Design and synthesis of α,β-epoxyketones as new anticancer agents

Article abstract of DOI:10.1002/cjoc.201190153

As epoxy functional group has high anticancer activity, α,β-epoxyketones were designed and synthesized as new anticancer agents, and their structures were confirmed by UV, ¹H NMR, IR, MS technigeces and elemental analysis. Their in vitro anticancer activities were evaluated by MTT method and the results showed that the compound 4c exhibited good activity with IC₅₀ of 17.8, 22.0 and 24.1 μg/mL against A-549, Hela and HepG2 cells, respectively. The dose of LD50 of the mice by intragastric administration was 1864.4 mg/kg. Therefore, the α,β-epoxyketones could potentially provide as new anticancer agents. A series of α,β-epoxyketones were synthesized in a four steps reaction and tested for their anticancer activities.

Full text of DOI:10.1002/cjoc.201190153

FULL PAPER
Design and Synthesis of α,β-Epoxyketones as
New Anticancer Agents
Ma, Zhengyue(马正月)
Zhang, Xinghua(张兴华)
Yang, Gengliang*(杨更亮)
Lu, Yuejuan(鲁悦娟)
Wang, Shikui(王士奎)
He, Yang(何洋)
Li, Beilei(李蓓蕾)
Yang, Junjie(杨俊杰)
Sun, Jiewei(孙杰威)
Key Laboratory for Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei
University, Baoding, Heibei 071002, China
As epoxy functional group has high anticancer activity, α,β-epoxyketones were designed and synthesized as
1
new anticancer agents, and their structures were confirmed by UV, H NMR, IR, MS technigeces and elemental
analysis. Their in vitro anticancer activities were evaluated by MTT method and the results showed that the com-
pound 4c exhibited good activity with IC50 of 17.8, 22.0 and 24.1 µg/mL against A-549, Hela and HepG2 cells, re-
spectively. The dose of LD50 of the mice by intragastric administration was 1864.4 mg/kg. Therefore, the
α,β-epoxyketones could potentially provide as new anticancer agents.
Keywords α,β-epoxyketones, thiochromanones, anticancer activity, Darzens condensation reaction
Introduction
quinoline derivatives22 etc. had been synthesized and re-
ported to have high antifungal activities. Furthermore,
(Z)-3-(chloromethylene)-6-methyl-thiochroman-4-one
was reported to be highly active to inhibit the growing
of many kinds of cancer cells.23
In view of the above reports, our interest in thio-
chromanones containing epoxide groups came to being,
and the design, synthesis and biological activities
evaluation of α,β-epoxyketones including the structure
of thiomanone or chromanone were done.
Cancer is a global issue and represents a major pub-
lic health problem. At present there are many anticancer
drugs, such as Bleomycin, Carboplatin, Carmustine,
Cisplatin, Cyclophosphamide, Fluorouracil, Oxaliplatin,
Paclitaxel, Vincristine and so on. But they all have some
drawbacks such as undesired side effects and multidrug
resistance. Therefore, new effective anticancer drugs are
desired all the time.
Epoxides were reported to have strong biological ac-
tivity, such as anticancer activity,1 pesticides activity,2
sterilization activity,3 growth regulating activity4 and so
on. For example, the triptolide is a diterpenoid epoxides
in tripterygium wilfordii, which contains epoxy function
groups and was regarded as the most promising anti-
cancer agents, especially for the treatment of ovarian
cancer, breast cancer and melanoma.5,6 And epoxy eth-
ane derivatives were also reported to have strong bacte-
ricidal activity.7-9
Besides epoxides, thiochromanones had been re-
ported to possess important biological activities such as
antifungal activity,10 anti-inflammatory activities,11
anticancer activity.12 For example, 3-bromo-4-thiochro-
manone derivatives,13,14 3-benzylienethiochromanone
derivatives,15,16 the Mannich base of thiochromanone
derivatives,17,18 3-halomethylene-thiochromanone de-
rivatives,19,20 2,3,3a,4-tetrahydrothiochromeno[4,3-c]-
pyrazole derivatives21 and 6H-thiochromeno-[4,3-b]-
Results and discussion
Chemistry
The syntheses of these α,β-epoxyketones were car-
ried out by the reaction of a properly substituted
3-bromo-4-(thio)chromanones with an equimolar
amount of a suitable aliphatic or aromatic aldehydes in
the presence of an excess of freshly prepared sodium
methoxide in anhydrous toluene (Scheme 1). The prod-
ucts obtained were purified by conventional workup in
satisfactory yield. The starting reagents for the synthesis
of α,β-epoxyketones were (thio)chromanones 1. In our
experiment, compounds 1 were synthezied through sub-
stitution reaction under microwave irradiation and cy-
clization reaction in the concentrated sulfuric acid.20,21,24
The yields were obviously higher than that of traditional
methods.25 The syntheses of compounds 2 were carried
out according to reported procedure,13,14 and all of the
*
E-mail: ygl@hbu.edu.cn; Tel.: 0086-0312-5079788; Fax: 0086-0312-5971107
Received August 29, 2010; revised January 9, 2011; accepted February 23, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20375010, 20675084), the Hebei Province Programs for Science and
Technology Development (Nos. 06276479B, 07276407D), Key Laboratory for Pharmaceutical Quality Control of Hebei Province Fund (No.
09265631D-14) and Hebei University Found (No. 2010Q33).
Chin. J. Chem. 2011, 29, 757— 764
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
757

Ma et al.
FULL PAPER
compounds 2 had good yields (85%—93%). The title
compounds 4 were obtained by Darzens condensation
1
reactions. Both analytical and H NMR spectral data of
all the synthesized compounds were in full agreement
with the proposed structures.
Scheme 1 Synthetic route of target compounds
or ketone might increase; on the other hand, HBr might
be removed from compound 2k, and the 2k was
changed into 6-fluoro-4H-thiochromen-4-one which did
not participate in Darzens condensation reaction.
Therefore, it was better maintaining the condensation
process at low temperature than high temperature.
Comparing the results of Entries 1 and 2, it was found
that the yield was not impoved greatly when the tem-
perature was maintained at 0 ℃ during the whole
process, so firstly we chose the condition of Entry 2.
The same reaction was also run with several other con-
densing agents and the results are also included in Table
1 (Entries 5, 6). Comparing CH3ONa with NaH and
t-BuONa, the system of NaH and t-BuONa exhibited
the similar yield to that of CH3ONa. Because CH3ONa
was cheaper and more accessible than the others, we
chose it as the condensing agent at last.
R1 R2
R3
CH3
R4
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
R5
X
S
S
S
S
S
S
S
S
S
O
S
S
S
S
S
S
a
b
c
d
e
f
H
H
H
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
F
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
phenyl
CH3
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
Cl
H
Table 1 The yields of 4l under different reaction conditions
H
Entry
Condensing agent
CH3ONa
CH3ONa
CH3ONa
CH3ONa
NaH
Temperature/℃
Yield/%
69
Cl
1
2
3
4
5
6
0
g
h
i
Cl
0—r.t.
