+], 77 (25) [C6H5+], 63 (47), 51 (20).
2-(4-Butoxyphenyl)-3-hydroxy-4H-chromen-4-one (10)
Method B; yield 1.3 g (32%); mp 145–147°C. 1H-NMR (200 MHz,
CDCl3): δ 0.99 (t, 3H, J = 7.2 Hz, -CH3), 1.43–1.61 (m, 2H, -CH2), 1.74–1.88
(m, 2H, -CH2), 4.04 (t, 2H, J = 6.5 Hz, -OCH2), 7.02 (dd, 2H, J = 7.0 Hz,
2.1 Hz, 3′/5′-H aromat.), 7.38 (ddd, 1H, J = 8.0 Hz, 6.9 Hz, 1.2 Hz, 6-H
aromat.), 7.55 (dd, 1H, J = 8.5 Hz, 0.7 Hz, 8-H aromat.), 7.67 (ddd, 1H, J =
8.5 Hz, 6.9 Hz, 1.7 Hz, 7-H aromat.), 8.21 (dd, 2H, J = 7.0 Hz, 2.1 Hz, 2′/6′-H
aromat.), 8.23 (dd, 1H, J = 8.1 Hz, 1.4 Hz, 5-H aromat.). 13C-NMR
(50.3 MHz, CDCl3): δ 13.8 (CH3), 19.3 (CH2), 31.2 (CH2), 67.9 (OCH2),
114.6 (C-3′/5′), 118.1 (C-8), 121.8 (C-10), 123.3 (C-1′), 124.4 (C-6), 125.4
(C-5), 129.5 (C-2′/6′), 133.3 (C-7), 137.6 (C-3), 145.5 (C-2), 155.3 (C-9),
160.7 (C-4′), 173.1 (C-4). MS (70 eV): m/z (%)310 (97) [M+], 254 (100) [M+
–C4H8], 253 (46) [M+ –C4H9], 237 (5), 197 (5), 57 (12). Anal. (C19H18O4).
3-Hydroxy-2-(2,3,4-trimethoxyphenyl)-4H-chromen-4-one (6)
Method B; yield 7.0 g (43%); mp 228–232 °C. 1H-NMR (200 MHz,
CDCl3): δ 3.92 (s, 3H, .OCH3), 3.94 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.61
(s, 1H, OH), 6.82 (d, 1H, J = 8.7 Hz, 5′ or 6′-H aromat.), 7.37 (d, 1H, J =
8.7 Hz, 5′ or 6′-H aromat.), 7.42 (ddd, 1H, J = 8.1 Hz, 7.0 Hz, 1.2 Hz, 6-H
aromat.), 7.51 (d, 1H, J = 8.6 Hz, 8-H aromat.), 7.69 (ddd, 1H, J = 8.6 Hz,
6.9 Hz, 1.7 Hz, 7-H aromat .), 8.28 (dd, 1H, J = 8.0 Hz, 1.7 Hz, 5-H aromat.).
13C-NMR (50.3 MHz, CDCl3): δ 56.2 (CH3), 60.9 (CH3), 61.6 (CH3), 107.5
(C-5′), 117.6 (C-1′), 118.2, 118,4 (C-8; C-6′), 121.4 (C-10), 124.4 (C-6),
125.6 (C-5), 133.3 (C-7), 138.7 (C-3), 142.8(C-3′), 145.8(C-2), 152.5(C-4′),
155.8; 155.9 (C-9; C-2′), 173.3 (C-4). MS (70 eV): m/z (%) 328 (41) [M+],
297 (36) [M+ –OCH3], 207 (20), 179 (62), 121 (100) [C7H5O2+], 92 (20)
[C7H8+], 77 (24) [C6H5+] 65 (23), 63 (20), 51 (19). Anal. (C18H16O6).
