Trifluoromethylation of flavonoids and anti-tumor activity of the trifluoromethylated flavonoid derivatives

Article abstract of DOI:10.1016/j.bmcl.2005.07.047

3-Trifluoromethylflavonoid derivatives were prepared for the first time by trifluoromethylation of 3-iodoflavonoid derivatives. Other C ring and B ring trifluoromethylated flavonoid derivatives were also prepared. All the compounds were tested for their effect on the U2OS cell cycle in vitro. Bistrifluoromethylated apigenin derivative 13 showed the strongest activity against the cell growth.

Full text of DOI:10.1016/j.bmcl.2005.07.047

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4456–4458
Trifluoromethylation of flavonoids and anti-tumor activity of the
trifluoromethylated flavonoid derivatives
a
Cai-Ling Wang, Hong-Qi Li, Wei-Dong Meng and Feng-Ling Qing
a
a
a,b,
*
a
Institute of Biological Sciences and Biotechnology, Donghua University, 1882 West Yanan Road, Shanghai 200051, China
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
54 Fenglin Road, Shanghai 200032, China
Received 18 April 2005; revised 5 July 2005; accepted 14 July 2005
Abstract—3-Trifluoromethylflavonoid derivatives were prepared for the first time by trifluoromethylation of 3-iodoflavonoid deriv-
atives. Other C ring and B ring trifluoromethylated flavonoid derivatives were also prepared. All the compounds were tested for their
effect on the U2OS cell cycle in vitro. Bistrifluoromethylated apigenin derivative 13 showed the strongest activity against the cell
growth.
ꢀ
2005 Elsevier Ltd. All rights reserved.
Cancer is one of the most serious threats against human
health in the world. In recent years, there has been grow-
ing interest in the search for anti-cancer substances with
interested in extending SosnovskikhÕs reaction conditions
to the synthesis of C-ring trifluoromethylated flavonoids.
Accordingly, methylation of chrysin 1 and genistein 2
with CH I in the presence of K CO afforded compounds
1
high efficacy, low toxicity, and minimum side effects.
3
2
3
Flavonoids possess a broad range of pharmacological
properties including anti-tumor effects. However, flavo-
noids generally exhibited low activity against tumor
3 and 4, respectively (Scheme 1). Treatment of 3 with
Me SiCF in the presence of a catalytic amount of anhy-
3
3
drous Me NF at 0 ꢁC for 24 h, followed by acid hydroly-
4
cells. It is known that the introduction of the CF group
3
sis, gave the 1,2-nucleophilic addition product 5, whereas
under the same reaction conditions the reaction of com-
pound 4 with Me SiCF proceeded as a 1,4-nucleophilic
into organic molecules often changes their physiological,
physical, and chemical properties without the introduc-
3
3
2
tion of extra steric hindrance. Recent studies carried
a
out in our laboratory have revealed that A-ring and
addition to give compound 6. The different performance
of 3 and 4 in the nucleophilic trifluoromethylation could
be ascribed to the interplay of steric hindrance.
3
3
b
B-ring trifluoromethylated flavonoids exhibited en-
hanced anti-tumor activity. These results have encour-
aged us to study other fluorinated flavonoids. Herein,
we describe the synthesis and anti-tumor activities of
C-ring and B-ring trifluoromethylated flavonoids.
As the first step to prepare 3-trifluoromethylated flavo-
noids, treatment of 3 with LDA, followed by addition
6
of I , produced 3-iodoflavonoid 7 (Scheme 2). Trifluo-
2
romethylation of 7 with FSO CF CO Me/CuI afforded
2
2
2
7
The nucleophilic trifluoromethylation reaction of a car-
bonyl group with trifluoromethyltrimethylsilane (Me3-
SiCF ) is rapidly becoming the method for introduction
of a trifluoromethyl group into organic compounds.
Recently, Sosnovskikh and co-workers reported a
3-trifluoromethyl-5,7-dimethoxychrysin 8. It was inter-
esting to note that the reaction of compound 9 with
LDA, followed by iodination, gave compounds 10 and
11, which were separated by column chromatography.
Trifluoromethylation of 10 and 11 gave products 12
and 13, respectively.
3
4
regioselective nucleophilic 1,4-trifluoromethylation of
5
2
-polyfluoroalkylchromones with Me SiCF . We were
3
3
8
The trifluoromethylated flavonoids 5, 6, 8, 12, and 13
were tested for their inhibitory effects on the cell cycle
of U2OS cells in vitro by the FCM Assay. U2OS cells,
obtained from American Type Culture Collection
(Manassas, VA), were seeded 3 · 10 cells/well in a
Keywords: Flavonoids; Trifluoromethylation.
*
Corresponding author. Tel.: +86 215 492 5187; fax: +86 21 641 66
28; e-mail: flq@mail.sioc.ac.cn
5
1
0
960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.047