50—70
110
67
OCH3
35
CH(CH3)2
30
j
Cl
F
F
F
F
F
F
0—r.t.
69
k
l
t-BuONa
0—r.t.
71
m
n
o
p
benzo[d][1,3]dioxole-5-yl
4-methoxyphenyl
CH2CH2CH3
The effects of R1, R2, R3, R4, R5 and X on yields of
compounds 4 are presented in Table 2. From the results
we could conclude that the R5 had a significant impact
CH(CH3)2
Table 2 The yields of compounds 4
In order to obtain a good yield of the compound 4,
Compound
Yield/%
66
Compound
Yield/%
62
the effects of temperature and condensing agents on the
yield of Darzens condensation reactions were investi-
gated. Our study was initiated by the reaction of
3-bromo-6-fluorothiochroman-4-one (2k) and benzal-
dehyde (3l) (Eq. 1). The effect of various temperature
conditions and different condensing agents on the con-
densation process was studied, and the results are sum-
marized in Table 1.
It turned out that better yields were obtained at 0 ℃
(Table 1, Entries 1—4). When the reaction temperature
rose, on the one hand, self-condensation of the aldehyde
4a
4b
4c
4d
4e
4f
4i
4j
62
67
70
4k
4l
71
71
67
67
4m
4n
4o
4p
64
73
60
4g
4h
65
51
61
45
758
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Chin. J. Chem. 2011, 29, 757— 764

Design and Synthesis of α,β-Epoxyketones as New Anticancer Agents
on the yields of compounds 4. When R5 was aryl groups,
the yields of compounds 4 were good and higher than
60%; when R5 was aliphatic groups, the yields were
lower than 51%. However, within the range of our ex-
periments, it had not been found that R1, R2, R3, R4 and
X had obvious effects on the yields of compounds 4.
LD50 of compound 4c on Kunming mice was obtained
by Statistical Program for Social Sciences (SPSS). The
LD50 of compound 4c was 1864.4 mg/kg. The
observations of death in mice are shown in Table 4.
Table 3 Anticancer activities of title compounds
IC50/(µg•mL－
Hela
39.6
37.9
22.0
23.9
28.1
31.9
33.0
43.1
39.7
25.8
38.9
60.1
54.0
50.7
50.1
50.9
9.0
)
1
Biological activity
Compound
A-549
40.0
39.5
17.8
24.0
29.5
30.0
31.9
40.0
35.9
27.7
35.1
57.9
60.7
45.9
52.0
56.0
30.0
HepG2
37.9
42.0
24.1
25.4
28.9
28.9
32.1
39.8
38.0
26.9
43.0
58.0
49.0
48.9
47.0
60.0
10.0
Evaluation of anticancer activity in vitro In or-
der to investigate structure-activity relations of com-
pounds 4 for anticancer activities against A-549 cells,
HeLa cells and HepG2 cells, firstly, compounds 4k—4p
were designed and synthesized, and their anticancer
activities were tested by MTT method with cisplatin as
the positive control. From the results of their activities
testing, it was shown that the designed compounds 4
possessed anticancer activities; moreover when R5 was
4-chlorophenyl, the compound 4k indicated the best
anticancer activity with IC50 of 35.1, 38.9 and 43.0
µg/mL against A-549, Hela and HepG2 cells, respec-
tively. Secondly, compounds 4a—4i were designed and
synthesized when R5 was fixed as 4-chlorophenyl.
Moreover their anticancer activities were investigated
by the method as before. The biological activities results
of these compounds revealed that 6'-chloro-3-(4-
chlorophenyl)-spiro[oxirane-2,3'-thiochroman]-4'-one
(4c) had the best activities against A-549, HeLa and
HepG2 cells, and the IC50 values reached 17.8, 22.0 and
24.1 µg/mL, respectively. And the activities of com-
pounds 4d against HeLa and HepG2 were as high as
that of 4c. So it was indicated when R1 was Cl or R3 was
Cl and the others among R1—R4 were H, compounds 4
possessed good anticancer activities. Especially, com-
pounds 4 had broader range of anticancer avtivities
when R3 was Cl. Thirdly, in order to investigate the im-
pact of X＝O on anticancer activity, 6-chloro-3'-(4-
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
Cisplatin
Table 4 Observations of death in mice
Number of experimental animals Number of death
Dose/
(mg•kg－
)
1
1000.0
1250.0
1562.5
1953.1
2441.4
3051.7
3814.7
10
10
10
10
10
10
10
0
2
chlorophenyl)-spiro[chroman-3,2'-oxiran]-4-one
(4j)
3
was designed and synthesized. And from the biological
activities of compound 4j, it was shown that the growth
of A-549, HeLa and HepG2 cells were also inhibited by
compound 4j to some extent, and the IC50 values were
27.7, 25.8 and 26.9 µg/mL, respectively. But its anti-
cancer activity was lower than that of 4c. The anticancer
activities of all the target compounds are shown in Ta-
ble 3.
From above, it was concluded that the structure of
designed α,β-epoxyketones had anticancer activity, and
when R1, R2 and R4 were H, R3 and R5 were Cl, and X
was S, compound 4 possesses the best anticancer activi-
ties. Although the mechanism of anticancer activities
remains to be not clarified, the compounds 4 could po-
tentially provide as new anticancer agents.
5
8
9
10
Conclusion
In summary, the designed α,β-epoxyketones were
successfully synthesized and confirmed with spectra.
And by optimizing the reaction condition, an economi-
cal preparing process of compounds 4 was constructed.
Moreover, the biological activities of these compounds
were evaluated, and all those were found to possess
anticancer activities; especially compound 4c had the
best activities, and the IC50 values against A-549, HeLa
and HepG2 cells reached 17.8, 22.0 and 24.1 µg/mL,
respectively. Moreover the acute toxicity of compound
4c was low, and its LD50 was 1864.4 mg/kg. Further-
more it was found that the anticancer activities of
Evaluation of acute toxicity After screening in
vitro, the acute toxicity of compound 4c which had the
best anticancer activity was investigated. The result of
toxicity investigation indicated that the acute toxicity of
compound 4c on Kunming mice was low; and the mice
were all dead at the dose of 3814.7 mg/kg. Moreover the
Chin. J. Chem. 2011, 29, 757— 764
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759

Ma et al.
FULL PAPER
α,β-epoxyketones were strongly dependent on its sub-
stituents. So the structure of α,β-epoxyketones could
provide as a new group of anticancer agents, and the
structures require optimizing deeply.
nm; 1H NMR (CDCl3, 600 MHz) δ: 3.01—3.03 (m, 2H,
COCH2), 3.24—3.29 (m, 2H, SCH2), 7.16 (d, J＝8.41
Hz, 1H, ArH), 7.34 (d, J＝8.42 Hz, 1H, A－rH); IR (KBr)
1
ν: 2929, 2853, 1697, 1558, 1507, 1469 cm ; MS (APCI)
m/z: 232.9 (M＋H)＋, 234.9 (M＋2＋H)＋. Anal. calcd
for C9H6Cl2OS: C 46.37, H 2.59, S 13.76; found C
46.40, H 2.53, S 13.70.