2-(3-Butoxyphenyl)-3-hydroxy-4H-chromen-4-one (11)
Method B; yield 2.1 g (13%); mp 91–92 °C. 1H-NMR (200 MHz, CDCl3):
δ 1.00 (t, 3H, J = 7.3 Hz, CH3), 1.44–1.62 (m, 2H, CH2), 1.75–1.89 (m, 2H,
CH2), 4.04 (t, 2H, J = 6.5 Hz, OCH2), 7.00 (ddd, 1H J = 8.3 Hz, 1.1 Hz,
0.9 Hz, 4′-H aromat.), 7.15 (s, 1H, OH), 7.40 (ddd, 1H, J = 8.0 Hz, 6.9 Hz,
1.2 Hz, 6-H aromat.), 7.42 (dd, 1H J = 8.2 Hz, 7.8 Hz, 5′-H aromat.), 7.57
(dd, 1H, J = 8.5 Hz, 0.8 Hz, 8-H aromat.), 7.69 (ddd, 1H, J = 8.5 Hz, 6.9 Hz,
1.6 Hz, 7-H aromat.), 7.81 (s, 1H, 2′-H aromat.), 7.83 (d, 1H J = 7.8 Hz, 6′-H
aromat.), 8.24 (dd, 1H, J = 8.0 Hz, 1.7 Hz, 5-H aromat.). 13C-NMR
(50.3 MHz, CDCl3): δ 13.9 (CH3), 19.3 (CH2), 31.3 (CH2), 67.9 (OCH2),
113.9; 116.5 (C-2′; C-4′), 118.3 (C-8′), 120.1 (C-6′), 120.6 (C-10), 124.5
(C-6), 125.5 (C-5), 129.6 (C-5′), 132.3 (C-1′), 133.6 (C-7), 138.6 (C-3=,
144.8 (C-2), 155.4 (C-9),159.2 (C-3′), 173.5 (C-4). MS (70 eV): m/z (%) 310
(64) [M+], 254 (100) [M+ –C4H8], 253 (73) [M+ –C4H9], 237 (18), 226 (14)
[254–CO], 197 (13), 121 (16) [C7H5O2+], 77 (14) [C6H5+], 65 (13, 59 (26),
55 (18). Anal. (C19H18O4).
2-(4-Ethoxyphenyl)-3-hydroxy-4H-chromen-4-one (7)
Method B; yield 0.6 g (25%); mp 173–174 °C. 1H-NMR (200 MHz,
CDCl3): δ 1.46 (t, 3H, J = 7.0 Hz, OCH2-CH3), 4.11 (q, 2H, J = 7.0 Hz,
-OCH2-CH3), 7.02 (dd, 2H, J = 7.0 Hz, 2.1 Hz, 3′/5′-H aromat.), 7.39 (ddd,
1H, J = 8.1 Hz, 6.9 Hz, 1.3 Hz, 6 H aromat.), 7.55 (dd, 1H, J = 8.5 Hz, 0.8 Hz,
8-H aromat.), 7.68 (ddd, 1H, J = 8.5 Hz, 6.9 Hz, 1.6 Hz, 7-H aromat.), 8.22
(dd, 2H, J = 7.0 Hz, 2.1 Hz, 2′/6′-H aromat.), 8.24 (dd, 1H, J = 8.1 Hz, 1.6 Hz,
5-H aromat.). 13C-NMR (50.3 MHz, CDCl3): δ 14.8 (CH3), 63.6 (OCH2),
114.6 (C-3′/5′), 118.2 (C-8), 120.8 (C-10), 123.4 (C-24,41 (C-6),125.4 (C-5),
129.5 (C-2′/6′), 133.3 (C-7), 137.7 (C-3), 145.5 (C-2), 155.3 (C-9), 160.5
(C-4′), 173.2 (C-4). MS (70 eV): m/z (%) = 282 (100) [M+], 253 (75) [M+
–C2H5], 225 (12), 197 (25) [225 –CO], 121 (18) [C7H5O2+], 77 (19) [C6H5+],
65 (22). Anal. (C18H14O4).
2-(3,4-Di-butoxyphenyl)-3-hydroxy-4H-chromen-4-one (12)
Method B; yield 4.0 g (21%); mp 96–97 °C. 1H-NMR (200 MHz, CDCl3):
δ 1.00 ( t, 3H, J = 7.3 Hz, CH3), 1.01 (t, 3H, J = 7.3 Hz, CH3), 1.46–1.64 (m,
4H, CH2-CH2), 1.78–1.92 (m, 4H, CH2-CH2), 4.09 (t, 2H, J = 6.5 Hz, OCH2),
4.12 (t, 2H, J = 6.5 Hz, OCH2), 7.00 (d, 1H, J = 9.2 Hz, 5′-H aromat.), 7.07
(s, 1H, OH), 7.39 (ddd, 1H, J = 8.0 Hz, 6.9 Hz, 1.3 Hz, 6-H aromat.), 7.56
(d, 1H, J = 8.5 Hz, 8-H aromat), 7.68 (ddd, 1H, J = 8.5 Hz, 6.8 Hz, 1.7 Hz,
7-H aromat.), 7.83–7.88 (m, 2H, 2′/6′-H aromat.), 8.23 (dd, 1H, J = 8.0 Hz,
1.3 Hz, 5-H aromat.). 13C-NMR (50.3 MHz, CDCl3): δ 13.9 (CH3), 14.0
(CH3), 19.3 (CH2/CH2), 31.3 (CH2), 31.4 (CH2), 68.8 (OCH2), 69.3 (OCH2),
113.0 (C-2′), 113.6 (C-5′), 118.2 (C-8), 120.8 (C-10), 121.7 (C-6′), 123.6
(C-1′), 124.4 (C-6), 125.5 (C-5), 133.3 (C-7), 137.8 (C-3), 145.4 (C-2), 148.9
(C-3′), 151.2 (C-4′), 155.3 (C-9), 173.1 (C-4). MS (70 eV): m/z (%)382 (31)
[M+],326 (28), 270 (100) [326–C4H8], 269 (36) [326–C4H9], 241 (10), 213
(8) [241–CO], 121 (16) [C7H5O2+], 65 (10), 57 (29), 55 (16). Anal.
