Synthesis and biological evaluation of flavonoids as vasorelaxant agents

Article abstract of DOI:10.1016/j.bmcl.2004.05.061

Several 5,7-dihydroxyflavone and quercetin 3-O-glycosides have been synthesized and evaluated for vasorelaxant activity. A logP-activity relationship amongst flavonoids was suggested.

Full text of DOI:10.1016/j.bmcl.2004.05.061

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3949–3952
Synthesis and biological evaluation of flavonoids as
vasorelaxant agents
Zhiwei Chen, Yongzhou Hu,* Haohao Wu and Huidi Jiang
Department of Medicinal Chemistry, Zhejiang University, School of Pharmaceutical Science, Hangzhou 310031, PR China
Received 16 April 2004;revised 21 May 2004;accepted 22 May 2004
Available online 17 June 2004
Abstract—Several 5,7-dihydroxyflavone and quercetin 3-O-glycosides have been synthesized and evaluated for vasorelaxant activity.
A log P–activity relationship amongst flavonoids was suggested.
Ó 2004 Elsevier Ltd. All rights reserved.
Flavonoids are a group of polyphenolic compounds
diverse in chemical structure and characteristic, they
occur naturally in fruit, vegetables, nuts, seeds, flowers,
and bark and are an integral part of the human diet.
They have been reported to exhibit a wide range of
biological effects, including antibacterial, antiviral, anti-
inflammatory, antiallergic, and vasodilatory actions. In
addition, flavonoids inhibit lipid peroxidation (LPO)
platelet aggregation, capillary permeability, and fragil-
ity, and the activity of enzyme systems including cyclo-
oxygenase and lipoxygenase.1 There has been a great
deal of interest due to flavonoids beneficial cardiovas-
cular effects in humans.2 Among them, quercetin 10 and
rutin 5 have been shown to cause endothelium-depen-
dent relaxation in the rat aorta,3;4 but the synthesis and
modification of which are surprisingly rarely reported
however.5;6 Our research approach is to use quercetin
and rutin as lead compounds and modify the structure
of these compounds to find more potent vasorelaxant
agents. Herein, we described the synthesis of quercetin
derivatives (or analogs) and their vasorelaxant actions in
the isolated rat thoracic aorta rings.
obtained through selective protection of quercetin with
dichlorodiphenylmethane. Glycosylation of ketal took
place completely at the position 3 using 1 equiv of
K2CO3 as base in DMF that led to 18a–d.8 Cleavage of
diphenylmethylene group was performed with hydro-
genolysis catalyzed by 10% Pd/C. Compound 1 was
afforded by removing the acetyl protecting group using
CH3OH and CH3ONa. Compounds 2, 3, 4 were ob-
tained according to the same procedure as described
above. The large proton coupling (compound 1, 2, 3, 4
J1;2 ¼ 7:2, 7.7, 7.3, 5.2 Hz, respectively) of the anomeric
proton demonstrated that target products 1–4 had
b,b,b,b-configuration.
Compounds 12–16 were prepared from phloroglucinol
(Scheme 2). Condensation of phloroglucinol with ace-
tonitrile catalyzed by ZnCl2 and followed by treatment
with HCl gas provided 2,4,6-trihydroxyacetophenone
19. Compound 19 reacted with an excess of aroyl chlo-
rides 20a–e in the biphasic system under tetrabutyl-
ammonium bromide to get the diarylpropane-1,3-diones
21a–e. The cyclization of 21a–e was carried out in re-
fluxing 5% aqueous potassium carbonate in 6 h then
treated with acetic acid leading to the expected com-
pounds 12–16 in 57–69% yield.9
The structures of the compounds utilized in this study
are indicated in Table 1. Compounds 5–10 were pur-
chased from commercial sources. Compound 11 was
prepared as previously described.7 The synthesis of
compounds 1–4 is shown in Scheme 1. Ketal 17 was
All compounds were evaluated for their vasorelaxant
activities in the rat thoracic aorta rings against PE-in-
duced contractions model.4 After 10À6 mol/L phenyl-
ephrine (PE) induced steady contraction in
endothelium-intact rings, flavonoids (36 lmol/L) were
added. The tension was recorded, and the maximal
relaxation (with standard error, SE) was calculated.
Octanol–water partition coefficients (log P) were
Keywords: 5,7-Dihydroxyflavone;Quercetin 3- O-glycosides;Vaso-
relaxant activity.
* Corresponding author. Tel.: +86-571-87217210;fax: +86-571- 8721-
7412;e-mail: huyz@zjuem.zju.edu.cn
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.061

