Synthesis and preliminary biological evaluation of chrysin derivatives as potential anticancer drugs

Article abstract of DOI:10.2174/157340610791208763

A series of chrysin derivatives were prepared from 2-hydroxyacetophenone, 2,4-dihydroxyacetophenone, 2,4,6-trihydroxy- acetophenone, using modified Baker-Venkataraman transformation. Their anticancer activities in vitro were evaluated by the standard MTT method. The results of biological test showed that some of chrysin derivatives showed stronger anticancer activity than 5-fluorouracil.

Full text of DOI:10.2174/157340610791208763

6
Medicinal Chemistry, 2010, 6, 6-8
Synthesis and Preliminary Biological Evaluation of Chrysin Derivatives as
Potential Anticancer Drugs
Xing Zheng1,*, Fei Fei Zhao1, Yun Mei Liu, Xu Yao, Zi Tong Zheng, Xing Luo and
Duan Fang Liao
Institute of Pharmacy & Pharmacology, University of South China, Hengyang 421001, China
Abstract: A series of chrysin derivatives were prepared from 2-hydroxyacetophenone, 2,4-dihydroxyacetophenone, 2,4,6-
trihydroxy- acetophenone, using modified Baker-Venkataraman transformation. Their anticancer activities in vitro were
evaluated by the standard MTT method. The results of biological test showed that some of chrysin derivatives showed
stronger anticancer activity than 5-fluorouracil.
INTRODUCTION
acetate gave 5-methoxy-flavones 4a-4c and 5,7-dimethoxy-
flavones 4d-4h, respectively. Reaction of 2-hydroxy-
acetophenone 2c with substituted benzoyl chlorides followed
by the flavone ring formation in same conditions gave the
flavone analogues 4i-4m.
Chrysin, a natural flavonoid widely distributed in plants,
has been reported to have various biological activities such
as anticancer [1], anti-inflammatory [2], anti-oxidant [3],
anti-anxiolytic [4], vasodilatory actions [5]. In anticancer
area, chrysin has been found to possess anti-proliferative
activity through inhibiting malignant cell growth by down-
regulated expression of PCNA in Hela cells [6], and induced
apoptosis through caspase activation and Akt inactivation in
U937 cells [7]. However, the anticancer activity of chrysin in
vivo studies on animals and humans has been disappointing
mainly due to extremely poor oral bioavailability [8]. The
crucial feature of chrysin in this respect is their unprotected
hydroxyl groups, which are rapidly and efficiently metabo-
lized via glucuronidation and sulfation [9]. As a part of our
current work on the search for anticancer substances with
high efficacy, low toxicity and minimum of side effects [10-
12], herein, we describe the synthesis of chrysin derivatives
and their anticancer activities against human gastric carci-
noma SGC-7901, human colon cancer HT-29, and human
promyelocytic leukemia HL-60 cell lines.
All the new compounds were characterized by detailed
o
spectroscopic analysis. 4a White powder, mp 142-143 C.
HRFABMS m/z 321.0733 [M+H]+ (C17H11F3O3, calc.
321.0738). IR (cm-1, KBr): 1365, 1438, 1501, 1589, 1613,
1642(C=O), 2948, 2976; 1H NMR (300MHz, CDCl3):
3.967(3H, s), 6.815(1H, s), 7.007-7.047(2H, m), 7.648-
7.701(1H, m), 7.791-7.817(1H, m), 8.065-8.091(1H, m),
8.139-8.171(1H, m), 8.194(1H, s). 4d White powder, mp
156-157 oC. HRFABMS m/z 351.0839 [M+H]+ (C18H13F3O4,
calc. 351.0844). IR (cm-1, KBr): 1390, 1437, 1460, 1489,
1
1602, 1614, 1653(C=O), 2945, 2971; H NMR (300MHz,
CDCl3): 3.942(3H, s), 3.973(3H, s), 6.308(1H, d, J = 2.1Hz),
6.718(1H, d, J = 2.1Hz), 6.745(1H, s), 7.617-7.670(1H, m),
7.760-7.788(1H, m), 8.023-8.050(1H, m), 8.150(1H, s). 4f
o
White powder, mp 186-187 C. HRFABMS m/z 317.0586
[M+H]+ (C17H13O4Cl, calc. 317.0580). IR (cm-1, KBr): 1417,
1
1459, 1487, 1584, 1605, 1660(C=O), 2847, 2944; H NMR
(300MHz, CDCl3): 3.920(3H, s), 3.964(3H, s), 6.392(1H, d,
J = 2.4Hz), 6.566(1H, d, J = 2.4Hz), 6.653(1H, s), 7.454-
7.500(2H, m), 7.788-7.834(2H, m). 4h White powder, mp
SYNTHESIS CHRYSIN DERIVATIVES
Among the reported methods to synthesize flavonoids,
the Baker-Venkataraman transformation is a largely applied
one. The synthesis of compounds 4a-4m were carried out
according to modified Baker-Venkataraman transformation
(Fig. 1). Commercially available 2,4-dihydroxyacetophenone
