Synthesis and antitumor activities of a new series of 4,5-dihydro-1H- thiochromeno[4,3-d]pyrimidine derivatives

Article abstract of DOI:10.1007/s11426-011-4477-6

A new series of 4,5-dihydro-1H-thiochromeno[4,3-d ]pyrimidine derivatives have been designed and synthesized. The antitumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay. Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines. The most potent compound 4-(benzo[d][1,3]dioxol-5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4, 5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50 = 0.44 μM, 3.07 μM) was 2.0 and 8.4 times more active than gefitinib (IC5₀ = 0.89 μM, 16.81 μM) against A549 and H460 cell lines, respectively.

Full text of DOI:10.1007/s11426-011-4477-6

SCIENCE CHINA
Chemistry
March 2012 Vol.55 No.3: 347–351
doi: 10.1007/s11426-011-4477-6
• ARTICLES •
Synthesis and antitumor activities of a new series of
4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives
GUO DeXiang, LIU YaJing, LI Ting, WANG Nan, ZHAI Xin, HU Chun* & GONG Ping*
Key Laboratory of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang 110016, China
Received April 22, 2011; accepted May 27, 2011; published online January 5, 2012
A new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized. The anti-
tumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549
(human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay. Most of the target compounds exhibited
significant antitumor activities against A549 and H460 cancer cell lines. The most potent compound 4-(benzo[d][1,3]dioxol-
5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50 = 0.44 M, 3.07
M) was 2.0 and 8.4 times more active than gefitinib (IC50 = 0.89 M, 16.81 M) against A549 and H460 cell lines, respec-
tively.
heterocycle, synthesis, 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives, antitumor activity
hypnotic, hypoglycaemic, antitumor and antihypertensive
1 Introduction
activities[3, 4]. It has been known that the 4,5-dihydro-
1H-thiochromeno[4,3-d]pyrimidine derivatives exhibited
various biological activities including anticancer, anti-
inflammatory, antifungal and herbicidal activities [57].
The thiochroman-4-one ring moiety belongs to the privi-
leged structure in modern medicinal chemistry, particularly
in the discovery of new antitumor and antiangiogenic agents
[8, 9]. In recent years, it has been found that the quinazo-
line-2(1H)-thione analogues which were obtained by the
high-throughput screening had good anti-Bcl-2 activity [10].
Due to both the importance of thiochroman derivatives and
the issues associated with their synthesis, we have directed
our efforts toward the development of effective methods for
the synthesis of these compounds. In this report, a series of
the 4,5-dihydro-1H-thiochromeno [4,3-d]pyrimidine deriva-
tives were designed and synthesized based on (i) the analy-
sis of the structure-activity relationship of the quinazo-
line-2(1H)-thione derivatives, (ii) quinazoline-2(1H)-thione
as the lead compound, and (iii) the combined principle of
bioisosterism and hybridization. The in vitro antitumor ac-
Cancer is a class of diseases in which a group of cells dis-
play uncontrolled growth, invasion that intrudes upon and
destroys adjacent tissues, and sometimes metastasis, i.e.
spreading to other locations in the body via lymph or blood.
Existing cancer solutions include chemotherapy, radiation
therapy, surgery, immunotherapy, monoclonal antibody
therapy and other methods. The most common way for
cancer treatment is based on the conventional chemotherapy
[1]. The molecules with quinazoline scaffold and thiochro-
man-4-one ring are potential anticancer agents to be devel-
oped as new drugs for chemotherapy.
The quinazoline scaffold is of great importance to chem-
ists and biologists as it is available in a large variety of nat-
urally occurring compounds [2]. It is also found in clinically
useful molecules with diverse biological activities, such as
antiviral, antimalarial, anticonvulsant, antibacterial, diuretic,
*Corresponding author (email: chunhu@syphu.edu.cn; gongpinggp@126.com)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

348
Guo DX, et al. Sci China Chem March (2012) Vol.55 No.3
tivities of the target compounds were evaluated.
ESI-MS (m/z): 205.0 ([M+Na]+).
6,7-Difluoro-3,4-dihydro-2H-1-benzothiopyran-4-one
(4c). White solid, 66% yield; mp: 101-102°C. ESI-MS (m/z):
223.0 ([M+Na]+).
