Synthesis and topoisomerase II inhibitory and cytotoxic activity of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.11.037

In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested. Compound 25 inhibited MCF7 (IC₅₀: 0.49 ± 0.21 μM) and HCT15 (IC₅₀: 0.23 ± 0.02 μM) carcinoma cell growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound 25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 μM concentrations. Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25 can be a possible lead compound for anticancer drug impeding the topoisomerase II function.

Full text of DOI:10.1016/j.bmcl.2010.11.037

Bioorganic & Medicinal Chemistry Letters 21 (2011) 211–214
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and topoisomerase II inhibitory and cytotoxic activity
of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives
Younghwa Na a, , Jung-Min Nam b
⇑
a College of Pharmacy, Catholic University of Daegu, Gyeongsan, Gyeongbuk 712-702, Republic of Korea
b College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed
and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their
pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds
prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested.
Received 13 September 2010
Revised 20 October 2010
Accepted 4 November 2010
Available online 12 November 2010
Compound 25 inhibited MCF7 (IC50: 0.49 0.21 lM) and HCT15 (IC50: 0.23 0.02 lM) carcinoma cell
growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were
inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound
25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 lM concentrations.
Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25
can be a possible lead compound for anticancer drug impeding the topoisomerase II function.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chalcone
Retrochalcone
Topoisomerase II
Anticancer agents
Oxiranylmethoxychalcone
Thiiranylmethoxychalcone
Topoisomerases are essential cellular enzymes necessary for
cell proliferation by solving topological hurdles during DNA
replication process.1 Topoisomerase enzymes are divided into
two types, type I and II, depending on the DNA cleavage pattern.
Topoisomerase I mediates the breaking and rejoining of single
strand of DNA duplex to relax the supercoiled condition of chromo-
somes. On the other hand, topoisomerase II produces the relaxa-
tion of DNA double helices by scissoring and rejoining two
strands. These critical role of topoisomerase enzymes during the
proliferative process introduced topoisomerases to be one of the
major targets for anticancer drug development. To date, numerous
compounds have been reported to inhibit topoisomerases inhibi-
tory activity. Among these compounds, normal chalcone were
reported to inhibit only topoisomerase II, but not I, while retroch-
alcone was found to inhibit topoisomerase I.2 Retrochalcones,3
missing 20 and 60-hydroxy group from normal chalcone core, are
unusual phenolic compound family and Glycyrrhiza inflata is a ma-
jor source for these compounds. Recently, licochalcone A (1) and E
(2), members of retrochalcone, have shown potent topoisomerase I
inhibitory activity.4
5
OH
4
OH
6
5'
4'
HO
HO
6'
3
1
2
OMe
OMe
3'
1'
2'
O
O
Licochalcone E (2)
Licochalcone A (1)
O
O
OH
O
O
O
O
N
O
O
S
O
3
4
Previously we reported that substitution of epoxide (3) or
thioepoxide (4) on the xanthone derivatives could engender the
selectivity on the topoisomearase I and II enzyme function.5
In order to extend the scaffold of the anticancer drug candidates
targeting topoisomerase enzyme, we have designed and synthe-
sized chalcone derivatives substituted with epoxide or thioepoxide
groups.
First the starting chalcone and retrochalcone were prepared
employing with the known methods.6 Chalcone compounds were
subsequently reacted with epichlorohydrin (3 equiv) or epit-
⇑
Corresponding author. Tel.: +82 53 850 3616; fax: +82 53 850 3602.
E-mail address: yna7315@cu.ac.kr (Y. Na).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.11.037

212
Y. Na, J.-M. Nam / Bioorg. Med. Chem. Lett. 21 (2011) 211–214
hiochlrohydrin (1.5 equiv) under K2CO3 basic condition in the ace-
tone and DMF (1:1) to give oxiranylmethoxy- and thiiranylmeth-
oxy-chalcone derivatives 8, 9, 14 and 15. Chlorohydrin
compounds 10 and 16 were generated after treatment of corre-
sponding epoxide compounds 8 and 14 with 3 M HCl in aqueous
EtOAc (Scheme 1).