C.-L. Wang et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4456–4458
4457
HO
O
O
CH I / K CO MeO
O
3
2
3
1) CF SiMe / Me NF MeO
O
3
3
4
2
) HCl
CF3
OH
OMe O
OMe OH
1
3
5
HO
O
MeO
O
CF3
CH3I / K2CO3 MeO
O
1
) CF3SiMe3 / Me4NF
2
) HCl
OH
O
OMe O
OH
OMe O
OMe
OMe
2
6
4
Scheme 1.
MeO
O
MeO
O
1
) LDA
FSO2CF2CO2Me MeO
CuI
O
2
) I2
I
CF3
OMe O
OMe O
OMe O
3
7
8
I
OMe
) LDA
) I2
OMe
OMe
I
MeO
O
MeO
O
1
MeO
O
+
2
I
OMe O
OMe O
OMe O
9
10
11
FSO2CF2CO2Me
CuI
CuI FSO2CF2CO2Me
CF3
OMe
OMe
MeO
O
MeO
O
CF3
CF3
OMe O
OMe O
1
2
13
Scheme 2.
9
6-well plate. When the density of cells cultured at 37 ꢁC
Table 1. Effect of the trifluoromethylated flavonoids on the cell cycle
of U2OS
reaches 40–50%, each compound was added, respective-
ly, to maintain the concentration of each compound at
5
cell cycle distribution was evaluated with a BD Biosci-
ences FACScan flow cytometer and CellQuest software.
Cells were maintained at 37 ꢁC with 5% CO in DMEM
supplemented with 10% fetal bovine serum (FBS). The
pharmacological activity of all compounds against the
U2OS cell cycle is shown in Table 1. Compound 13,
the bistrifluoromethylated apigenin derivative, showed
the strongest inhibitory effect on U2OS cells in the G2/
M phase. Compound 5 had so strong a cytotoxicity that
Compound
Content of cell cycle (%)
S
00 nM. The suspensions were incubated for 24 h. The
G
1
G
2
/M
a
Control
b
5
48.21
—
41.90
—
9.89
2
—
6
8
46.69
53.06
44.09
55.08
48.02
31.95
49.24
44.92
5.29
14.99
6.67
12
1
3
0.00
a
Negative control added 1%DMSO.
In the concentration, all the cell died.
b

