Syntheses of antioxidant flavonoid derivatives

Article abstract of DOI:10.3987/COM-10-S(E)102

Quercetin-caffeic acid and quercetin-curcumin conjugates have been synthesized as potent antioxidants to prevent age-related macular degeneration. Thus, the widely disributed plant antioxidant quercetin was linked to other plant antioxidants, caffeic acid and curucumin, to enhance its antioxidative properties. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)102

HETEROCYCLES, Vol. 82, No. 2, 2011
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HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1151 - 1155. © The Japan Institute of Heterocyclic Chemistry
Received, 4th August, 2010, Accepted, 21st September, 2010, Published online, 22nd September, 2010
DOI: 10.3987/COM-10-S(E)102
SYNTHESES OF ANTIOXIDANT FLAVONOID DERIVATIVES
Emiko Yanase,a Young P. Jang,b and Koji Nakanishi*
Dept. Chem., Columbia University, New York, NY 10027: kn5@columbia.edu
aCurrent address: Faculty of Applied Biological Sciences, Gifu University,
b
Yanagido, Gifu 501-1193 Current address: College of Pharmacy, Kyung Hee
University, Hoegi-dong Dongdaemun-gu, Seoul, Korea 130-701
To celebrate the 85th birthday of Professor Albert Eschenmoser
Abstract – Quercetin-caffeic acid and quercetin-curcumin conjugates have been
synthesized as potent antioxidants to prevent age-related macular degeneration.
Thus, the widely disributed plant antioxidant quercetin was linked to other plant
antioxidants, caffeic acid and curucumin, to enhance its antioxidative properties.
Flavonoids (Figure 1), plant secondary metabolites are also called polyphenols due to the presence of
multiple phenolic hydroxyls. The flavonols, represented by quercetin 1, are the most abundant flavonoid,
and are present in fruits and vegetables either as aglycones or as glycosides. With respect to the their
bioregulatory functions, activities such as antibiotic, antiviral, antiallergic, antimutagenic and
antihypertensive are known.1,2 Most of these activities are due to the antioxidative properties of the
multiple phenolic functions.3-5 The anthocyanins, glycosides of anthocyanidins, are primarily
responsible for various colors of flowers and fruits, are renown for their effect against ocular fatigue
diseases and age-related macular degeneration (AMD).
OH
OH
OH
OH
OH
HO
O
O
HO
O
OH
OGlc
OH
OH
quercetin
anthocyanin
Figure 1. Flavanoids: quercetin and an anthocyanin

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HETEROCYCLES, Vol. 82, No. 2, 2011
In AMD, fluorescent granules accumulate in the macular region or visual focal region due to natural
aging. No efficient remedy is known and in worst cases lead to blindness. So far it has been elucidated
that with aging, A2E6a (Figure 2) biosynthesized within the eye from two molecules of vitamin A and
phosphatidylethanolamine6b accumulates in the retinal pigment epithelium cell and is oxidized to an
unprecedented nonaoxirane7-9; the electrophilic oxiranes react with protein and nucleic acid amino groups
leading to their destruction.
O
O
O
O
O
OH
OH
N
N
O
O
O
O
A2E nonaoxirane
A2E
Figure 2. A2E and A2E nonaoxirane
We have shown that anthocyanins in bilberry are effective in preventing the photooxidation of A2E.10
However, due to the presence of the cationoid oxygen in anthocyanins (Figure 1), they are unstable,
difficult to isolate in large quantities and to modify chemically. We thus investigated the antioxidative
properties of quercetin and its glycoside, renown potent antioxidants. This showed that they exhibited
potent activity against A2E photooxidation (unpublished). We therefore targeted the preparation of
antioxidants that are more potent than known flavonoids. The syntheses of these antioxidants are
reported.
Our plan was to synthesize modified flavonoid derivatives carrying additional functional groups that
would further increase the antioxidant activity of the natural flavonoid. We thus designed quercetin
derivatives connected to other natural products, e.g., the antioxidants caffeic acid and curcumin I, linked
via an appropriate linker (Figure 2).
quercetin
quercetin
OH
OH
OH
HO
O
O
HO
O
O
OH
3
3
curcumin I
O
O
OH
OH
caffeic acid
O
O
MeO
O
OMe
OH
OH
linker
HN
HN
linker
OH
O
O
Quercetin-caffeic acid conjugate
Quercetin-curcumin conjugate
Figure 3. Potent antioxidants