(C23H26O5).
2-(3-Ethoxyphenyl)-3-hydroxy-4H-chromen-4-one (8)
Method B; yield 3.7 g (29%); mp 160–161 °C. 1H-NMR (200 MHz,
CDCl3): δ 1.46 (t, 3H, J = 7.0 Hz, -OCH2-CH3), 4.11 (q, 2H, J = 7.0 Hz,
-OCH2-CH3), 6.99 (ddd, 1H, J = 8.3 Hz, 1.1 Hz, 0.9 Hz, 4′-H aromat.), 7.16
(s, 1H, OH), 7.39 (ddd, 1H, J = 8.0 Hz, 6.9 Hz, 1.2 Hz, 6-H aromat.), 7.41
(dd, 1H, J = 8.2 Hz, 7.7 Hz, 5′-H aromat.), 7.55 (ddd, 1H, J = 8.6 Hz, 1.2 Hz,
0.5 Hz, 8-H aromat.), 7.68 (ddd, 1H, J = 8.6 Hz, 6.9 Hz, 1.7 Hz, 7-H aromat.),
7.81 (s, 1H, 2′-H aromat.), 7.82 (d, 1H, J = 7.7 Hz, 6′-H aromat), 8.23 (dd,
1H, J = 8.0 Hz, 1.7 Hz, 5-H aromat.). 13C-NMR (50.3 MHz, CDCl3): δ 14.8
(CH3], 63.7 (OCH2), 113,9; 116.5 (C-2′; C-4′), 118.3 (C-8), 120.2 (C-6′),
120,.6 (C-10), 124.5 (C-6), 125.5 (C-5), 129.6 (C-5′), 132.3 (C-1′), 133.6
(C-7), 138.6 (C-3), 144.7 (C-2), 155.4 (C-9), 159.0 (C-3′), 173.5 (C-4). MS
(70 eV): m/z (%) = 282 (100) [M+], 267 (31) [M+ -CH3], 253 (54) [267 –CH2],
237 (21) [M+ –OC2H5], 226 (14), 197 (16) [226–CO–H], 141 (16), 121 (16)
[C7H5O2+], 92 (17) [C7H8+], 77 (16) [C6H5+], 65 (17). Anal. (C18H14O4).
2-(4-Benzyloxyphenyl)-3-hydroxy-4H-chromen-4-one (13)
Method B; yield 6,4 g (54%); mp 178–179 °C (176.5–177.5 °C [32]).
1H-NMR (200 MHz, CDCl3): δ 5.14 (s, 2H, OCH2), 7.10 (dd, 2H, J = 7.1 Hz,
2.1 Hz, 3′/5′-H aromat.), 7.29–7.48 (m, 6H, H aromat.), 7.54 (dd, 1H, J =
8.5 Hz, 0.7 Hz, 8-H aromat.), 7.67 (ddd, 1H, J = 8.5 Hz, 6.9 Hz, 1.7 Hz, 7-H
aromat.), 8.22 (dd, 2H, J = 7.1 Hz, 2.1 Hz, 2′/6′-H aromat.), 8.23 (d, 1H, J =
8.0 Hz, 5-H aromat.). 13C-NMR (50.3 MHz, CDCl3): δ 70.2 (OCH2), 115.1
2-(3,4-Diethoxyphenyl)-3-hydroxy-4H-chromen-4-one (9)
Method B; yield 1.0 g (34%); mp 148–150 °C. 1H-NMR (200 MHz,
CDCl3): δ 1.42 (t, 3H, J = 7.0 Hz, -OCH2CH3), 1.43 (t, 3H, J = 7.0 Hz,
-OCH2CH3), 4.11 (q, 2H, J = 7.0 Hz, -OCH2CH3), 4.12 (q, 2H, J = 7.0 Hz,
Arch. Pharm. Pharm. Med. Chem. 333, 205–210 (2000)

Flavonol Derivatives
209
(C-3′/5′), 118.2 (C-8), 120.9 (C-10), 123.9 (C-1′), 124.4 (C-6), 125.5 (C-5),
127.5 (C-2′′/6′′), 128.2 (C-4′′), 128.7 (C-3′′/5′′), 129.6 (C-2′/6′), 133.4 (C-7),
136.6 (C-1′′), 137.8 (C-3), 145.8 (C-2), 155.4 (C-9), 160.4 (C-4′), 173.2
(C-4). MS (70 eV): m/z (%) = 344 (13) [M+], 253 (6), 91 (100) [C7H7+], 65
(12).
