Synthesis and anticancer effect of chrysin derivatives

Article abstract of DOI:10.1016/S0960-894X(02)01081-8

A series of chrysin derivatives, prepared by alkylation, halogenation, nitration, methylation, acetylation and trifluoromethylation, were tested in vitro against human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma (HT-29) cells. Among these derivatives of chrysin, 5,7-dimethoxy-8-iodochrysin 3 and 8-bromo-5-hydroxy-7-methoxychrysin 11 have the strongest activities against SGC-7901 and HT-29 cells, respectively. 5,7-Dihydroxy-8-nitrochrysin 12 were found to have strong activities against both SGC-7901 and HT-29 cells.

Full text of DOI:10.1016/S0960-894X(02)01081-8

Bioorganic & Medicinal Chemistry Letters 13 (2003) 881–884
Synthesis and Anticancer Effect of Chrysin Derivatives
Xing Zheng,a Wei-Dong Meng,a Yang-Yan Xu,b Jian-Guo Caob and Feng-Ling Qinga,*
aCollege of Chemistry and Chemical Engineering, Donghua Unversity, 1882 West Yanan Lu, Shanghai 200051, PR China
bCancer Research Institute, Nanhua University, Hengyang, Hunan 421001, PR China
Received 15 October 2002; accepted 12 December 2002
Abstract—A series of chrysin derivatives, prepared by alkylation, halogenation, nitration, methylation, acetylation and tri-
fluoromethylation, were tested in vitro against human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma
(HT-29) cells. Among these derivatives of chrysin, 5,7-dimethoxy-8-iodochrysin 3 and 8-bromo-5-hydroxy-7-methoxychrysin 11
have the strongest activities against SGC-7901 and HT-29 cells, respectively. 5,7-Dihydroxy-8-nitrochrysin 12 were found to have
strong activities against both SGC-7901 and HT-29 cells.
# 2003 Elsevier Science Ltd. All rights reserved.
Chemistry
Introduction
The readily available Chrysin 1 was the starting material
Flavonoids are a broad class of polyphenolic secondary
metabolites abundant in plants and in various common
foods such as apples, onions, tea and red wine. Apart
from their important biological roles in nitrogen fix-
ation and chemical defense, flavonoids possess a broad
range of pharmacological properties including anti-oxi-
dant, anti-cancer, anti-viral and anti-inflammatory
for the preparation of chrysin derivatives. Treatment of
chrysin 1 with CH3I in the presence of K2CO3 gave 5,7-
dimethoxychrysin 2. Iodination of 2 with ICl in the
presence of acetic acid in DMSO provided 5,7-dime-
thoxy-8-iodochrysin 3. Considerable attention has been
given to trifluoromethyl-containing organic compounds
as agrochemical and pharmaceutical agents due to their
unique properties arising from altered electron density,
acidity and lipophilicity.13 Accordingly, we were inter-
ested in the synthesis of trifluoromethylated chrysins.
Treatment of 3 with FSO2CF2CO2Me14 in the presence
of CuI in DMF afforded 5,7-dimethyl-8-trifluoro-
methylchrysin 4 (Scheme 1).
properties.1 Chrysin,
a naturally wide distributed
flavonoid, has been reported to have many different
biological activities such as anti-oxidant,2 anti-virus,3
anti-diabetogenic activity4 and anti-anxiolytic effect.5
Furthermore, chrysin has demonstrated anti-cancer
activities. Chrysin can inhibit the metabolism of the
carcinogen benzo[a]pyrene by hamster embryo cells in
tissue culture6 and markedly augment the cytotoxicity
of TNF (tumor necrosis factor-a).7 Chrysin is also
found to have tyrosinase inhibitory activity,8 and mod-
erate aromatase inhibitory activity.9 Itcan also inhibit
the estradiol-induced DNA synthesis.10 In order to
improve the biological activities of chrysin, a number of
its derivatives had been prepared.1,4,11 Such as C-iso-
prenylated hydrophobic derivatives of chrysin are
potential P-glycoprotein (Pgp) modulators in tumor
cells.12 Herein, we described the synthesis of chrysin
derivatives and their anti-cancer activities against
human gastric adenocarcinoma cell line (SGC-7901)
and colorectal adenocarcinoma (HT-29) cells.
A mixture of 1, acetic anhydride (used as both reactant
and solvent) and a drop of pyridine was heated at reflux
temperature for 7 h to provide 5,7-diacetoxychrysin 5.
However, when the reaction mixture was stirred at
room temperature, 5-hydroxy-7-acetoxychrysin 6 was
obtained. Iodination of 5 and 6 with ICl gave the same
product6,8-diiodo-5-hydroxy-7-aceotxychrysin
fluoromethylation of with FSO2CF2CO2Me/CuI
afforded 6,8-ditrifluoromethyl-5-hydroxy-7-acetoxy-
7. Tri-
7
chrysin 8 (Scheme 2).
Treatment of chrysin 1 with ICl gave 6,8-diiodo-5,7-
dihydroxychrysin 9. The reaction of 1 with Br2/H2O
provided 6,8-dibromo-5,7-dihydroxychrysin 10. How-
ever, bromination of 2 with Br2/H2O resulted in no
reaction and 2 was recovered. Fortunately, bromination
*Corresponding author. Fax: +86-21-6416-6128; e-mail: flq@pub.
sioc.ac.cn
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(02)01081-8