Experimental
Instruments
6,8-Dichlorothiochroman-4-one (1f): Yellow solid,
yield 70%, m.p. 84—85 ℃; UV-vis (MeOH) λmax: 248
nm; 1H NMR (CDCl3, 600 MHz) δ: 2.96—2.98 (m, 2H,
COCH2), 3.24—3.27 (m, 2H, SCH2), 7.50 (d, J＝2.33
Hz, 1H, ArH), 8.03 (d, J＝2.35 Hz, 1H, ArH); IR (KBr)
Melting points of all compounds synthesized were
determined with an SGW X-4 melting point apparatus.
1
The H NMR spectra were recorded in CDCl3 at 600
MHz with an AVANCE 600 spectrometer (internal
standard TMS). The MS spectra were measured on
LC-MSD Trap XCT spectrometer. Elemental analysis
(C, H, S) was realized on Carlo Erba-1106 EA instru-
ment.
－1
ν: 2933, 2833, ＋1685, 1566, 1471 cm ＋; MS (APCI) m/z:
232.9 (M＋H) , 234.9 (M＋2＋H) . Anal. calcd for
C9H6Cl2OS: C 46.37, H 2.59, S 13.76; found C 46.40, H
2.54, S 13.72.
6,7-Dichlorothiochroman-4-one (1g) Pink solid,
General procedure for synthesis of compounds 1
yield 73%, m.p. 133—135 ℃; UV-vis (MeOH) λ
:
max
Compounds 1 were synthesized according to pub-
248 nm; 1H NMR (CDCl3, 600 MHz) δ: 2.93—2.99 (m,
2H, COCH2), 3.23—3.28 (m, 2H, SCH2), 7.40 (s, 1H,
ArH), 8.16 (s, 1H, ArH); IR (KBr) ν: 2947, 2847, 1668,
lished procedures.20,21,23
6-Methylthiochroman-4-one (1a): Light yellow solid,
yield 61%, m.p. 70—72 ℃; UV-vis (MeOH) λmax: 254
－1
1569, 1507, 1444 cm ; MS (APCI) m/z: 232.9 (M＋
nm; H NMR (CDCl3, 600 MHz) δ: 2.47 (s, 3H, CH3),
H)＋, 234.9 (M＋2＋H)＋. Anal. calcd for C9H6Cl2OS: C
46.37, H 2.59, S 13.76; found C 46.40, H 2.53, S 13.73.
6-Methoxythiochroman-4-one (1h): Yellow solid,
yield 55%, m.p. 30—33 ℃; UV-vis (MeOH) λmax: 240
nm; 1H NMR (CDCl3, 600 MHz) δ: 2.95—2.97 (m, 2H,
SCH2), 3.19—3.23 (m, 2H, SCH2), 3.82 (s, 3H, OCH3),
7.01 (dd, J＝8.68, 2.96 Hz, 1H, ArH), 7.19 (d, J＝8.68
Hz, 1H, ArH), 7.62 (d, J＝2.97 Hz, 1H, ArH); IR (KBr)
1
2.83—2.85 (m, 2H, COCH2), 3.26—3.28 (m, 2H,
CH2S), 6.89—7.01 (m, 1H, ArH), 7.12 (d, J＝8.6 Hz,
1H, ArH), 7.55 (d, J＝2.8 Hz, 1H, ArH); IR (KBr) ν:
－1
2923, 2854, 1674, ＋1599, 1469, 1398 cm ; MS (APCI)
m/z: 178.9 (M＋H) . Anal. calcd for C10H10OS: C 67.38,
H 5.65, S 17.99; found C 67.30, H 5.68, S 17.93.
7-Fluoro-6-methylthiochroman-4-one (1b): Yellow
－1
solid, yield 65%, m.p. 48—49 ℃; UV-vis (MeOH) λ
:
ν: 2937, 2833,＋1681, 1598, 1473 cm ; MS (APCI) m/z:
max
1
254 nm; H NMR (CDCl3, 600 MHz) δ: 2.45 (s, 3H,
CH3), 2.86—2.89 (m, 2H, COCH2), 3.25—3.27 (m, 2H,
SCH2), 6.89—7.01 (m, 1H, ArH), 7.59 (d, J＝2.9 Hz,
1H, ArH); IR (KBr) ν: 2925, 2854, 1671, 1588, 146＋9,
194.9 (M＋H) . Anal. calcd for C10H10O2S: C 61.83, H
5.19, S 16.51; found C 61.90, H 5.15, S 16.57.
6-Isopropylthiochroman-4-one (1i): Red oil, yield
1
67%, UV-vis (MeOH) λmax: 238 nm; H NMR (CDCl3,
－1
1469, 1398 cm ; MS (APCI) m/z: 196.9 (M＋H) .
600 MHz) δ: 1.24 [d, J＝7.04 Hz, 6H, CH-(CH3)2], 2.86
— 2.93 [m, 1H, CH-(CH3)2], 2.96 — 2.98 (m, 2H,
COCH2), 3.20—3.24 (m, 2H, SCH2), 7.21 (d, J＝8.17
Hz, 1H, ArH), 7.26—7.28 (m, 1H, ArH), 7.99 (d, J＝
1.89 Hz,－1H, ArH); IR (KBr) ν: 2960, 2869, 1677, 1598,
Anal. calcd for C10H9FOS: C 61.20, H 4.62, S 16.34;
found C 61.16, H 4.68, S 16.30.
6-Chlorothiochroman-4-one (1c): Yellow solid, yield
65%, m.p. 69—70 ℃; UV-vis (MeOH) λmax: 243 nm;
1H NMR (CDCl3, 600 MHz) δ: 2.95—2.97 (m, 2H,
COCH2), 3.17—3.19 (m, 2H, SCH2), 6.97—7.01 (m,
1H, ArH), 7.19 (d, J＝8.4 Hz, 1H, ArH), 7.60 (d, J＝3.2
Hz, 1H, ArH); IR (KBr) ν: 2910, 2846, 167＋8, 1598,
＋
1
1471 cm ; MS (APCI) m/z: 207 (M＋H) . Anal. calcd
for C12H14OS: C 69.86, H 6.84, S 15.54; found C 68.80,
H 6.88, S 15.50.