Bisoxiranylmethoxy- and bisthiiranylmethoxy-chalcone deriva-
tives were prepared with excess amounts of epichlorohydrin
(6 equiv) or epithiochlrohydrin (4 equiv) under K2CO3 or Cs2CO3
basic condition (Scheme 2). Analytical data of the compounds pre-
pared were described in the reference section.7
and etoposide as positive controls.5c Data were analyzed and eval-
uated with LabWork 4.5 Software to calculate the inhibition ratio.
Test results were indicated in Figure 1 and Table 2. In the topoiso-
merase I relaxation assay, none of the compounds were active. This
observation is conflict on the previous reports that retrochalcones
are efficient topoisomerase I inhibitor,2 which means that substit-
uents on the retrochalcones affect the topoisomerase I inhibitory
activity. But most compounds inhibited topoisomerase II function
moderately. Compound 25 was most active inhibitor on topoiso-
merase II enzyme with comparable extent to etoposide at
100 lM concentration. This observation suggests that proximity
All the compounds prepared were evaluated for the cytotoxicity
against several human cancer cell lines using adriamycin, etopo-
side and camptothecin as references. Typical MTT assay procedure
was employed for the test.5c The result is indicated in Table 1. Most
compounds showed moderate cytotoxic activity on the cancer cell
lines tested. Of the compounds, compound 25 showed most potent
cytotoxic activity over the tested cancer cell lines. Compound 25
of the two thiiranylmethoxy groups enhance the inhibitory func-
tion of the chalcone compound on topoisomerase II.
In conclusion, we have designed and synthesized 10
oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives and
evaluated their pharmacological activity. Most compounds showed
moderate cytotoxicity and topoisomerase II inhibitory activity but
were inactive to topoisomerase I function. Compound 25 exhibited
consistent pharmacological activity between cytotoxicity and
topoisomerase II inhibition, which implicates the topoisomerase
II inhibition of the compound 25 on the cytotoxicity. Our findings
suggest that elaborate optimization of the chalcone structure with
oxiranylmethoxy- and thiiranylmethoxy-groups can produce po-
inhibited MCF7 (IC50
:
0.49 0.21
lM) and HCT15 (IC50:
0.23 0.02
references.
lM) carcinoma cell growth more efficiently than
Topoisomerases relaxation inhibitory activities were evaluated
using human topoisomerase I and II (Topogen) with camptothecin
A
OH
CH3O
CH3O
O
O
1) NaOH, EtOH
+
CH3
2) 4M-HCl
OHC
O
O
7
5
6
K2CO3, acetone/DMF
Epichlorohydrin or
Epithiochlorohydrin
O
O
3M-HCl/EtOAc
CH3O
CH3O
HO
X
Cl
O
10
O
8 X = O
9 X = S
B
OCH3
HO
O
O
1) NaOH, EtOH
2) 4M-HCl
OCH3
+
CH3
OHC
O
O
13
12
11
K2CO3, acetone/DMF
Epichlorohydrin or
Epithiochlorohydrin
OCH3
3M-HCl/EtOAc
OCH3
O
O
X
OH
Cl
O
O
16
14X = O
15X = S
Scheme 1. Synthetic methods for mono-epoxide analogues.

Y. Na, J.-M. Nam / Bioorg. Med. Chem. Lett. 21 (2011) 211–214
213
A
O
B
O
O
O
O
O
OCH3
+
+
CH3
CH3
OHC
OHC
R
OH
O
O
6
R = H
11
23
17R = OCH3
1) NaOH, EtOH
2) 4M-HCl
1) Ba(OH)2, EtOH
2) 4M-HCl
OH
OCH3
HO
HO
R
O
OH
O
18R = H
24
19R = OCH3
K2CO3, acetone/DMF
Epichlorohydrin or
Epithiochlorohydrin
Cs2CO3, acetone/DMF
Epithiochlorohydrin
O
OCH3
O
O
X
R
X
S
O
O
O
20R = H, X = O
21R = H, X = S
22R = OCH3, X =O
S
25
Scheme 2. Synthetic methods for bis-epoxide analogues.