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X. Zheng et al. / Bioorg. Med. Chem. Lett. 13 (2003) 881–884
of
8-bromo-5-hydroxy-7-methoxychrysin 11 (Scheme 3).
2
with N-bromosuccinimide (NBS) afforded
chrysin 12. Under the same reaction conditions, 5,7-
dimethoxychrysin was converted into 8-iodo-5-
hydroxy-7-methoxy-6-nitrochrysin 13 (Scheme 4).
2
Several years ago, Li et al. reported that treatment of
flavone with iodine-cerium(IV)ammonium nitrate (I2/
CAN) in anhydrous CH3CN gave 3-iodoflavone.15
However, when we extended Li’s reaction conditions to
chrysin 1, the reaction was very complicated and the
separation of the reaction mixture by column chroma-
tography proved very tedious. Fortunately, when acetic
acid was used as the solvent instead of CH3CN, the
reaction of 1 with I2/CAN gave 5,7-dihydroxy-8-nitro-
Biological Activity
All the above compounds were tested for their in vitro
anticancer activities against SGC-7901 and HT-29 cells
by MTT-based assay. The assays were performed in 96-
well plates essentially as described by Mosmann.16 The
IC50 concentration represents the concentration which
Scheme 1.
Scheme 2.
Scheme 3.

X. Zheng et al. / Bioorg. Med. Chem. Lett. 13 (2003) 881–884
883
Scheme 4.
results in a 50% decrease in cell growth after 6 days
incubation. The given values are mean values of three
experiments.
stituted chrysin derivatives (8 and 13) were more efficient
for inhibition of HT-29 cells than for SGC-7901 cells.
In conclusion, we have synthesized a series of chrysin
derivatives.17 The preliminary biological activities screen-
ing tests indicated that 8-bromo-5-hydroxy-7-
methoxychrysin 11 was identified as the most potent
anti-HT-29 tumor cells and 5,7-dimethoxy-8-iodochrysin
3 showed the most significant activity against SGC-7901
tumor cells.
Results and Discussion
The pharmacological results were summarized in Table
1 for anti-HT-29 and anti-SGC-7901 cells respectively.
It appeared that these closely related molecules did not
display a remarkable difference in cytotoxicity. As
shown in Table 1, we disclosed that compounds 2, 3, 5,
6, 7, 9, 10, 11 and 12 showed stronger cytotoxicity
towards SGC-7901 cells than chrysin, and compounds
2, 3, 4, 5, 7, 8, 11, 12 and 13 had better inhibitory
activities to HT-29 cells than chrysin. 8-Bromo-5-
hydroxy-7- methoxychrysin 11 was identified as the
most potent anti-HT-29 tumor cells and 5,7-dimethoxy-
8-iodochrysin 3 showed the most significant activity to
SGC-7901 tumor cells. Although general structure–
activity relationship of the chrysin derivatives to anti-
cancer effect was not elucidated from these data, the
following points were noteworthy: (1) The 8-substituted
chrysin derivatives (3, 11 and 12) had stronger activities
against both SGC-7901 and HT-29 tumor cells. (2) The
6,8-dihalo substituted chrysin derivatives (9 and 10)
showed better inhibitory activities against SGC-7901
cells than against HT-29 cells. While the other 6,8-disub-
Acknowledgements
We thank the National Natural Science Foundation of
China and the Ministry of Education of China for
financial support.
References and Notes
1. (a) Flavonoids in Health and Disease Rice-Evans, C. A.,
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2. Chan, E. C. H.; Patchareewan, P.; Owen, L. W. J. Cardio-
vasc. Pharmacol. 2000, 35, 326.
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Saengyak Hakhoechi 1999, 30, 34.
4. Shin, J. S.; Kim, K. S.; Kim, M. B.; Jeong, J. H.; Kim, B. K.
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6. Liu, Y. L.; Ho, D. K.; Cassady, J. M. J. Nat. Prod. 1992,
55, 357.
Table 1. In vitro cytotoxicity against the SGC-7901 and HT-29 cell
lines
7. Hebtemariam, S. J. Nat. Prod. 1997, 60, 775.
8. Kubo, I.; Kinst-Hori, I.; Chaudhuri, S. K.; Kubo, Y.; San-
chez, Y.; Ogura, T. Bioorg. Med. Chem. 2000, 8, 1749.
9. Suresh, C. T.; Leena, S.; Sari, M.; Risto, S. J. Med. Food
1999, 2, 235.
10. Wang, C. F.; Kurzer, M. S. Nutr. Cancer 1998, 31, 90.
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Bioorg. Med. Chem. Lett. 2000, 10, 835.
12. Comte, G.; Daskiewicz, J. B.; Bayet, C.; Conseil, G.;
Viornery-Vanier, A.; Dumontet, C.; Pietro, A.; Barron, D. J.
Med. Chem. 2001, 44, 763.
13. Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
14. (a) Qing, F. L.; Fan, J.; Sun, H.; Yue, X. J. Chem. Soc.
Perkin Trans. 1 1997, 3053. (b) Chen, Q. Y.; Wu, S. W. J.
Chem. Soc., Chem. Commun. 1989, 705.
Compd
SGC-7901 (IC50 mM )
HT-29 (IC50 mM )
1
2
3
4
5
6
7
8
5.8
3.7
2.2
5.9
4.5
3.6
4.2
8.6
2.9
5.1
2.5
2.8
6.4
3.1
2.0
2.6
2.3
2.6
3.8
3.0
2.9
4.4
4.0
1.9
2.3
2.3
9
10
11
12
13