6-Chlorochroman-4-one (1j): White solid, yield 65%,
－1
1
1479 cm ;＋ MS (APCI) m/z: 198.9 (M＋H) , 200.9
m.p. 102—103 ℃; UV-vis (MeOH) λmax: 222 nm; H
(M＋2＋H) . Anal. calcd for C9H7ClOS: C 54.41, H
NMR (CDCl3, 600 MHz) δ: 2.81 (t, J＝6.60 Hz, 2H,
OCH2), 4.54 (t, J＝6.60 Hz, 2H, OCH2), 6.94 (d, J＝
8.85 Hz, 1H, ArH), 7.41 (dd, J＝8.86, 2.64 Hz, 1H,
ArH), 7.85 (d, J＝2.60 Hz, 1－H, ArH); IR (KBr) ν: 2933,
3.55, S 16.14; found C 54.45, H 3.50, S 16.10.
8-Chlorothiochroman-4-one (1d): Light yellow solid,
yield 67%, m.p. 93—95 ℃; UV-vis (MeOH) λmax: 244
nm; 1H NMR (CDCl3, 600 MHz) δ: 2.95—2.97 (m, 2H,
COCH2), 3.24—3.27 (m, 2H, SCH2), 7.13 (t, J＝7.85
Hz, 1H, ArH), 7.49 (dd, J＝7.84, 1.35 Hz, 1H, ArH),
8.05 (dd, J＝7.92, 1.36 Hz, 1H, ArH); IR (KBr) ν: 2923,
1
2840, 1677, 1573, 1469 cm ; MS (APCI) m/z: 182.9
(M ＋ H) ＋ , 184.9 (M ＋ 2 ＋ H) ＋ . Anal. calcd for
C9H7ClO2: C 59.20, H 3.86; found C 59.27, H 3.90.
6-Fluorothiochroman-4-one (1k): Light yellow solid,
yield 64%, m.p. 92—94 ℃; UV-vis (MeOH) λmax: 254
nm; 1H NMR (CDCl3, 600 MHz) δ: 2.96—2.99 (m, 2H,
COCH2), 3.23—3.25 (m, 2H, SCH2), 7.11—7.16 (m,
2H, ArH), 8.07 (dd, J＝7.96, 1.39 Hz, 1H, A－rH); IR
(KBr) ν: 2923, 2854, 1660, 1588, 1469 cm 1; MS
－1
1664, 1574, 1427 cm ; MS (APCI) m/z: 198.9 (M＋
H)＋, 200.9 (M＋2＋H)＋. Anal. calcd for C9H7ClOS: C
54.41, H 3.55, S 16.14; found C 54.40, H 3.58, S 16.10.
5,8-Dichlorothiochroman-4-one (1e): Yellow solid,
yield 70%, m.p. 74—75 ℃; UV-vis (MeOH) λmax: 239
760
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 757— 764

Design and Synthesis of α,β-Epoxyketones as New Anticancer Agents
(APCI) m/z: 182.9 (M＋H)＋. Anal. calcd for C9H7FOS:
C 59.32, H 3.87, S 17.60; found C 59.27, H 3.90, S
17.64.
3-Bromo-5,8-dichlorothiochroman-4-one
(2e):
Yellow solid, yield 91%, m.p. 70—73 ℃; UV-vis
1
(MeOH) λmax: 250 nm; H NMR (CDCl3, 600 MHz) δ:
3.51 (dd, J＝14.14, 8.44 Hz, 1H, SCH2), 3.72 (dd, J＝
14.17, 3.77 Hz, 1H, SCH2), 4.93 (dd, J＝8.46, 3.77 Hz,
1H, CHBr), 7.22 (d, J＝8.53 Hz, 1H, ArH), 7.39 (d, J＝
8.48 Hz, 1H, ArH); IR (KBr) ν: 2948, 1699, 1558, 154＋2,
General procedure for the synthesis of compounds 2
15.0 mmol compound 1 was dissolved in 15 mL of
glacial acetic acid at about 40 ℃, then a solution of
15.0 mmol bromine in 8 mL of glacial acetic acid was
added dropwise, over a period of 40 min at 40 ℃. The
reaction mixture was stirred for 3.5 h, then cooled and
added 80 mL of saturated NaHSO3 solution, the solid
precipitated was filtered, abundantly washed with water,
then air dried. The crude product was recrystallized
from 95% (φ) EtOH to afford the compound 2.
－1
1419 cm ; MS (APCI) m/z: 230.9 (M－HBr＋H) ,
232.9 (M－HBr＋2＋H)＋. Anal. calcd for C9H5Br-
Cl2OS: C 34.65, H 1.62, S 10.28; found C 34.69, H 1.65,
S 10.20.
3-Bromo-6,8-dichlorothiochroman-4-one (2f): Light
yellow solid, yield 90%, m.p. 113—115 ℃; UV-vis
1
(MeOH) λmax: 250 nm; H NMR (CDCl3, 600 MHz) δ:
3-Bromo-6-methylthiochroman-4-one (2a): Brown
3.48 (dd, J＝14.34, 7.91 Hz, 1H), 3.68 (dd, J＝14.33,
3.13 Hz, 1H), 4.92 (dd, J＝7.91, 3.18 Hz, 1H), 7.55 (d,
J＝2.31 Hz, 1H), 8.08 (d, J＝2.30 Hz, 1H); IR (KBr) ν:
solid, yield 88%, m.p. 57—58 ℃; UV-vis (MeOH) λ
:
max
250 nm; 1H NMR (CDCl3, 600 MHz) δ: 2.19—2.52 (m,
3H, CH3), 3.50 (dd, J＝14.02, 8.44 Hz, 1H, SCH2), 3.66
(dd, J＝14.04, 3.31 Hz, 1H, SCH2), 4.98 (dd, J＝8.46,
3.31 Hz, 1H, CHBr), 7.21 (d, J＝8.09 Hz, 1H, ArH),
7.28—7.31 (m, 1H, ArH), 7.90—8.29 (m, 1H, ArH); IR
(KBr) ν: 2977, 2844, 1672, 1606, 1589, 1469, 1398
－1
2916, 1681, 1569, 1400 cm ; MS (APCI) m/z : 230.9
(M－HBr＋H)＋, 232.9 (M－HBr＋2＋H)＋. Anal. calcd
for C9H5BrCl2OS: C 34.65, H 1.62, S 10.28; found C
34.62, H 1.68, S 10.23.
3-Bromo-6,7-dichlorothiochroman-4-one
(2g):
－1
＋
cm ; MS (APCI) m/z: 176.9 (M－HBr＋H) . Anal.
calcd for C10H9BrOS: C 46.71, H 3.53, S 12.47; found
C 46.67, H 3.58, S 12.43.