2 Experimental
2.1 Chemistry
Synthesis of 2-methyl-2-thiopseudourea sulfate (6)
A mixture of thiourea (5) (7.6 g, 0.1 mol), TEBA (0.2 g,
0.01 mol), (CH3O)2SO2 (12.6 g, 0.1 mol), and water (50 mL)
was refluxed for 6 h and the reaction was monitored by
TLC. After cooling to room temperature, the precipitated
product was filtered off and washed with ethanol to give 6
as a white solid in 78% yield.
All reagents and solvents were obtained from commercial
suppliers and used without purification. Melting points were
determined by the capillary tube method and the melting
point instrument was uncorrected. Mass spectra (MS) were
recorded in ESI mode on the Agilent 1100LC-MS spec-
trometer (Agilent, Palo Alto, CA, USA). IR spectra were
recorded in the range of 4000400 cm1 using KBr pellets
1
Synthesis of aminocarboximidamides (7)
on a Bruker AFS55 spectrometer. H NMR spectra were
A solution of 2-methyl-2-thiopseudourea sulfate (1.4 g, 5
mmol), and organic amine (5 mmol) in water (20 mL) was
heated under reflux for 2 h. Then a solution of barium chlo-
ride (1.0 g, 5 mmol) in water (12.5 mL) was added dropwise
to the reaction mixture over 30 min. After addition, the re-
action mixture was refluxed for 1 h and then allowed to cool
to room temperature. After cooling and filtration, the filtrate
was concentrated leaving a syrup, dissolved in ethanol (5
mL), and the resulting solution was stripped. The obtained
solid was recrystallized from methanol.
Piperidine-1-carboximidamide (7a). White solid, 68%
yield; mp: 158159 °C. ESI-MS (m/z): 128.1 ([M+H]+).
Morpholine-4-carboximidamide (7b). White solid, 88%
yield; mp: 138139 °C (lit. [14] 138139 °C). ESI-MS
(m/z): 130.1 ([M+H]+).
4-Methylpiperazine-1-carboximidamide (7c). White solid,
78% yield; mp: 148149 °C. ESI-MS (m/z): 143.0
([M+H]+).
4-Benzylpiperazine-1-carboximidamide (7d). White sol-
id, 70% yield; mp: 184185 °C. ESI-MS (m/z): 219.0
([M+H]+).
performed on a Bruker spectrometer (Bruker Bioscience,
Billerica, MA, USA) operating at 300 MHz in DMSO-d6
with TMS as the internal standard. 13C NMR spectra were
performed on the same Bruker spectrometers operating at
75 MHz in DMSO-d6 with TMS as the internal standard.
The microwave irradiated reactions were performed in a
Yuhua WBFY-201 domestic household microwave oven.
Synthesis of 3-(arylthio)propa-noic acids (3)
The solution of thiophenol (1) (0.5 mol) in aqueous KOH
(10%, 250 mL) and EtOH (300 mL) was mixed with
3-chloropropanoic acid (0.5 mol) in the saturated aqueous
solution of K2CO3 (0.5 mol). The resulting mixture was
refluxed for 5 h, cooled to room temperature, concentrated
under vacuum, and neutralized with 18% HCl solution until
pH 3. The resulting precipitate was filtered and washed se-
quentially with water (20 mL) and petroleum ether (20 mL)
to give 3-(arylthio)propanoic acid (3) as a white solid.
3-(2-Methoxyphenylthio)propanoic acid (3a). White sol-
id, 66% yield; mp: 9192 °C (lit. [11] 9293 °C). ESI-MS
(m/z): 234.9 ([M+Na]+), 251.0 ([M+K]+).
3-(4-Fluorophenylthio)propanoic acid (3b). White solid,
90% yield; mp: 7576 °C (lit. [10] 7576 °C). ESI-MS (m/z):
222.9 ([M+Na]+), 239.0 ([M+K]+).
4-(4-Methoxyphenyl)piperazine-1-carboximidamide (7e).
White solid, 78% yield; mp: 145146 °C. ESI-MS (m/z):
234.9 ([M+H]+).
3-(3,4-Difluorophenylthio)propanoic acid (3c). White
solid, 90% yield; mp: 9293 °C. ESI-MS (m/z): 241.0
([M+Na]+), 256.9 ([M+K]+).