4458
C.-L. Wang et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4456–4458
all the cells were killed at the test concentration. Com-
pounds 6 and 12 showed some activities and compound
Sosnovskikh, V. Y.; Sevenard, D. V.; Usachev, B. I.;
R o¨ schenthaler, G. V. Tetrahedron Lett. 2003, 44, 2097.
. Costa, A. M. B. R. C. S.; Dean, F. M.; Jones, M. A.;
Varma, R. S. J. Chem. Soc. Perkin Trans. 1 1985, 799.
. (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.
6
7
8
had the lowest activity in the series. From the above
results, it seems reasonable to conclude that: (1) B-ring
trifluoromethylated flavonoids showed stronger inhibi-
tory effects on U2OS cells than C-ring trifluoromethylat-
ed flavonoids and (2) the strong cytotoxicity of
compound 5 is attributed, at least partly, to the existence
of the 4-hydroxy group.
8
. All the new compounds were characterized by the detailed
spectroscopic analysis. 5: m.p. 100–101 ꢁC; MS (EI, 70 eV)
m/z: 352 (M , 16), 335 (9), 332 (13), 321 (14), 105 (100), 77
+
(
30); IR (KBr): 3298 (OH), 2962, 2844, 1655, 1612, 1517,
1
In conclusion, we have synthesized a series of trifluo-
romethylated flavonoid derivatives. The preliminary
1436, 1354; H NMR (400 MHz, CDCl
.89 (3H, s), 5.38 (1H, s), 5.66 (1H, s), 6.36 (1H, d,
J = 2.32 Hz), 6.45 (1H, d, J = 2.32 Hz), 7.42–7.44 (3H, m),
3
): 3.71 (3H, s),
3
0
0
biological activity screening tests indicated that 3 ,5 -
bistrifluoromethylapigenin derivative 13 was the most
active compound against U2OS cells.
1
9
7
.76–7.78 (2H, m); F NMR (376 MHz): ꢀ81.60. Anal.
Calcd. for C18 : C, 61.36 H, 4.26. Found: C, 61.55
H, 4.12. 6: m.p. 127–128 ꢁC; MS (EI, 70 eV) m/z: 382
15 4 3
H O F
+
(
M ), 181 (13), 180 (100), 152 (19), 137 (15); IR (KBr):
1
1
(400 MHz, CDCl ): 3.75 (3H, s), 3.78 (1H, d, J = 3.4 Hz),
674 (C@O), 1612, 1572, 1513, 1469, 1427; H NMR
Acknowledgment
3
3
(1H, d, J = 2.24 Hz), 6.30 (1H, d, J = 2.24 Hz), 6.77–6.80
.83 (3H, s), 3.89 (3H, s), 4.97 (1H, q, J = 3.4 Hz), 6.18
We thank the National Natural Science Foundation of
China, the Ministry of Education of China and Shanghai
Municipal Scientific Committee for funding this work.
1
9
(
2H, m), 7.13–7.16 (2H, m);
73.56. Anal. Calcd. for C19
Found: C, 59.26 H, 4.56. 8: m.p. 166–167 ꢁC; MS (EI
F NMR (376 MHz):
ꢀ
17 5 3
H O F : C, 59.69 H, 4.45.
+
7
0 eV) m/z: 350 (M , 14), 151 (15), 100 (23), 87 (100), 77
(
11); IR (KBr): 1655 (C@O), 1635, 1611, 1474, 1449, 1425,
1
355; H NMR (300 MHz, CDCl
References and notes
1
s), 6.39-6.42 (1H), 6.44–6.47 (1H), 7.53–7.56 (5H, m);
3
): 3.88 (3H, s), 3.96 (3H,
1
9
F
1
. (a) Kumar, S. K.; Hager, E.; Pettit, C.; Gurulingappa, H.;
Davidson, N. E.; Khan, S. R. J. Med. Chem. 2003, 46, 2813;
NMR (282 MHz): ꢀ59.28. Anal. Calcd. for C H O F :
1
8
13
4 3
C, 61.71 H, 3.71. Found: C, 61.75 H, 4.12. 12: m.p. 186–
+
(
b) Wang, Y. Q.; Yuan, H. L.; Wang, H.; Wright, S. C.;
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1
11, 4069.
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2
3
. Welch, J. T. Tetrahedron 1987, 43, 3123.
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1
9
J = 8.7 Hz); F NMR (282 MHz): ꢀ56.18. Anal. Calcd.
for C H O F : C, 60.00 H, 3.95. Found: C, 59.53 H,
15
1
9
5 3
+
4.17. 13: m.p. 159–160 ꢁC; MS (EI 70 eV) m/z: 448 (M ,
6); IR (KBr): 1655 (C@O), 1634, 1611, 1467, 1450, 1355;
H NMR (400 MHz, CDCl ): 3.89 (3H, s), 4.02 (3H, s),
4.05 (3H, s), 6.44 (1H, s), 6.99 (1H, d, J = 2.04 Hz), 7.01
(1H, d, J = 2.04 Hz), 7.60-7.62 (2H);
4
. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757;
1
(
(
b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613;
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3
1
9
112, 123; (d) Qiu, X. L.; Qing, F. L. J. Org. Chem. 2002, 67,
F
NMR
7
162; (e) Langlois, B. R.; Billard, T. Synthesis 2003, 185.
(376 MHz): ꢀ54.11 (3F, s), ꢀ56.30 (3F, s). Anal. Calcd.
5
. (a) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.;
R o¨ schenthaler, G. V. J. Org. Chem. 2003, 68, 7747; (b)
for C H O F : C, 53.57 H, 3.13. Found: C, 52.99 H,
2
0
14
5 6
3.43.