Yellow solid, yield 89%, m.p. 123—125 ℃; UV-vis
1
(MeOH) λmax: 254 nm; H NMR (CDCl3, 600 MHz) δ:
3.69 (dd, J＝14.25, 3.15 Hz, 1H, SCH2), 3.47 (dd, J＝
14.23, 7.83 Hz, 1H, SCH2), 4.92 (dd, J＝7.84, 3.21 Hz,
1H, CHBr), 7.42 (s, 1H, ArH), 8.2－1 (s, 1H, ArH); IR
3-Bromo-7-fluoro-6-methylthiochroman-4-one (2b):
Pale brown solid, yield 90%, m.p. 143 — 145 ℃ ;
1
1
UV-vis (MeOH) λmax: 245 nm; H NMR (CDCl3, 600
(KBr) ν: 2918, 1683, ＋1573, 1442 cm ; MS (APCI) m/z:
230.9 (M－HBr＋H) , 232.9 (M－HBr＋2＋H)＋. Anal.
calcd for C9H5BrCl2OS: C 34.65, H 1.62, S 10.28;
found C 34.61, H 1.65, S 10.32.
MHz) δ: 2.25—2.39 (m, 3H, CH3), 3.48 (dd, J＝14.08,
8.23 Hz, 1H), 3.66 (dd, J＝14.11, 3.27 Hz, 1H, SCH2),
4.95 (dd, J＝8.24, 3.26 Hz, 1H, CHBr), 7.09—7.23 (m,
1H, ArH), 7.73—7.90 (m, 1H, ArH); IR (KBr) ν: 2925,
3-Bromo-6-methoxythiochroman-4-one
(2h):
－1
2854, 1683, 1606, 1586, 1510, 147＋3, 1382 cm ; MS
Yellow solid, yield 92%, m.p. 62—64 ℃; UV-vis
1
(APCI) m/z: 194.9 (M－HBr＋H) . Anal. calcd for
C10H8BrFOS: C 43.65, H 3.53, S 11.65; found C 43.61,
H 2.88, S 11.60.
(MeOH) λmax: 245 nm; H NMR (CDCl3, 600 MHz) δ:
3.46 (dd, J＝14.00, 8.33 Hz, 1H, SCH2), 3.63 (dd, J＝
13.99, 3.34 Hz, 1H, SCH2), 3.83 (s, 3H, OCH3), 4.96
(dd, J＝8.32, 3.33 Hz, 1H, CHBr), 7.06 (dd, J＝8.77,
2.90 Hz, 1H, ArH), 7.20 (d, J＝8.69 Hz, 1H, ArH), 7.64
(d, J＝2.93 Hz, 1H, ArH); IR (KBr) ν: 2960, 2831, 1662,
3-Bromo-6-chlorothiochroman-4-one (2c): Light
yellow solid, yield 90%, m.p. 108—110 ℃; UV-vis
1
(MeOH) λmax: 245 nm; H NMR (CDCl3, 600 MHz) δ:
－1
3.50 (dd, J＝14.17, 8.12 Hz, 1H, SCH2), 3.70 (dd, J＝
14.18, 3.25 Hz, 1H, SCH2), 4.96 (dd, J＝8.11, 3.24 Hz,
1H, CHBr), 7.26 (d, J＝8.52 Hz, 1H, ArH), 7.36—7.51
(m, 1H, ArH), 8.14 (d, J＝2.40 Hz, 1H, ArH); IR (KBr)
1596, 1475,＋1226, 1024 cm ; MS (APCI) m/z: 193 (M
－HBr＋H) . Anal. calcd for C10H9BrO2S: C 43.97, H
3.32, S 11.74; found C 43.93, H 3.36, S 11.69.
3-Bromo-6-isopropylthiochroman-4-one (2i): Red
oil; yield 89%, UV-vis (MeOH) λmax: 245 nm; 1H NMR
(CDCl3, 600 MHz) δ: 1.24 [d, J ＝ 6.98 Hz, 6H,
CH-(CH3)2], 2.87—2.94 [m, 1H, CH-(CH3)2], 3.45—
3.49 (m, 1H, SCH2), 3.64 (dd, J＝14.03, 3.32 Hz, 1H,
SCH2), 4.96 (dd, J＝8.43, 3.31 Hz, 1H, CHBr), 7.22 (d,
J＝8.18 Hz, 1H, ArH), 7.32 (dd, J＝8.23, 2.16 Hz, 1H,
ArH), 8.02 (d, J＝2.15 Hz, 1H, ArH); IR (KBr) ν: 2960,
－1
ν: 2920, 2850, 1687, ＋1577, 1458 cm ; MS (APCI) m/z:
196.9 (M－HBr＋H) , 198.9 (M－HBr＋2＋H)＋. Anal.
calcd for C9H6BrClOS: C 38.94, H 2.18, S 11.55; found
C 38.89, H 2.15, S 11.59.
3-Bromo-8-chlorothiochroman-4-one (2d): Yellow
oil, yield 90%, UV-vis (MeOH) λmax: 245 nm; 1H NMR
(CDCl3, 600 MHz) δ: 3.50 (dd, J＝14.26, 8.31 Hz, 1H,
SCH2), 3.68 (dd, J＝14.23, 3.29 Hz, 1H, SCH2), 4.95
(dd, J＝8.35, 3.18 Hz, 1H, CHBr), 7.19 (t, J＝7.90 Hz,
1H, ArH), 7.54 (dd, J＝7.79, 1.26 Hz, 1H, ArH), 8.10
(dd, J＝8.03, 1.30 Hz, 1H, ArH); IR (KBr) ν: 2920,
－1
2869, 1681,＋1598, 1475 cm ; MS (APCI) m/z: 205 (M
－HBr＋H) . Anal. calcd for C12H13BrOS: C 50.54, H
4.59, S 11.24; found C 50.50, H 4.56, S 11.20.
3-Bromo-6-chlorochroman-4-one (2j): White solid,
yield 93%, m.p. 97—99 ℃; UV-vis (MeOH) λmax: 245
nm; 1H NMR (CDCl3, 600 MHz) δ: 4.58—4.67 (m, 3H,
OCH2 and CHBr), 7.01 (d, J＝8.86 Hz, 1H, ArH), 7.49
(dd, J＝8.92, 2.66 Hz, 1H, ArH), 7.90 (d, J＝2.66 Hz,
－1
1685 1577, 1550, 1402 cm ; MS (APCI) m/z: 196.9 (M
－HBr＋H)＋, 198.9 (M－HBr＋2＋H)＋. Anal. calcd
for C9H6BrClOS: C 38.94, H 2.18, S 11.55; found C
38.90, H 2.15, S 11.51.
Chin. J. Chem. 2011, 29, 757— 764
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
761

Ma et al.
FULL PAPER
－1
1H, ArH); IR (KBr) ν: 2929, 1697, 1598, 1473 cm ;
MS (APCI) m/z: 180.9 (M－HBr＋H)＋, 182.9 (M－
HBr＋2＋H)＋. Anal. calcd for C9H6BrClO2: C 41.34, H
2.31; found C 41.37, H 2.30.
＋H)＋, 339 (M＋2＋H)＋. Anal. calcd for C16H10Cl2O2S:
C 56.99, H 2.99, S 9.51; found C 56.92, H 2.90, S 9.55.