Synthesis of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrim-
idines (CH01CH11)
A mixture of aldehyde (8) (0.01 mol), ketone (4) (0.01
mol), and aminocarboximidamide (7) (0.01 mol) was sub-
jected to microwave heating for 5 min using acetonitrile (5
mL) as the energy transfer medium and the KOH aqueous
solution (0.5 mL) as the catalyst. The reaction mixture was
allowed to stand at room temperature for a few hours. Upon
completion of the reaction as monitored by TLC, the solvent
was removed by distillation, and the resulting mixture was
adjusted to pH 7 with AcOH at 10 °C. The precipitate was
collected by filtration, and purified by silica gel column
chromatography (eluent : CH2Cl2-MeOH, 9:1) to give the
4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives
as the target compounds.
Synthesis of 3,4-dihydro-2H-1-benzothiopyran-4-ones (4)
According to the reported procedure [12], 3-(arylthio)
propanoic acid (3) (0.2 mol) was dissolved in concentrated
H2SO4 (200 mL) at 5 °C and set aside overnight. Then 200
g ice was poured in, and cooled for 1 h. The solid was fil-
tered and recrystallized from petroleum ether to give
3,4-dihydro-2H-1-benzothiopyran-4-one (4).
8-Methoxy-3,4-dihydro-2H-1-benzothiopyran-4-one (4a).
White solid, 75% yield; mp: 6061 °C. ESI-MS (m/z):
216.9 ([M+Na]+), 232.9 ([M+K]+).
6-Fluoro-3,4-dihydro-2H-1-benzothiopyran-4-one (4b).
White solid, 80% yield; mp: 9697 °C (lit. [13] 9697 °C).

Guo DX, et al. Sci China Chem March (2012) Vol.55 No.3
349
8,9-Difluoro-2-(4-(4-methoxyphenyl)piperazin-1-yl)-4-
phenyl-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine
(CH01). Yield: 45%. mp: 195196 °C; ESI-MS (m/z):
504.9, 505.9; IR (KBr, cm-1): 3420.0, 2840.4, 1591.0,
8,9-Difluoro-2-(4-(4-methoxyphenyl)piperazin-1-yl)-4-(3,
4,5-trimethoxyphenyl)-4,5-dihydro-1H-thiochromeno[4,3-d
]pyrimidine (CH06). Yield: 61%. mp: 209213 °C; ESI-MS
(m/z): 595.2, 596.2; IR (KBr, cm1): 3442.4, 2937.7, 1590.7,
1
1
1512.7, 1300.9, 1249.3, 1033.7; H NMR (DMSO-d6, 300
1510.5, 1305.8, 1248.8, 1126.3; H NMR (DMSO-d6, 300
MHz) : 2.963.06 (m, 4H), 3.133.18 (m, 2H), 3.483.53
(m, 4H), 3.68 (s, 3H), 5.02 (s, 1H), 6.84 (d, 1H, J = 9 Hz),
6.93 (d, 2H, J = 9 Hz), 7.277.37 (m, 5H), 7.39 (s, 1H),
7.48 (d, 1H, J = 2.7 Hz), 7.86 (dd, 1H, J1 = 3.9 Hz, J2 = 12
Hz), 10.20 (s, 1H).
4-(Benzo[d][1,3]dioxol-5-yl)-8,9-difluoro-2-(4-(4-metho-
xyphenyl)piperazin-1-yl)-4,5-dihydro-1H-thiochromeno
[4,3-d]pyrimidine (CH02). Yield: 56%. mp: 155157 °C;
ESI-MS (m/z): 548.8, 548.6; IR (KBr, cm-1): 3412.3, 2891.5,
1593.8, 1512.9, 1342.3, 1248.3, 1037.0; 1H NMR
(DMSO-d6, 300 MHz) δ: 2.973.05 (m, 4H), 3.133.18 (m,
1H), 3.4854 (m, 4H), 3.68 (s, 3H), 4.95 (s,1H), 5.98 (s,
2H), 6.836.93 (m,6H), 7.31 (dd, 1H, J1 = 3.3 Hz, J2 = 10.2
Hz), 7.45 (d, 1H, J = 3.3 Hz), 7.86 (dd, 1H, J1 = 9 Hz, J2 =
12 Hz), 9.80 (s,1H).
9-Fluoro-2-(piperidin-1-yl)-4-(3,4,5-trimethoxyphenyl)-4,
5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH03).