Table 1
Result of cytotoxicity of compounds synthesized against various cancer cells
a
Compound/cells
IC50
(
lM)
MCF
K562
DU145
HCT15
Adriamycin
Etoposide
Camptothecin
1.69 0.12 1.33 0.11
1.98 0.28 1.21 0.16
2.43 0.31 0.59 0.02
1.75 0.24
1.44 0.50
0.61 0.13
1.25 0.13
2.03 0.24
0.80 0.15
8
9
10.86 0.14 33.47 0.19 36.89 1.38 30.43 0.51
11.46 0.17 32.49 1.40 >50 28.42 0.48
11.64 0.26 27.95 1.61 43.30 1.26 27.13 0.94
14
15
10
16
20
21
22
25
23.58 0.29 >50
19.41 0.25
10.08 1.11
20.55 1.62
20.46 1.17
18.50 0.86
12.19 0.68
4.82 0.14
0.23 0.02
29.15 3.00 29.07 1.65 >50
18.45 0.16 16.23 3.06 >50
3.87 0.00 7.27 0.73
>50
21.71 0.70 13.39 1.16 >50
3.64 0.02 13.66 0.78 >50
Figure 1. Topoisomerase
Compounds were examined in a final concentration of 20 and 100
I
(A) and II (B) inhibitory activities of compounds.
M, respectively,
0.49 0.21 7.60 0.38
1.07 0.59
l
a
as designated. (A) Lane D: pBR322 only, Lane T: pBR322 + Topo I, Lane C:
pBR322 + Topo I + camptothecin, Lanes 1–10: pBR322 + Topo I + compounds in
order of 8, 9, 14, 15, 10, 16, 20, 21, 22, and 25. (B) Lane D: pBR322 only, Lane T:
pBR322 + Topo II, Lane E: pBR322 + Topo II + etoposide, Lanes 1–10: pBR322 + Topo
II + compounds as the same as the order of (A).
Each data point represents mean SD from three different experiments per-
formed in triplicate.
tential anticancer drug candidates targeting on topoisomerase II
enzyme. But topoisomerase II inhibitory activities of compound
25 might not directly related to the corresponding cytotoxicities,
which implies that we can’t exclude the possibility that additional
targets can be involved in the mechanism of action of compound
25.

214
Y. Na, J.-M. Nam / Bioorg. Med. Chem. Lett. 21 (2011) 211–214
143.9, 160.5, 163.5, 188.9 ppm; EI-MS: m/e 310.2 [M]+. Compound 9: Yield
Table 2
45.9%; Rf: 0.69 (EtOAC/n-hexane = 1:1); mp 106–108 °C; 1H NMR (400 MHz,
CDCl3) d 2.35 (d, J = 5.2 Hz, 1H), 2.64 (dd, J = 5.2 Hz, 1H), 3.28–3.31 (m, 1H), 3.90
(s, 3H), 3.98 (dd, J = 10.0, 6.8 Hz, 1H), 4.25 (dd, J = 10.0, 5.6 Hz, 1H), 6.94 (d,
J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 15.6 Hz, 1H), 7.61 (d, J = 8.4 Hz,
2H), 7.78 (d, J = 15.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
24.1, 31.4, 55.6 (55.7), 72.8 (72.9), 114.0, 115.1, 115.2, 120.1, 128.6, 130.4, 130.9,
131.0, 131.5, 143.7, 143.8, 160.4, 163.5, 188.9 ppm; EI-MS: m/e 326.1 [M]+.