8'-Chloro-3-(4-chlorophenyl)spiro[oxirane-2,3'-thio-
chroman]-4'-one (4d): Light yellow solid, yield 71%,
1
3-Bromo-6-fluorothiochroman-4-one (2k): Pale
brown solid, yield 91%, m.p. 103—105 ℃; UV-vis
m.p. 136—139 ℃; UV-vis (MeOH) λmax: 248 nm; H
NMR (CDCl3, 600 MHz) δ: 2.60 (d, J＝13.57 Hz, 1H,
SCH2), 3.75 (d, J＝13.58 Hz, 1H, SCH2), 4.37 (s, 1H,
OCH), 7.22 (t, J＝7.89 Hz, 1H, ArH), 7.36—7.43 (m,
4H, ArH), 7.55 (d, J＝7.80 Hz, 1H, ArH), 8.10 (d, J＝
7.9－6 Hz, 1H, ArH); IR (KBr) ν: 168＋5, 1573, 1488, 127＋8
1
(MeOH) λmax: 250 nm; H NMR (CDCl3, 600 MHz) δ:
3.50 (dd, J＝14.13, 8.26 Hz, 1H), 3.68 (dd, J＝14.12,
3.26 Hz, 1H), 4.98 (dd, J＝8.25, 3.26 Hz, 1H), 7.10—
7.24 (m, 1H), 7.30 (dd, J＝8.73, 4.88 Hz, 1H), 7.87 (dd,
J＝9.16, 2.88 Hz, 1H－); IR (KBr) ν: 2920, 2831, 1687,
1
cm ; MS (APCI) m/z: 337 (M＋H) , 339 (M＋2＋H) .
1
1600, 1573, 1469 cm ; MS (APCI) m/z: 180.9 (M－
Anal. calcd for C16H10Cl2O2S: C 56.99, H 2.99, S 9.51;
found C 56.93, H 2.91, S 9.54.
HBr＋H)＋. Anal. calcd for C9H6BrFOS: C 41.40, H
2.32, S 12.28; found C 41.37, H 2.36, S 12.23.
5',8'-Dichloro-3-(4-chlorophenyl)spiro[oxirane-2,3'-
thiochroman]-4'-one (4e): Yellow solid, yield 67%, m.p.
1
General procedure for the synthesis of compounds 4
131—133 ℃; UV-vis (MeOH) λmax: 248 nm; H NMR
10.0 mmol compound 2 and 10.0 mmol substituted
aldehyde 3 were dissolved in 25 mL of dry toluene and
cooled to 0 ℃, then added 20.0 mmol freshly prepared
sodium methoxide. After all the base was added, the
reaction mixture was permitted to warm slowly to room
temperature and stirred for 8—10 h. Then the reaction
mixture was poured into 30 mL of water, the organic
layer was obtained and dried over anhydrous MgSO4,
then filtered and evaporated. The crude product was
purified by silica-gel column chromatography [V(ethyl
acetate)∶V(petroleum)＝1∶60—1∶10] to afford the
compound 4.
(CDCl3, 600 MHz) δ: 2.71 (d, J＝13.77 Hz, 1H, SCH2),
3.48 (d, J＝13.77 Hz, 1H, SCH2), 4.51 (s, 1H, OCH),
7.26 (d, J＝3.50 Hz, 1H, ArH), 7.34—7.42 (m, 5H,
－1
ArH); IR (KBr) ν: 1697, ＋1598, 1490, 1274 cm ; MS
(APCI) m/z: 371 (M＋H) , 373 (M＋2＋H)＋, 375 (M
＋4＋H)＋. Anal. calcd for C16H9Cl3O2S: C 51.71, H
2.44, S 8.63; found C 51.76, H 2.40, S 8.68.
6',8'-Dichloro-3-(4-chlorophenyl)spiro[oxirane-2,3'-
thiochroman]-4'-one (4f): Yellow solid, yield 73%, m.p.
1
153—154 ℃; UV-vis (MeOH) λmax: 254 nm; H NMR
(CDCl3, 600 MHz) δ: 2.61 (d, J＝13.68 Hz, 1H, SCH2),
3.74 (d, J＝13.57 Hz, 1H, SCH2), 4.37 (s, 1H, OCH),
7.41 (d, J＝8.57 Hz, 2H, ArH), 7.38 (d, J＝8.55 Hz, 2H,
ArH), 7.55 (d, J＝2.28 Hz, 1H, ArH), 8.07 (d, J＝2.27
Hz, 1H, ArH); IR (KBr) ν: 1691,＋ 1567, 1494, 126＋1
3-(4-Chlorophenyl)-6'-methylspiro[oxirane-2,3'-
thiochroman]-4'-one (4a): White solid, yield 66%, m.p.
1
154—156 ℃; UV-vis (MeOH) λmax: 247 nm; H NMR
－1
(CDCl3, 600 MHz) δ: 2.36 (s, 3H, CH3), 2.51 (d, J＝
13.45 Hz, 1H, SCH2), 3.75 (d, J＝13.50 Hz, 1H, SCH2),
4.37 (s, 1H, OCH), 7.16 (d, J＝8.02 Hz, 1H, ArH), 7.24
—7.27 (m, 2H, ArH), 7.38 (s, 4H, ArH), 7.96 (d, J＝
0.89 Hz, 1H, ArH); IR (KBr) ν: 2923, 2854, 1674, 159＋6,
cm ; MS (APCI)＋m/z: 371 (M＋H) , 373 (M＋2＋H) ,
375 (M＋4＋H) . Anal. calcd for C16H9Cl3O2S: C
51.71, H 2.44, S 8.63; found C 51.75, H 2.48, S 8.60.
6',7'-Dichloro-3-(4-chlorophenyl)spiro[oxirane-2,3'-
thiochroman]-4'-one (4g): Yellow solid, yield 65%, m.p.
－1
1
1469, 1398, 1286 ＋cm ; MS (APCI) m/z: 317 (M＋H) ,
166—167 ℃; UV-vis (MeOH) λmax: 254 nm; H NMR
319 (M＋2＋H) . Anal. calcd for C17H13ClO2S: C
64.45, H 4.14, S 10.12; found C 64.39, H 4.19, S 10.08.
3-(4-Chlorophenyl)-7'-fluoro-6'-methylspiro[oxirane-
2,3'-thiochroman]-4'-one (4b): Yellow-green solid, yield
62%, m.p. 139—141 ℃; UV-vis (MeOH) λmax: 247 nm;
1H NMR (CDCl3, 600 MHz) δ: 2.29 (s, 3H, CH3), 2.52
(d, J＝13.50 Hz, 1H, SCH2), 3.74 (d, J＝13.50 Hz, 1H,
SCH2), 4.37 (s, 1H, OCH), 7.09 (d, J＝6.60 Hz, 1H,
ArH), 7.36—7.40 (m, 4H, ArH), 7.76 (d, J＝9.89 Hz,
1H, ArH); IR (KBr)－ν: 2923, 2854, 1681, 1608, 149＋4,
(CDCl3, 600 MHz) δ: 2.56 (d, J＝13.59 Hz, 1H, SCH2),
3.76 (d, J＝13.57 Hz, 1H, SCH2), 4.38 (s, 1H, OCH),
7.41—7.36 (m, 5H, ArH), 8.19－(s, 1H, ArH),; IR (KBr)
1
ν: 1697,＋1568, 1488, 1257 cm ; MS (APCI) m/z: 371
(M＋H) , 373 (M＋2＋H)＋, 375 (M＋4＋H)＋. Anal.
calcd for C16H9Cl3O2S: C 56.99, H 2.99, S 9.51; found
C 56.93, H 2.93, S 9.55.