Yield: 52%. mp: 180181 °C; ESI-MS (m/z): 469.9, 471.8;
IR (KBr, cm1): 3397.2, 2935.4, 1592.0, 1555.5, 1323.9,
1236.2, 1127.2; 1H NMR (DMSO-d6, 300 MHz) δ:
1.411.54 (m, 6H), 3.153.31 (m, 2H), 3.43 (s, 4H), 3.62 (s,
3H), 3.73 (s, 6H), 4.95 (s, 1H), 6.73 (s, 1H), 6.97 (d, 1H, J =
6 Hz), 7.2 (m, 2H), 7.63 (d, 1H, J=9 Hz), 10.19 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz): δ 153.6, 153.4, 142.9, 140.9,
137.5, 137.0, 128.5, 127.6, 114.7, 114.4, 112.5, 112.2,
104.5, 60.6, 58.2, 56.5, 47.0, 27.1, 26.1, 25.0.
4-(8,9-Difluoro-4-(3,4,5-trimethoxyphenyl)-4,5-dihydro-
1H-thiochromeno[4,3-d]pyrimidin-2-yl)morpholine (CH04).
Yield: 49%. mp: 115116 °C; ESI-MS (m/z): 490.3, 491.3;
IR (KBr, cm1): 3397.8, 2963.8, 1593.8, 1563.8, 1351.9,
1233.2, 1125.4; 1H NMR (DMSO-d6, 300 MHz) δ:
3.153.23 (m, 2H), 3.343.48 (m, 4H), 3.523.61 (m, 4H),
3.63 (s, 3H), 3.74 (s, 6H), 5.01 (s, 1H), 6.71 (s, 1H), 7.32
(dd, 1H, J1 = 10 Hz, J2 = 12 Hz), 7.37 (s,1H), 7.82 (dd,1, J1
= 8 Hz, J2 = 12 Hz), 10.19 (s,1H).
MHz) δ: 2.973.06 (m, 4H), 3.133.18 (m, 2H), 3.543.59
(m, 4H), 3.62 (s, 3H), 3.68 (s, 3H), 3.72 (s, 6H), 5.01 (s,
1H), 6.72 (s, 2H), 6.816.93 (m, 4H), 7.33 (dd, 1H, J1 = 7.8
Hz, J2 = 10.5 Hz), 7.46 (s, 1H), 7.85 (dd, 1H, J1 = 9 Hz, J2 =
12.3 Hz), 10.20 (s. 1H); 13C NMR (DMSO-d6, 75 MHz) δ:
153.9, 153.6, 149.5, 148.1, 146.3 146.0, 140.6, 137.5, 136.6,
136.5, 129.1, 120.9, 118.5,115.0, 104.5, 58.1, 57.3, 56.5,
55.9, 51.1, 50.4, 45.6, 27.0.
2-(4-Benzylpiperazin-1-yl)-8,9-difluoro-4-(3,4,5-trimeth-
oxyphenyl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine
(CH07). Yield: 57%. mp: 212213 °C; ESI-MS (m/z):
578.9, 579.9; IR (KBr, cm1): 3427.1, 2940.1, 1591.2,
1
1488.9, 1303.8, 1232.7, 1128.2; H NMR (DMSO-d6, 300
MHz) δ: 2.342.39 (m, 4H), 3.133.18 (m, 2H), 3.393.52
(m, 4H), 3.63 (s, 3H), 3.73 (s, 6H), 3.82 (s, 2H), 4.97 (s,
1H), 6.70 (s, 2H), 7.257.32 (m, 5H), 7.657.77 (m, 2H),
10.20 (s. 1H).
8,9-Difluoro-2-(piperidin-1-yl)-4-(3,4,5-trimethoxyphenyl)-
4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine
(CH08).
Yield: 48%. mp: 9495 °C; ESI-MS (m/z): 487.9, 488.9; IR
(KBr, cm1): 3464.2, 2934.7, 1593.9, 1562.8, 1350.2,
1233.4, 1126.0; 1H NMR (DMSO-d6, 300 MHz) δ:
1.471.57（m, 6H）, 3.213.32 (m, 2H), 3.47 (s, 4H), 3.64 (s,
3H), 3.74 (s, 6H), 5.00 (s, 1H), 6.76 (s, 2H), 7.367.42 (m,
1H), 7.727.79 (m, 1H), 10.20 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 153.6, 153.4, 143.3 140.8, 137.5,
136.6, 136.5, 129.0, 115.9, 114.5, 114.2, 104.5, 60.7, 58.0,
56.5, 46.4, 27.1, 26.1, 24.9.