Topoisomerase I and II inhibitory activities of compounds
Compound
Topo I (% inhibition)
100
Topo II (% inhibition)
l
M
100
—
l
M
20
—
lM
Camptothecin
Etoposide
8
9
14
15
10
16
20
21
22
25
64.30
—
61.85
22.03
31.55
28.79
31.55
30.10
34.88
33.46
34.65
28.52
61.00
38.03
15.18
15.50
17.58
14.75
14.01
16.27
19.34
18.01
13.96
20.77
Compound 10: Yield 76.2%; Rf: 0.24 (EtOAC/n-hexane = 1:1); mp 106–108 °C; 1
H
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
NMR (400 MHz, CDCl3) d 2.64 (d, J = 5.6 Hz, 1H), 3.75 (dd, J = 11.2, 5.6 Hz, 1H),
3.80 (dd, J = 11.2, 7.2 Hz, 1H), 3.89 (s, 3H), 4.14–4.18 (m, 2H), 4.23–4.28 (m, 1H),
6.96 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 15.6 Hz, 1H), 7.61 (dd,
J = 8.8 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) 46.1, 55.6, 68.8, 70.0, 114.0, 115.2, 120.2, 128.8, 130.3, 130.4,
130.9, 131.0, 131.5, 143.7, 143.8, 160.2, 163.6, 189.0 ppm; EI-MS: m/e 346.1
[M]+. Compound 14:8 Yield 74.6%; Rf: 0.42 (EtOAC/n-hexane = 1:1); mp 80–82 °C;
1H NMR (400 MHz, CDCl3) d 2.79–2.80 (m, 1H), 2.93–2.95 (m, 1H), 3.39 (br s,
1H), 3.86 (s, 3H), 4.03 (dd, J = 10.8, 5.6 Hz, 1H), 4.33 (dd, J = 10.8, 2.4 Hz, 1H),
6.94 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 15.6 Hz, 1H), 7.60 (d,
J = 8.4 Hz, 2H), 7.78 (d, J = 15.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) 44.8, 50.1 (50.2), 55.5 (55.7), 69.0 (69.1), 114.5, 114.6, 119.6,
119.8, 128.0, 130.3, 130.4, 130.9, 131.0, 132.0, 144.1, 144.2, 161.7, 162.2,
188.9 ppm; EI-MS: m/e 310.1 [M]+. Compound 15: Yield 34.8%; Rf: 0.41 (EtOAC/
n-hexane = 1:2); mp 116–118 °C; 1H NMR (400 MHz, CDCl3) d 2.36 (dd, J = 5.2,
1.2 Hz, 1H), 2.64 (dd, J = 6.0 Hz, 1H), 3.28–3.32 (m, 1H), 3.86 (s, 3H), 4.02 (dd,
J = 10.0, 6.8 Hz, 1H), 4.27 (dd, J = 10.0, 5.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.99 (d,
J = 8.8 Hz, 2H), 7.43 (d, J = 15.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.79 (d,
J = 15.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) 24.0, 31.2,
55.6, 72.9, 114.5, 114.6, 114.7, 119.7, 128.0, 130.4, 130.9, 131.0, 132.0, 144.2,
161.8, 162.2, 188.9 ppm; EI-MS: m/e 326.1 [M]+. Compound 16: Yield 76.2%; Rf:
0.27 (EtOAC/n-hexane = 1:1); mp 84–86 °C; 1H NMR (400 MHz, CDCl3) d 2.63 (d,
J = 6.4 Hz, 1H), 3.77 (dd, J = 11.2, 5.6 Hz, 1H), 3.82 (dd, J = 11.2, 5.6 Hz, 1H), 3.87
(s, 3H), 4.18 (d, J = 2.4 Hz, 1H), 4.19 (d, J = 1.6 Hz, 1H), 4.28 (quint, J = 5.6 Hz, 1H),
6.95 (dd, J = 6.8, 1.6 Hz, 2H), 7.01 (dd, J = 6.8, 1.6 Hz, 2H), 7.42 (d, J = 16.0 Hz, 1H),
7.61 (dd, J = 6.8, 2.4 Hz, 2H), 7.79 (d, J = 16.0 Hz, 1H), 8.04 (d, J = 6.8, 2.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) 46.1, 55.6 (55.7), 68.9, 69.9, 114.6, 127.9, 130.3,