HETEROCYCLES, Vol. 82, No. 2, 2011
1153
Caffeic acid is a component of the polyphenolic chlorogenic acid, while curcumin is the yellow pigment
of the popular Indian curry spice turmeric that exhibits radical scavenging ability.11,12 We expected such
condensation products to enhance both the chemical stability as well as antioxidative activities.
Scheme 1 summarizes the synthesis ofthe quercetin-caffeic acid conjugate 7. The linker was attached to
the quercetin 3-OH, since it was considered that attachment at this position would only exert a small
effect on the antioxidant capability. Quercetin with the protected phenolic hydroxyl was prepared from
rutin, the glycoside of quercetin.13 Benzylquercetin 1 was derivatized to aminoquercetin 2 and then to 3,
in 74% overall yield from 1. The carboxyl group of caffeic acid 4 was converted to activated ester 6 to
form the amide bond with aminoquercetin 3, in 76% overall for the two steps. Finally, coupling of
activated-ester 6 and quercetin derivative 3 followed by hydrolysis of the acetyl-group14 yielded the new
flavonid 7, 67% overall yield for the three steps.
3'
OBn
OBn
4' OH
2'
1'
8
5'
OH
OBn
OBn
BnO
O
O
HO
8b
4a
O
4
2
3
7
6'
Br
BnO
O
O
NHBoc
H2, 10% Pd/C
MeOH, 98%
6
O
O
5
OH
OH
O
1"
K2CO3, DMF, 76%
2"
OH
OH
3"
4"
NHBoc
NHBoc
3
1
2
OAc
OAc
OH
OH
O
OAc WSC, DMF
Ac2O
1M NaOH aq.
O
N
O
HO
HO
OAc
O
O
N
HO
O
O
O
5
4
6
yield 76% (2 steps)
3'
6'
4' OH
2'
1'
8
5'
8b
2
3
HO
O
7
OH
4
6
4a
O
℃
1. 25% HBr/AcOH, 40
5
3
OH
O
1"
2"
11"
12"
2. 6, Et3N, DMF
3. NH4OAc, MeOH, H2O, 40
OH
13"
10"
9"
3"
4"
℃
7"
5"
HN
OH
6"
14"
8"
O
yield 67% (3 steps)
7
Scheme 1. The synthesis of Quercetin-caffeic acid conjugate
Scheme 2 summarizes the synthesis of quercetin-curcumin I conjugate 11. The phenolic hydroxyl in
curcumin I 8 is elongated to the linker attached 9 in 44% overall yield in three steps. The terminal
carboxyl is then converted to activated ester 10. Coupling of 10 with quercetin derivative 3 followed by
hydrolysis of the acetate with ammonium acetate14 afforded the flavonoid 11. Finally, coupling of
activated-ester 10and quercetin derivative 3 followed by hydrolysis of the acetyl group gave the new
flavonid 11.

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HETEROCYCLES, Vol. 82, No. 2, 2011
1. K2CO3, DMF
O
O
O
O
13
7
15
2
5
O
1
MeO
3
16 OMe
14
19
MeO
OMe
Br
9
11
OMe
10
8
12
4
17
OAc
6
O
2. 1M NaOH, Dioxane
3. Ac O, Pyr
18
HO
OH
2
4'
3'
HO
1'
2'
curcumin
9
O
yield 44% (3 steps)
O
O
MeO
O
OMe
OAc
WSC , DMF
O
O
N
HO
O
O
N
10
yield 73%
O
O
3'
6'
2'
1'
OH
OH
4'
5'
8
HO
8b O
2
3
7
1. 25% HBr/AcOH,
40
6
4
℃
4a
O
3
5
OH
O
1"
2. 10, Et
3
N, DMF
2"
O
O
3. NH OAc, MeOH, H2O,
40
4
℃
7c
13c
14c
2c
15c
9c
10c
11c
12c
MeO 3c
9"
16c OMe
1c
6c
3"
4"
5"
8c
7"
6" 8"
17c
OH
4c
HN
19c
O
5c
18c
O
yield 73% (3 steps)
11
Scheme 2
The synthesis of Quercetin-curcumin conjugate
We have thus achieved the syntheses of new type of antioxidants, quercetin/caffeic acid derivative 7 and
quercetin/curcumin derivative 11 from natural flavonoids via an appropriate linker. In addition, this
synthetic approach via linker can be applied to similar types of flavonoid derivatives. We plan to compare
the antioxidant properties of the quercetin derivatives with other known antioxidants. The study of the
antioxidant activity of the mentioned compounds against A2E photooxidation is under study.
ACKNOWLEDGEMENTS
The studies were supported by NIH GM36564 and a grant from Shionogi & Co.
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