2-(4-Benzylpiperazin-1-yl)-7-methoxy-4-phenyl-4,5-
dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH09). Yield:
45%. mp: 150152 °C; ESI-MS (m/z): 483.3, 485.3; IR
(KBr, cm1): 3426.0, 2931.4, 1593.1, 1529.1, 1353.0,
1236.1, 1134.0; 1H NMR (DMSO-d6, 300 MHz) δ:
2.342.39 (m, 4H), 3.133.18 (m, 2H), 3.413.48 (m, 6H),
3.71 (s, 3H), 4.95 (s, 1H), 6.69 (d, 2H, J = 9 Hz), 7.257.35
(m, 10H), 7.82 (d, 1H, J = 8.4 Hz), 10.20 (s, 1H).
4-(7-Methoxy-4-(3,4,5-trimethoxyphenyl)-4,5-dihydro-
1H-thiochromeno[4,3-d]pyrimidin-2-yl)morpholine (CH10).
Yield: 46%. mp : 113115 °C; ESI-MS (m/z): 483.9, 484.9;
IR (KBr, cm1): 3386.3, 2935.9, 1594.8, 1566.9, 1348.4,
1266.8, 1126.8; 1H NMR (DMSO-d6, 300 MHz) δ:
3.123.17 (m, 2H), 3.343.46 (m, 4H), 3.533.60 (m, 4H),
3.63 (s, 3H), 3.72 (s, 3H), 3.74 (s, 6H), 4.97 (s, 1H), 6.70 (d,
1H, J = 8.4 Hz), 6.73 (s, 2H), 7.28 (s, 1H), 7.82 (d, 1H, J =
8.4Hz), 10.20 (s, 1H).
4-(Denzo[d][1,3]dioxol-5-yl)-8,9-difluoro-2-(4-methylpi-
perazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine
(CH05). Yield: 55%. mp: 201202 °C; ESI-MS (m/z):
456.8, 457.8; IR (KBr, cm1): 3448.8, 2934.6, 1593.3,
1
1556.7, 1347.3, 1292.2, 1151.2; H NMR (DMSO-d6, 300
MHz) δ: 2.17 (s, 3H), 2.222.34 (m, 4H), 3.123.17 (m,
2H), 3.363.44 (m, 4H), 4.92 (s,1H), 5.98 (s, 2H),
6.816.88 (m, 2H), 7.30 (dd, 1H, J1 = 6.6 Hz, J2 = 10.8 Hz),
7.33 (s, 1H), 7.82 (dd, 1H, J1 = 3.3 Hz, J2 = 12.6 Hz), 10.20
(s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 153.4, 148.2,
147.4, 139.4, 136.1, 128.9, 127.7, 120.5,115.8, 115.5, 114.5,
114.3, 108.8, 107.7, 104.3, 101.7, 57.9, 55.1, 46.5, 45.2,
26.9.
4-(8,9-Difluoro-4-phenyl-4,5-dihydro-1H-thiochromeno
[4,3-d]pyrimidin-2-yl)morpholine (CH11). Yield: 47%. mp:

350
Guo DX, et al. Sci China Chem March (2012) Vol.55 No.3
190192 °C; ESI-MS(): 502.9, 503.9; IR (KBr, cm1):
3335.3, 2977.3, 1588.2, 1552.8, 1392.1, 1273,2, 1120.9; H
NMR (DMSO-d6, 300 MHz) δ: 2.17 (s, 3H), 22.50 (m,
4H), 3.193.24 (m, 2H), 3.413.53 (m, 4H), 3.63 (s, 3H),
3.74 (s, 6H), 4.97 (s, 1H), 6.71 (s, 2H), 7.267.32 (dd, 1H,
J1 = 8 Hz, J2 = 10.8 Hz), 7.747.78(dd, 1H, J1 = 8.7 Hz, J2 =
12.6 Hz), 10.20 (s, 1H).
thesized in satisfactory yields, and the synthetic pathways
are described in Scheme 1. The 3-(arylthio)propanoic acid
(3) derivatives were synthesized from substituted thiophenol
(1) and 3-chloropropanoic acid (2). Subsequently the key
intermediate thiochroman-4-ones (4) have been prepared by
Friedel-Crafts intermolecular acylation from 3-(arylthio)
propanoic acids with yields from 66% to 80% according to
the literature method [10]. Meanwhile, methyl carbamimi-
dothioate (6) was synthesized by methylation of thiourea (5)
with dimethyl sulfate in 78% yield, and methyl carbamimi-
dothioate (6) was heated with amines under reflux for 2 h to
give aminocarboximidamides (7) with yields from 68% to
88% according to the literature method [12]. Finally, a
one-pot condensation of thiochroman-4-ones (4) with ami-
nocarboximidamides (7) and aldehydes (8) has provided the
target compounds (CH01CH11) in 45% to 61% yield. All
target compounds were unreported in the literature, and
characterized by NMR and MS.