3-(4-Chlorophenyl)-6'-methoxyspiro[oxirane-2,3'-
thiochroman]-4'-one (4h): Yellow solid, yield 61%, m.p.
1
130—134 ℃; UV-vis (MeOH) λmax: 248 nm; H NMR
1
1471, 1394, 1272＋cm ; MS (APCI) m/z: 335 (M＋H) ,
(CDCl3, 600 MHz) δ: 2.51 (d, J＝13.41 Hz, 1H, SCH2),
3.75 (d, J＝13.33 Hz, 1H, SCH2), 3.85 (s, 3H, OCH3),
4.38 (s, 1H, OCH), 7.05 (dd, J＝8.66, 2.96 Hz, 1H,
ArH), 7.17 (d, J＝8.65 Hz, 1H, ArH), 7.39 (s, 4H, ArH),
7.62 (d, J＝2.92 Hz, 1H, ArH); IR (KBr)－ν: 2923, 2825,
337 (M＋2＋H) . Anal. calcd for C17H12ClFO2S: C
60.99, H 3.61, S 9.58; found C 60.94, H 3.65, S 9.51.
6'-Chloro-3-(4-chlorophenyl)spiro[oxirane-2,3'-thio-
chroman]-4'-one (4c): White solid, yield 70%, m.p. 148
1
1
—149 ℃; UV-vis (MeOH) λmax: 248 nm; H NMR
1679, 1595, 1558,＋1473, 1398, 1290 ＋cm ; MS (APCI)
(CDCl3, 600 MHz) δ: 2.55 (d, J＝13.54 Hz, 1H, SCH2),
3.76 (d, J＝13.49 Hz, 1H, SCH2), 4.38 (s, 1H, OCH),
7.22 (d, J＝8.45 Hz, 1H, ArH), 7.38—7.40 (m, 5H,
ArH), 8.11 (d, J＝2.37 Hz, 1H, ArH); IR (KBr) ν: 1679,
m/z: 333 (M＋H) , 335 (M＋2＋H) . Anal. calcd for
C17H13ClO3S: C 61.35, H 3.94, S 9.63; found C 61.30,
H 3.90, S 9.70.
3-(4-Chlorophenyl)-6'-isopropylspiro[oxirane-2,3'-
thiochroman]-4'-one (4i): Yellow solid, yield 62%, m.p.
－1
1577, 1490, 1454, 1240 cm ; MS (APCI) m/z: 337 (M
762
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 757— 764

Design and Synthesis of α,β-Epoxyketones as New Anticancer Agents
1
161—163 ℃; UV-vis (MeOH) λmax: 247 nm; H NMR
60%, m.p. 150—152 ℃; UV-vis (MeOH) λmax: 236 nm;
1H NMR (CDCl3, 600 MHz) δ: 2.51 (d, J＝13.44 Hz,
1H, SCH2), 3.74 (d, J＝13.39 Hz, 1H, SCH2), 3.85 (s,
3H, OCH3), 4.38 (s, 1H, OCH), 7.05 (dd, J＝8.65, 2.90
Hz, 1H, ArH), 7.25—7.41 (m, 5H, ArH), 7.62 (d, J＝
2.91 Hz, 1H, ArH); IR (KBr) ν: 2923, 2852, 1681, 159＋5,
(CDCl3, 600 MHz) δ: 1.26 [d, J ＝ 6.95 Hz, 6H,
CH-(CH3)2], 2.51 (d, J＝13.45 Hz, 1H, SCH2), 2.89—
2.96 [m, 1H, CH-(CH3)2], 3.76 (d, J＝13.50 Hz, 1H,
SCH2), 4.37 (s, 1H, OCH), 7.20 (d, J＝8.11 Hz, 1H,
ArH ), 7.32 (dd, J＝8.12, 2.09 Hz, 1H, ArH), 7.36—
7.40 (m, 4H, ArH), 8.02 (d, J＝2.03 Hz, 1H, ArH); IR
(KBr) ν:－2923, 2864, 1681, 1596, 1490, 1471, 1370,
－1
1558, 1471, 1228 cm ; MS (APCI) m/z: 317 (M＋H) .
Anal. calcd for C17H13FO3S: C 64.54, H 4.14, S 10.14;
found C 61.49, H 4.19, S 10.09.
＋
1
1267＋cm ; MS (APCI) m/z: 345 (M＋H) , 347 (M＋2
＋H) . Anal. calcd for C19H17ClO2S: C 66.17, H 4.97, S
9.30; found C 66.12, H 4.93, S 9.35.
6'-Fluoro-3-propylspiro[oxirane-2,3'-thiochroman]-
4'-one (4o): White solid, yield 51%, m.p. 76—79 ℃;
1
6-Chloro-3'-(4-chlorophenyl)spiro[chroman-3,2'-
oxiran]-4-one (4j): White solid, yield 67%, m.p. 176—
177 ℃; UV-vis (MeOH) λmax: 224 nm; 1H NMR
(CDCl3, 600 MHz) δ: 4.09 (d, J＝12.63 Hz, 1H, OCH2),
4.52—4.55 (m, 2H, OCH and OCH2), 6.94 (d, J＝8.83
Hz, 1H, ArH), 7.30 (d, J＝8.43 Hz, 2H, ArH), 7.41 (d,
J＝8.47 Hz, 2H, ArH), 7.47 (dd, J＝8.89, 2.67 Hz, 1H,
ArH), 7.93 (d, J＝2.66 Hz, 1H, ArH); IR (KBr) ν: 1683,
UV-vis (MeOH) λmax: 242 nm; H NMR (CDCl3, 600
MHz) δ: 1.03 (t, J＝7.26 Hz, 3H, CH3), 1.60—1.86 (m,
4H, CH2CH2), 2.87 (d, J＝13.69 Hz, 1H, SCH2), 3.23—
3.26 (m, 1H, OCH), 3.82 (d, J＝13.63 Hz, 1H, SCH2),
7.15—7.19 (m, 1H, ArH), 7.30 (dd, J＝8.71, 4.84 Hz,
1H, ArH), 7.80 (dd, J＝9.14, 2.92 Hz, 1H, ArH); IR
(KBr) ν: 2960－, 2869, 1456, 1398, 1683, 1598, 1558,
＋
1
1471, 1263 cm ; MS (APCI) m/z: 253 (M＋H) . Anal.
calcd for C13H13FO2S: C 61.89, H 5.19, S 12.71; found
C 61.84, H 5.15, S 12.68.