138.5 (C-3), 146.2 (C-4′), 147.2 (C-2), 155.0 (C-9), 173.4 (C-4). MS (70 eV):
m/z (%) 286 (100) [M+], 269 (11) [M+ –OH], 213 (11), 121 (27) [C7H5O2],
92 (15) [C7H8+], 77 (11) [C6H5+], 64 (12).
Pharmacology
Wistar rats weighing 150–200 g of either sex were housed at room
temperature with free access to rat chow and water. The animals were
anaesthetized by i.p. injection of pentobarbitone. The edema were induced
by a subplantar injection of 0.1 ml of a solution containing 300 mg car-
rageenin in isotonic saline into the right hind paw. Injection of 0.1 ml saline
into the left hind paw served as control. A dose of 25 mg/kg of the test
compounds in saline/Tween 80 (90:10, v/v) was administered i.p. 1 h prior
to the experiments. The control group received only the vehicle. The paw
volume was measured right before and 1, 2 and 4 h after the carrageenin
General Method for the Preparation of 14–18
0.9–2.9 mmol of the respective methoxyflavonol were refluxed in 5–10 ml
57% hydroiodic acid in a darkened flask. The reaction was monitored by
TLC. After cooling to room temperature the precipitate was removed by
filtration, washed with water and recrystallized from ethanol.
3-Hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (14)
Yield 0.20 g (59%); mp 282–285 °C (282–284 °C [18]). 1H-NMR
(200 MHz, CDCl3): δ 6.96 (dd, 2H, J = 8.8 Hz, 2.8 Hz, 3′/5′-H aromat.), 7.46
(ddd, 1H, J = 8.0 Hz, 6.3 Hz, 1.6 Hz, 6-H aromat.), 7.71–7.84 (m, 2H, 7/8-H
aromat.), 8.09–8.15 (m, 3H, 2′/5/6′-H aromat.), 9.67 (bs, 1H, OH). 13C-NMR
(50.3MHz, CDCl3):δ 115.4(C-3′/5′), 118.1 (C-8), 121.3; 121.9 (C-10; C-1′),
124.3; 124.6 (C-6; C-5), 129.5 (C-2′/6′), 133.3 (C-7), 137.7 (C-3), 146.1
(C-2), 154.3 (C-9), 159.1 (C-4′), 172.4 (C-4). MS (70 eV): m/z (%) 254 (100)
[M+], 226 (12), 197 (24) [226–CO–H], 121 (36) [C7H5O2+], 105 (13), 93
(17), 77 (20) [C6H5+], 65 (48), 51 (20).
injection using a plethysomograph modified according to Winder et al. [21]
.
In Vitro Enzyme Inhibition
Platelets and polymorphonuclear leucocytes were isolated from bovine
blood and incubated with the compounds as described [24]. 0.8 ml of a
suspension of the respective cells was preincubated with 2.5 ml of a solution
of the flavonols in DMSO for 10 min at 37 °C. The cells were stimulated by
the addition of calcium ionophore A 23187 (final concentration 20 mM). The
incubations were quenced by the addition of a mixture of acetonitrile/metha-
nol (1:1, v/v), cooled to 0 °C and centrifuged at 4000 g for 15 min at 0 °C.