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X. Zheng et al. / Bioorg. Med. Chem. Lett. 13 (2003) 881–884
15. Zhang, F. J.; Li, Y. L. Synthesis 1993, 565.
16. Mosman, T. J. Immunol. Methods 1983, 65, 55.
m), 8.116 (2H, m), 13.575 (1H, s). Anal. calcd for C16H11BrO4:
C, 55.36, H, 3.19; found C, 55.53, H, 3.40. 12 MS (EI, 70 ev)
1
17. All the new compounds were characterized by detailed
spectroscopic analysis. 7 MS (EI, 70 ev) m/z: 548; IR umax
(cmꢀ1, KBr): 1774 (C¼O), 3068 (OH); 1H NMR (300 MHz,
DMSO-d6): 3.293 (3H, s), 7.285 (1H, s), 7.596 (3H, m), 8.159
(2H, m), 13.949 (1H, s). 8 MS (EI, 70 ev) m/z: 432; IR umax
(cmꢀ1, KBr): 1791 (C¼O); 19F NMR (300 MHz) ꢀ55.541,
ꢀ56.692; 1H NMR (300 MHz, DMSO-d6): 3.363 (3H, s), 7.277
(1H, s), 7.702 (3H, m), 8.152 (2H, m). 11 MS (EI, 70 ev) m/z:
m/z: 299; IR umax (cmꢀ1, KBr): 1656 (C¼O), 3068 (OH); H
NMR (300 MHz, DMSO-d6): 6.356 (1H, s), 7.148 (1H, s),
7.579 (3H, m), 7.948 (2H, m). 13C NMR (300 MHz, DMSO-
d6): 98.875 (C-6), 103.124 (C-10), 105.923 (C-3), 121.422 (C-8),
126.357 (C-20,60), 129.279 (C-30,50), 129.880 (C-10), 132.527(C-
40), 149.897 (C-9), 157.961 (C-5), 162.714 (C-2), 163.160 (C-7),
181.235 (C-4). Anal. calcd for C15H9NO6: C, 60.20, H, 3.03,
N, 4.68; Found C, 59.79, H, 3.21, N, 4.65. 13 MS (EI, 70 ev)
m/z: 439; 1H NMR (300 MHz, CDCl3): 4.115 (3H, s), 6.866
(1H, s), 7.570 (3H, m), 7.852 (2H, m), 14.219 (1H, s).
347; IR umax (cmꢀ1, KBr): 1660 (C¼O), 3067 (OH); H NMR
1
(300 MHz, DMSO-d6): 3.968 (3H, s), 7.062 (1H, s), 7.601 (3H,