1
2.2 Antitumor activities assay in vitro
The antitumor activities of the target compounds
(CH01CH11) were evaluated with human alveolar ade-
nocarinoma cell line A549 and human lung cancer cell line
H460 by the standard MTT assay in vitro [12], with ge-
fitinib as the positive control. The cancer cell lines were
cultured in minimum essential medium (MEM) supple-
mented with 10% fetal bovine serum (FBS). Approximately
4 × 103 cells, suspended in MEM, were plated onto each
well of a 96-well plate and incubated in 5% CO2 at 37 °C
for 24 h. The tested compounds at the indicated final con-
centrations were added to the culture medium and the cell
cultures were continued for 72 h. Fresh MTT was added to
each well at the terminal concentration of 5 g/mL and in-
cubated with cells at 37 °C for 4 h. The formazan crystals
were dissolved in 100 L DMSO each well, and the absor-
bency at 492 nm (for absorbance of MTT formazan) and
630 nm (for the reference wavelength) was measured using
the ELISA reader. All of the compounds were tested twice
in each of the cell lines. The results expressed as IC50 (in-
hibitory concentration 50%) were the averages of two
measurements and calculated by using the Bacus Laborato-
ries Incorporated Slide Scanner (Bliss) software.
3.2 Biological activities
The antitumor activities were determined by the standard
MTT assay against two cancer cell lines A549 and H460
with gefitinib, a standard anticancer drug, as the positive
control. The screening results expressed as IC50 are summa-
rized in Table 1. The IC50 values were the average of two
independent experiments.
According to the antitumor activity data, some of the
target compounds exhibited potential anticancer activities.
For example, the target compound CH05 showed the high-
est potency against A549 and H460 cancer cell lines while
compounds CH11 and CH08 were nearly as active as ge-
fitinib against A549 and H460 cancer cell lines. In all test-
ed compounds, CH10 was inactive. As shown in Table 1,
the target compound CH02 was more potent against H460
cancer cell line than against A549 cancer cell line. These
results suggest the series of the target compounds possessed
selectivity for A549 cancer cell line.
3 Result and discussion
3.1 Chemistry
In general, the target compounds (CH01CH11) were syn-
Scheme 1 The synthetic route of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives.

Guo DX, et al. Sci China Chem March (2012) Vol.55 No.3
351
Table 1 The antitumor activities of the target compounds
IC50 (M)
IC50 (M)
A549
6.15
5.12
6.18
0.20
0.44
13.00
H460
17.06
1.04
A549
5.01
0.68
4.14
37.26
0.78
0.89
H460
8.65
CH01
CH02
CH03
CH04
CH05
CH06
CH07
CH08
2.66
8.95
CH09
3.11
4.90
CH10
88.00
4.76
3.07
CH11
12.20
Gefitinib
16.81
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nocarboximidamides was crucial for improving their activi-
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4 Conclusions
In summary, a new series of 4,5-dihydro-1H-thiochrome-
no[4,3-d]pyrimidine derivatives were synthesized via the
modified method of a one-pot three-component condensa-
tion reaction. The antitumor activities of the target com-
pounds were evaluated against two human cancer cell lines
(A549 and H460). Most of the target compounds displayed
from moderate to excellent antitumor activities against one
or two cancer cell lines. In particular, the target compound
CH05 showed potent antitumor activity against both cancer
cell lines. Further studies are in progress in our laboratories
and will be reported in the future.
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This work was supported by the National Natural Science Foundation of
China (20474053). The authors would like to thank Analytical and Testing
Center, Shenyang Pharmaceutical University for acquiring the NMR spec-
tra data.
1
Dai LJ, Moniri MR, Zeng ZR, Zhou JX, Rayat J, Warnock GL. Po-