Following solid phase extraction 12-hydroxyheptadecatrienoic acid, leuk-
otriene B4, and 12-hydroxyeicosatetraenoic acid were analyzed by HPLC
3-Hydroxy-2-(2-hydroxyphenyl)-4H-chromen-4-one (15)
Yield 0.34 g (46%); mp 205–207 °C (204–206 °C [18]). 1H-NMR
(200 MHz, CDCl3): δ 6.91–7.03 (m, 2H, H aromat.), 7.36 (ddd, 1H, J =
1.2 Hz, 7.3 Hz, 8.1 Hz, 6-H aromat.), 7.44–7.51 (m, 2H, H aromat.), 7.62 (d,
1H, J = 8.3 Hz, 8-H aromat.), 7.77 (ddd, 1H, J = 1.2 Hz, 7.1 Hz, 8.3 Hz, 7-H
aromat.), 8.16 (d, 1H, J = 7.9 Hz, 5-H aromat.), 9.77 (bs, 1H OH). 13C-NMR
(50.3MHz, CDCl3):δ 116.4(C-3′), 118.3; 118.7(C-8; C-5′), 121.9 (C-1′/10),
124.2 (C-6), 124.7 (C-5), 130.8(C-4′), 131.3 (C-6′), 133.3 (C-7), 138.8 (C-3),
147.5 (C-2), 155.0; 155.3 (C-2′; C-9), 172.7 (C-4). MS (70 eV): m/z (%) 254
(69) [M+], 237 (100) [M+ –OH], 134 (12), 121 (35) [C7H5O2+], 77 (18),
[C6H5+], 65 (20), 59 (15), 51 (15).
[24]
.
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Yield 0.25 g (58%); mp 241–242 °C (241–242 °C [33]). 1H-NMR
(200 MHz, CDCl3): δ 6.93 (ddd, 1H, J = 8.0 Hz, 1.5 Hz, 0.8 Hz, 4′-H
aromat.), 7.38 (t, 1H, J = 8.0 Hz, 5′-H aromat.), 7.49 (ddd, 1H, J = 8.0 Hz,
6.7 Hz, 1.2 Hz, 6-H aromat.), 7.67–7.87 (m, 4H, 2′/6′/7/8-H aromat.), 8.14
(dd, 1H, J = 8.0 Hz, 1.2 Hz, 5-H aromat.), 9.60 (s, 1H, OH), 9.80 (s, 1H, OH).
13C-NMR (50.3 MHz, CDCl3): δ 114.5 (C-2′), 117.0 (C-4′), 118.2; 118.4
(C-8; C-6′), 121.2 (C-10), 124.4; 124.7 (C-6; C-5), 129.4 (C-5′), 132.4 (C-1′),
133.6 (C-7), 139.0 (C-3), 145.2 (C-2), 154.5 (C-9), 157.2 (C-3′), 172.9 (C-4).
MS (70 eV): m/z (%) = 254 (100) [M+], 237 (18) [M+ –OH], 197 (19), 121
(24) [C7H5O2+], 93 (14, 77 (20) [C6H5+], 65 (29), 51 (23).
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2-(3,4-Dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one (17)
Yield 0.20 g (44%); mp 295–297 °C (293–296 °C [18]). 1H-NMR
(200 MHz, CDCl3): δ 6.90 (d, 1H, J = 8.5 Hz, 5′-H aromat.), 7.43 (dd, 1H,
J = 6.9 Hz, 7.5 Hz, 6-H aromat.), 7.57–7.75 (m, 4H, 2′/6′/7/8-H aromat.),
8.08 (d, 1H, J = 7.4 Hz, 5-H aromat.), 9.30 (s, 1H, OH), 9.59 (s, 1H, OH).
13C-NMR (50.3 MHz, CDCl3): δ 115.2; 115.6 (C-2′; C-5′), 118.1 (C-8),
119.9 (C-6′), 121.2 (C-10), 122.3 (C-1′), 124.3; 124.6 (C-5;, C-6), 133.3
(C-7), 137.8(C-3), 145.0(C-3′), 146.1 (C-2), 147.6 (C-4′), 154.3 (C-9), 172.4
(C-4). MS (70 eV): m/z (%) 270 (100)[M+], 253 (6) [M+ –OH], 242 (5) [M+
–CO], 213 (5) [242–CO–H], 65 (3).
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Yield 0.15 g (57%); mp 295–300 °C. 1H-NMR (200 MHz, CDCl3): δ 7.32
(s, 2H, 2′/6′-H aromat.), 7.46 (ddd, 1H, J = 1.2 Hz, 6.9 Hz, 8.0 Hz, 6-H
aromat.), 7.67 (d, 1H, J = 8.5 Hz, 8-H aromat.), 7.79 (ddd, 1H, J = 1.7 Hz,
6.9 Hz, 8.5 Hz, 7-H aromat.), 8.10 (dd, 1H, J = 1.3 Hz, 8.0 Hz, 5-H aromat.),
9.23 (bs, 3H, OH). 13C-NMR (50.3 MHz, CDCl3): δ 108.2 (C-2′/6′), 118.8
(C-8), 121.6; 121.9 (C-10; C-1′), 125.3 (C-5/6), 134.4 (C-7), 136.5 (C-3′/5′),
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Arch. Pharm. Pharm. Med. Chem. 333, 205–210 (2000)

210
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