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Z. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3949–3952
Table 1. Vasorelaxant effects for compounds 1–16 against PE-induced contractions in rat aortic rings
Com-
pound
Structure
Maximal
relaxation (%)
log P
Com-
pound
Structure
Maximal
relaxation (%)
log P
OH
OH
OH
OH
HO
O
O
HO
O
O
1
2
3
4
5
48.6 Æ 2.9
34.0 Æ 4.7
35.1 Æ 3.2
24.7 Æ 4.3
24.7 Æ 2.7
1.28
9
70.2 Æ 2.3
45.9 Æ 2.9
71.6 Æ 7.0
80.8 Æ 5.6
77.2 Æ 5.9
2.30
O-β- D-Glu
OH
OH
OH
OH
OH
OH
HO
O
O
HO
O
1.26
1.44
1.45
1.18
10
11
12
13
2.10
2.42
3.53
3.81
O-β
O-β
O-β
- D-Gal
OH
OH
OH
O
OH
OH
OH
OH
HO
O
O
HO
HO
O
OCH2OCH3
- D-Xyl
OH
O
OH
OH
OH
OCH3
O
O
HO
O
O
- D-Ara
OH
OH
OH
OH
HO
O
CH3
HO
O
O
OH
O
rutinose
OH
HO
HO
O
O
Cl
GluA-O
HO
O
O
6
7
20.1 Æ 2.3
36.2 Æ 3.0
1.74
1.50
14
15
92.7 Æ 4.1
95.0 Æ 2.9
3.90
4.03
OH
OH
Br
Glu-O
HO
O
O
OH
O
OH
O
O
OH
CH
3
O
O
HO
H C
HO
O
O
8
64.4 Æ 3.5
2.99
16
91.3 Æ 3.4
3.36
3
OH
O
OH
OH
Values are expressed as mean Æ SE (n ¼ 8) c ¼ 36 lmol/L.
measured using a reversed-phase HPLC method.10 The
results are listed in Table 1. We found that 8–16 showed
stronger vasorelaxant activity than 2–7. Compound 15,
which has the maximal log P value, was identified as the
most potent vasodilator activity. Although general
structure–activity relationship of those compounds was
not evident, from the data in Table 1, the following
points were noteworthy: (1) The vasorelation actions of
these compounds depended on log P values. In general,
compounds had stronger activity with the augment of
log P values. (2) Glycosylation of quercetin reduced the
vasodilator activity. For example, compound 10 had
stronger activity than 2–5. (3) Comparing 10 with 11, we
found that 3-alkoxy substituted product 11 increased the
vasodilator potency. (4) The lesser vasorelaxant activity
of 10 in comparison to 9, 12–15 suggested that the

Z. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3949–3952
3951
OH
OH
O
O
HO
O
O
Ph 2CCl2
HO
O
O
180˚C , 5min
OH
OH
OH
10
OH
17
O
OH
O
a)10%Pd/C, H2
b)MeONa, MeOH
OH
O-acetylglycosyl bromide
HO
O
O
HO
O
K2CO3/DMF
OR
OR'
OH
OH
O
1-4
18a- d
OH
OH
OH
OAc
OAc
2 R'=
18a R=
AcO
O
18b R=
OAc
1 R'=
O
O
O
HO
HO
HO
D-Galactose
OH
OH
AcO
OAc
AcO
OAc
D-Glucose
OH
3 R'=
HO
18c R=
AcO
OAc
4 R'=
O
O
18d R=
O
O
HO
HO
AcO
OH
OAc
OH
D-Arabinose
AcO
OAc
D-Xylose
Scheme 1.
HO
OH
HO
OH
a)CH3CN/ZnCl2
b)HCl (g)
OH
OH
O
19
HO
OH
O
HO
OH
COCl
a)K2CO3/H2O/benzene
b)(n-C4H9)NBr
R
R
+
OH
O
OH
O
20a- e
21a- e
R
20a R=3 '-OCH3 20b R=4'-CH3
20c R=4'-Cl
HO
O
a)5%K2CO3
20d R=3 '-Br
20e R=3',4'-OCH2O
b)AcOH, ∆
OH
O
12-16
Scheme 2.
presence of the –OH group in position 3 attenuated the
vasorelaxant activity of the flavonoids.
References and notes
1. Cook, N. C.;Sammam, S. J. Nutr. Biochem. 1996, 7, 66.
2. Harbored, J. B.;Williams, C. A. Photochemistry 2000, 55, 481.
3. Chen, C. K.;Pace-Asciak, C. R. Gen. Pharmacol. 1996,
27(2), 363.
4. Ajay, M.;Genial, A. H.;Mustafa, M. R. Life Sci. 2003,
74, 603.
In summary, we have designed and synthesized a series
of quercetin derivatives or analogs.11 These compounds
exert vasodilatory effects that are related to the log P
values. The presence of a sugar substitution reduces the
vasorelaxant actions of these compounds.