130.4, 130.9, 131.0, 132.2, 144.4, 161.8, 162.0, 189.0 ppm; EI-MS: m/e 346.1
[M]+. Compound 20:9 Yield 45.7%; Rf: 0.06 (EtOAC/n-hexane = 1:2); mp 110–
112 °C; 1H NMR (400 MHz, CDCl3) d 2.77–2.80 (m, 2H), 2.92–2.96 (m, 2H), 3.37–
3.41 (m, 2H), 4.00 (dd, J = 11.2, 6.0 Hz, 1H), 4.04 (dd, J = 10.8, 5.6 Hz, 1H), 4.30
(dd, J = 11.2, 3.2 Hz, 1H), 4.33 (dd, J = 10.8, 3.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H),
7.01 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 15.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.78 (d,
J = 15.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) 44.8, 50.1,
69.0, 114.6, 115.2, 115.3, 120.0, 128.5, 130.4, 130.9, 131.0, 132.0, 143.9, 160.5,
162.3, 188.9 ppm; EI-MS: m/e 352.2 [M]+. Compound 21: Yield 15.0%; Rf: 0.72
(EtOAC/n-hexane = 1:1); mp 120–122 °C; 1H NMR (400 MHz, CDCl3) d 2.34–2.37
(m, 2H), 2.63–2.65 (m, 2H), 3.26–3.33 (m, 2H), 3.98 (dd, J = 10.8, 7.2 Hz, 1H),
4.02 (dd, J = 10.0, 6.8 Hz, 1H), 4.24 (dd, J = 10.0, 5.6 Hz, 1H), 4.28 (dd, J = 10.4,
5.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.99 (dd, J = 8.8, 2.0 Hz, 2H), 7.43 (d,
J = 15.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 15.6 Hz, 1H), 8.03 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) 24.0, 31.3, 72.8, 114.5, 115.1, 115.2,
119.9, 128.5, 130.3, 130.9, 131.0, 131.9, 143.9, 160.5, 162.2, 188.8 ppm; ESI-MS:
m/e 385.3 [M+1]+. Compound 22: Yield 39.1%; Rf: 0.36 (EtOAC/n-hexane = 2:1);
mp 104–106 °C; 1H NMR (400 MHz, CDCl3) d 2.77–2.80 (m, 2H), 2.93–2.95 (m,
2H), 3.37–3.39 (m, 2H), 3.91 (s, 3H), 3.99 (dd, J = 10.8, 5.6 Hz, 1H), 4.03 (dd,
J = 11.2, 6.0 Hz, 1H), 4.30 (dd, J = 11.2, 3.2 Hz, 1H), 4.33 (dd, J = 11.2, 3.2 Hz, 1H),
6.53 (d, J = 6.4 Hz, 1H), 6.55 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 15.6 Hz,
1H), 7.56 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 15.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) 44.9, 50.2, 55.8, 69.1, 99.4, 99.5, 106.0, 114.5, 118.0,
120.7, 120.8, 130.8, 132.3, 139.8, 160.5, 161.8, 162.1, 189.6 ppm; EI-MS: m/e
382.2 [M]+. Compound 25: Yield 3.5%; Rf: 0.735 (EtOAC/n-hexane = 1:2); 1H NMR
(400 MHz, CDCl3) d 2.30–2.34 (m, 2H), 2.51 (d, J = 6.0 Hz, 1H), 2.59 (d, J = 6.0 Hz,
1H), 3.21–3.26 (m, 2H), 3.81 (s, 3H), 4.00 (dd, J = 10.0, 6.8 Hz, 1H), 4.08–4.18 (m,
3H), 6.44 (d, J = 2.0 Hz, 1H), 6.55 (dd, J = 8.8, 2.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H),
7.47 (d, J = 15.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 15.6 Hz, 1H), 7.72 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) 23.7, 23.9, 31.3, 55.6, 72.9, 73.4,
100.4, 100.5, 114.5, 123.3, 125.2, 128.2, 130.2, 130.3, 131.2, 142.3, 159.1, 161.5,
162.8, 190.5 ppm; ESI-MS: m/e 415.3 [M+1]+.