1a and 2,4,6-trihydroxyaceto- phenone 1b were treated with
anhydrous potassium carbonate and dimethyl sulfate in ace-
tone to give 2a and 2b, respectively. 2a and 2b were reacted
with substituted benzoyl chlorides in the anhydrous potas-
sium carbonate in acetone to afford the corresponding 1,3-
diketones 3a-3c and 3d-3h, respectively. Treatment of 3a-3c
and 3d-3h with glacial acetic acid and anhydrous sodium
o
177-178 C. HRFABMS m/z 313.1076 [M+H]+ (C18H16O5,
calc. 313.1075 ). IR (cm-1, KBr): 1429, 1458, 1493, 1574,
1592, 1601, 1634(C=O), 2954; 1H NMR (300MHz, CDCl3):
3.900(3H, s), 3.933(3H, s), 3.958(3H, s), 6.367(1H, d, J =
2.1Hz), 6.535(1H, d, J = 2.1Hz), 7.012-7.060(2H, m), 7.082-
7.110(1H, m), 7.423-7.481 (1H, m), 7.853-7.885(1H, m) 4i
o
White needles, mp 146-147 C. HRFABMS m/z 291.0633
[M+H]+ (C16H9F3O2, calc. 291.0632). IR (cm-1, KBr): 1382,
1
1445, 1466, 1577, 1605, 1625, 1667(C=O), 3139; H NMR
(300MHz, CDCl3): 6.879(1H, s), 7.437-7.491(1H, m), 7.609-
7.831(4H, m), 8.090-8.120(1H, m), 8.202-8.268(2H, m).
BIOLOGICAL ACTIVITY
*Address correspondence to this author at the Institute of Pharmacy &
Pharmacology, University of South China, Hengyang 421001, China; Tel:
+86-734-8281408; Fax: +86-734-8281239;
All of the chrysin derivatives were tested for their anti-
cancer activity in vitro against HL-60, HT-29 and SGC-7901
cells by MTT-Based Assay, using 5-Fluorouracil as control.
E-mail :zhengxing5018@yahoo.com
1These two authors contributed equally to this article.
1573-4064/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Synthesis and Preliminary Biological Evaluation
Medicinal Chemistry, 2010, Vol. 6, No. 1
7
R2
OH
R2
OH
O
R2
OH
b
a
R
R1
O
O
R1
R1
O
3a-3c R1 = H, R2 = OMe
3d-3h R1 = R2 = OMe
3i-3m R1 = R2 = H
2a R1 = H, R2 = OMe
2b R1 = R2 = OMe
2c R1 = R2 = H
1a R1 = H, R2 = OH
1b R1 = R2 = OH
R
R2
O
c
R1
O
4a-4c R1 = H, R2 = OMe
4d-4h R1 = R2 = OMe
4i-4m R1 = R2 = H
R : = 3'-CF3, 4'-NO2, 4'-Cl, 4'-OMe, 2'-OMe
Fig. (1). Reagents and conditions: (a) dimethyl sulfate, K2CO3, acetone, rt; (b) substituted benzoyl chlorides, K2CO3, acetone, reflux; (c) NaOAc, HAc, reflux.
Table 1. The Structures and Anticancer Activities of the Target Compounds In Vitro
IC50 ( μmol/L)
÷
R1
R2
R
HL-60
HT-29
SGC-7901
4a
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
3'-CF3
4'-NO2
4'-Cl
5.38
5.56
6.19
5.86
5.78
3.57
6.89
2.46
4.86
6.08
12.05
12.24
13.28
6.25
6.15
14.92
7.98
5.28
4b
4c
H
6.92
4.37
4d
OMe
OMe
OMe
OMe
OMe
H
3'-CF3
4'-NO2
4'-Cl
3.03
3.80
4e
5.29
5.81
4f
5.00
5.22
4g
4'-OMe
2'-OMe
3'-CF3
4'-NO2
4'-Cl
11.37
16.57
13.03
8.84
10.16
14.90
14.00
11.79
8.33
4h
4i
4j
H
H
4k
H
H
6.34
4l
4m
H
H
4'-OMe
2'-OMe
18.45
11.98
12.92
15.56
9.88
H
H
5-Fluorouracil
9.56
The assays were performed in 96-well plates essentially as
described by Mosmann [13].
these data, the following points were noteworthy: (1) com-
pound 4d was the most active one, showing a significant
activity toward all the tested cell lines. This is probably due
to the presence of CF3 at 3'-position which is the most elec-
As shown in Table 1, although general structure-activity
relationship of these compounds was not elucidated from

8
Medicinal Chemistry, 2010, Vol. 6, No. 1
Zheng et al.
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Only compounds 4b, 4d, 4e showed better inhibitory activity
towards SGC-7901 cell than 5-fluorouracil.
[4]
[5]
[6]
[7]
In conclusion, we have synthesized a series of chrysin
derivatives. The preliminary biological activity screening
tests indicated that 4d was the most active compound against
all the tested cell lines.
[8]
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ACKNOWLEDGMENTS
This research was supported by the Key Project of Chi-
nese Ministry of Education.(No. 20809), Fund of Hunan
Provincial Education Department (No. 2008-269-132), Sci-
entific Research Fund of Hunan Provincial Education De-
partment (No. 07B065) Science and Technology Bureau of
Hunan Province (No. 2007FJ4155), and Hunan Provincial
Natural Science Foundation (No. 07JJ6157).
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Received: August 30, 2009
Revised: December 12, 2009
Accepted: December 13, 2009