3952
Z. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3949–3952
5. Dick, A. J.;Smith, K. C. J. Agric. Food Chem. 1990, 38(4),
923.
6. Demetzos, C.;Skaltsounis, K.;Tillequin, F.;Koch, K.
Carbohydr. Res. 1990, 207, 131.
7. Zhou, J.;Hu, Y. Z. J. Zhejiang Univ. (Med. Sci.) 2002,
31(6), 410.
8. Bouktaib, M.;Atmani, A.;Rolando, C. Tetrahedron Lett.
2002, 43, 6263.
9. Saxena, S.;Makrandi, J. K.;Grover, S. K. Synthesis 1985,
697.
10. Griffin, S.;GrantWyllie, S.;Markham, J. J. Chromatogr.
A. 1999, 864, 221.
11. Selected data for these compounds. Compound 4, IR mmax
(cmÀ1, KBr): 3382, 1656, 1604, 1507, 1499, 1442, 1358,
1300, 1199, 1166, 1069, 1016; 1H NMR (400 MHz,
DMSO-d6): 3.77–3.20 (m, 5H, sugar-H), 4.55 (1H, s,
sugar-OH), 4.68 (1H, s, sugar-OH), 5.22 (1H, s, sugar-
OH), 5.27 (1H, d, J ¼ 5:2 Hz, 100-H), 6.19 (1H, d,
J ¼ 2:0 Hz, 6-H), 6.40 (1H, d, J ¼ 2:0 Hz, 8-H), 6.84
(1H, d, J ¼ 8:4 Hz, 50-H), 7.50 (1H, d, J ¼ 2:2 Hz, 20-H),
7.66 (1H, dd, J ¼ 8:4, 2.2 Hz, 60-H), 9.16 (1H, s, 30-OH),
9.74 (1H, s, 40-OH), 10.88 (1H, s, 7-OH), 12.65 (1H, s,
5-OH); 13C NMR (400 MHz, DMSO-d6): 64.23 (500-C),
66.01 (400-C), 70.66 (300-C), 71.58 (200-C), 93.47 (8-C), 98.62
(6-C), 101.35 (100-C), 103.82 (10-C), 115.23 (20-C), 115.70
(50-C), 120.82 (10-C), 121.95 (60-C), 133.66 (3-C), 144.89
(30-C), 148.52 (40-C), 156.20 (2, 9-C), 161.12 (5-C), 164.15
(7-C), 177.43 (4-C);MS-ESI: 434.1 (M þÀ1). 15, mp
269–271 °C;IR mmax (cmÀ1, KBr): 3443, 1658, 1618,
1569, 1500, 1426, 1356, 1168, 641; 1H NMR (400 MHz,
DMSO-d6): 6.23 (1H, d, J ¼ 2:0 Hz, 6-H), 6.56 (1H, d,
J ¼ 2:0 Hz, 8-H), 7.07 (1H, s, 3-H), 7.51–7.55 (1H, m,
50-H), 7.80 (1H, d, J ¼ 8:8 Hz, 60-H), 8.08 (1H, d,
J ¼ 8:0 Hz, 40-H), 8.27 (1H, s, 20-H), 10.95 (1H, s,
7-OH), 12.76 (1H, s, 5-OH);MS (EI, 70 ev) m=z: 332
(Mþ).