The values of % inhibition are the means from at least three independent experi-
ments. The mark ‘—’ indicates that the experiment was not performed.
Acknowledgment
This work was financially supported by the grant of Catholic
University of Daegu in 2010.
References and notes
1. (a) Berger, J. M. Biochim. Biophys. Acta 1998, 1400, 3; (b) Kaufmann, S. H. Biochim.
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3. (a) Kajiyama, K.; Demizu, S.; Hiraga, Y.; Kinoshita, K.; Koyama, K.; Takahashi, K.;
Tamura, Y.; Okada, K.; Kinoshita, T. Phytochemistry 1992, 31, 3229; (b)
Haraguchi, H.; Tanimoto, K.; Tamura, Y.; Mizutani, K.; Kinoshita, T.
Phytochemistry 1998, 48, 125.
4. Yoon, G.; Kang, B. Y.; Cheon, S. H. Arch. Pharmacol. Res. 2007, 30, 313.
5. (a) Woo, S.; Jung, J.; Lee, C.; Kwon, Y.; Na, Y. Bioorg. Med. Chem. Lett. 2007, 17,
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7. General synthetic procedure: (a) Synthesis for compounds 8, 9, 14, 15, 20–22, 25:
To a mixture of chalcone and K2CO3 or Cs2CO3 (1.1–2.2 equiv) in acetone/DMF
(1:1) was added epi- or epithio-chlorohydrin(1.5–6.0 equiv). The reaction
mixture was stirred at 70–80 °C (overnight) and poured into H2O. If solid
formed, solid was filtered, collected and dried. If solid was not formed, the
mixture was extracted with ethyl acetate and then the organic layer was
washed with brine and dried over Na2SO4. Solvent was evaporated under
reduced pressure and the residue was purified by silica gel column
chromatography.
(b) Synthesis for compounds 10 and 16: A mixture of compound 8 or 14 in
aqueous 3 M HCl in ethyl acetate was stirred at rt (30 min). Solvent was
removed under reduced pressure and H2O was added to the residue. The
mixture was extracted with CH2Cl2 (ꢀ2 times). Combined organic layer was
washed with H2O and brine and dried over Na2SO4. After evaporation of solvent,
the residue was purified by silica gel column chromatography.
Compound 8: Yield 63.8%; Rf: 0.27 (EtOAC/n-hexane = 1:1); mp 92–94 °C; 1H
NMR (400 MHz, CDCl3) d 2.78 (dd, J = 4.8, 2.8 Hz, 1H), 2.94 (dd, J = 8.8, 8.0 Hz,
1H), 3.36–3.40 (m, 1H), 3.90 (s, 3H), 4.00 (dd, J = 11.2, 5.6 Hz, 1H), 4.29 (dd,
J = 11.2, 6.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.44 (d,
J = 15.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 15.6 Hz, 1H), 8.04 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) 44.9, 50.1 (50.2), 55.6 (55.8), 69.0
(69.1), 114.0, 115.2, 120.0, 120.2, 128.6, 130.2, 130.4, 130.9, 131.0, 131.5, 143.7,
8. Satyanarayana, M.; Tiwari, P.; Tripathi, B. K.; Srivastava, A. K.; Pratap, R. Bioorg.
Med. Chem. 2004, 12, 883.
9. Choi, D. H.; Cha, Y. K. Bull. Korean Chem. Soc. 2002, 23, 587.