－1
1604, 1571, 1490, 1261＋cm ; MS (APCI) m/z: 321 (M
＋H)＋, 323 (M＋2＋H) . Anal. calcd for C16H10Cl2O3:
C 59.84, H 3.14; found C 59.80, H 3.10.
6'-Fluoro-3-isopropylspiro[oxirane-2,3'-thiochro-
man]-4'-one (4p): White solid, yield 45%, m.p. 124—
126 ℃; UV-vis (MeOH) λmax: 242 nm; 1H NMR
(CDCl3, 600 MHz) δ: 1.16 [dd, J＝24.01, 6.69 Hz, 6H,
CH-(CH3)2], 1.67 [ddd, J＝13.38, 6.70, 2.75 Hz, 1H,
CH-(CH3)2], 2.88 (d, J＝13.73 Hz, 1H, SCH2), 2.97 (d,
J＝9.47 Hz, 1H, OCH), 3.82 (d, J＝13.71 Hz, 1H,
SCH2), 7.15—7.20 (m, 1H, ArH), 7.30 (dd, J＝8.70,
4.84 Hz, 1H, ArH), 7.81 (dd, J＝9.16, 2.91 Hz, 1H,
ArH); IR (KBr) ν: 29－23, 2852, 1676, 1600, 1559, 148＋8,
3-(4-Chlorophenyl)-6'-fluorospiro[oxirane-2,3'-thio-
chroman]-4'-one (4k): Light yellow solid, yield 71%,
1
m.p. 164—165 ℃; UV-vis (MeOH) λmax: 240 nm; H
NMR (CDCl3, 600 MHz) δ: 2.54 (d, J＝13.54 Hz, 1H,
SCH2), 3.76 (d, J＝13.51 Hz, 1H, SCH2), 4.39 (s, 1H,
OCH), 7.16—7.20 (m, 1H, ArH), 7.24—7.26 (m, 1H,
ArH), 7.37—7.41 (m, 4H, ArH), 7.82 (dd, J＝9.07, 2.91
Hz, 1H, ArH); IR (KBr) ν: 1681,＋ 1600, 1488, 124＋4
－1
cm ; MS (APCI) m/z: 321 (M＋H) , 323 (M＋2＋H) .
1
Anal. calcd for C16H10ClFO2S: C 59.91, H 3.14, S 10.00;
found C 59.89, H 3.10, S 10.03.
1467, 1382, 1269 cm ; MS (APCI) m/z: 253 (M＋H) .
Anal. calcd for C13H13FO2S: C 61.89, H 5.19, S 12.71;
found C 61.84, H 5.13, S 12.76.
6'-Fluoro-3-phenylspiro[oxirane-2,3'-thiochroman]-
4'-one (4l): Light yellow solid, yield 67%, m.p. 129—
131 ℃; UV-vis (MeOH) λmax: 244 nm; 1H NMR
(CDCl3, 600 MHz) δ: 2.61 (d, J＝13.51 Hz, 1H, SCH2),
3.76 (d, J＝13.54 Hz, 1H, SCH2), 4.44 (s, 1H, OCH),
7.15—7.19 (m, 1H, ArH), 7.25 (dd, J＝8.68, 4.86 Hz,
1H, ArH), 7.38—7.45 (m, 5H, ArH), 7.83 (dd, J＝9.11,
2.9－0 Hz, 1H, ArH); IR (KBr) ν: 1685,＋1598, 1471, 1276
Biological activity evaluation
In vitro anticancer activity The anticancer activi-
ties of target compounds were evaluated in vitro on
A-549 (human lung cancer cell lines), HeLa (human
cervical cancer cell lines) and HepG2 (Human liver
cancer cell lines) by measuring cell viability according
to the MTT method described in the literature26,27 with
cisplatin as the positive control. The cells were seeded
in RPMI 1640 medium (100 µL) in a 96-well plate at a
concentration of 6000—7000 cells per well. After cul-
turing for 12 h at 37 ℃ and 5% CO2, cells were incu-
bated with various concentrations of the samples for 24
h. Twenty microliter of MTT (5 mg/mL) was added and
incubated with the cells for 4 h. The formazan product
was dissolved by adding dimethyl sulfoxide (DMSO,
100 µL) to each well, and the plates were read at 570
nm. All measurements were performed in triplicate and
each experiment was repeated at least three times. IC50
values were determined as the drug and sample concen-
tration at 50% inhibition of the cell growth.
1
cm ; MS (APCI) m/z: 287 (M＋H) . Anal. calcd for
C16H11FO2S: C 67.12, H 3.87, S 11.20; found C 67.09,
H 3.77, S 11.17.
3-(Benzo[d][1,3]dioxol-5-yl)-6'-fluorospiro[oxirane-
2,3'-thiochroman]-4'-one (4m): Yellow solid, yield 64%,
1
m.p. 200—202 ℃; UV-vis (MeOH) λmax: 245 nm; H
NMR (CDCl3, 600 MHz) δ: 2.65 (d, J＝13.43 Hz, 1H,
SCH2), 3.77 (d, J＝13.38 Hz, 1H, SCH2), 4.34 (s, 1H,
OCH), 6.01 (s, 2H, OCH2O), 6.84 (d, J＝7.94 Hz, 1H,
ArH), 6.89—6.93 (m, 2H, ArH), 7.17 (dt, J＝8.55, 8.17,
2.85 Hz, 1H, ArH), 7.23—7.26 (m, 1H, ArH), 7.81 (dd,
J＝9.10, 2.82 Hz, 1H, ArH); IR (KBr) ν: 1685, 159＋8,
－1
1488, 1450, 1259 cm ; MS (APCI) m/z: 331 (M＋H) .
Anal. calcd for C17H11FO4S: C 61.81, H 3.36, S 9.71;
found C 61.89, H 3.29, S 9.68.
Acute toxicity test The experimental procedure
was operated according to the reported procedure and
guidelines.28 Kunming mice, which weighed 20—25 g
6'-Fluoro-3-(4-methoxyphenyl)spiro[oxirane-2,3'-
thiochroman]-4'-one (4n): Yellow-green solid, yield
Chin. J. Chem. 2011, 29, 757— 764
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
763

Ma et al.
FULL PAPER
(supplied from the Experimental Animal Center, Hebei
Medical University), were randomly divided into 7
groups (10 in each group, male and female in half).
Before the test, mice were fasted for 12 h. According to
the results of previous experiments, LD100 was 3814.7
mg/kg, LD0 was 1000.0 mg/kg. Solutions of different
concentrations were prepared, then the mice were fed
with different doses of liquid by intragastric administra-
tion according to the weight, and the dose volume was
10 mL/kg. After administration, they were observed for
2 weeks continuously, toxic reactions and the death
were recorded.
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 757— 764