Design, synthesis and cytotoxicity of novel 2-arylvinyl-4- aminoquinoline derivatives

Article abstract of DOI:10.1248/cpb.60.659

With an aim to develop promising anti-tumor agents, a novel series of 2-arylvinyl-4-aminoquinoline derivatives were designed, synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2 and SGC-7901 cell lines in vitro. The pharmacological results indicated that most compounds were more potent than the positive controls, especially compounds 8, 14 and 16 with IC₅₀ values ranging from 0.05 to 0.85 μM against all tested cell lines respectively, which were 5.7- to 112-fold better than Iressa. The most active compound 14 (IC₅₀ values of 0.05, 0.25, 0.16, 0.68 μM), bearing 4-fluorostyryl at C-2 position and 3-(dimethylamino)-1-propylamino at C-4 position, showed great promise as a lead for the development of more effective quinoline analogues.

Full text of DOI:10.1248/cpb.60.659

May 2012
Regular Article
Chem. Pharm. Bull. 60(5) 659–664 (2012)
659
Design, Synthesis and Cytotoxicity of Novel 2-Arylvinyl-4-
aminoquinoline Derivatives
Nan Jiang, Xin Zhai, Zhichao Chen, Chuang Liang, Chao Sun, Jing Han,* and Ping Gong*
Key Lab of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering,
Shenyang Pharmaceutical University; 110016 Shenyang, P.R. China.
Received February 7, 2012; accepted March 8, 2012
With an aim to develop promising anti-tumor agents, a novel series of 2-arylvinyl-4-aminoquinoline
derivatives were designed, synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2
and SGC-7901 cell lines in vitro. The pharmacological results indicated that most compounds were more
potent than the positive controls, especially compounds 8, 14 and 16 with IC50 values ranging from 0.05 to
0.85µM against all tested cell lines respectively, which were 5.7- to 112-fold better than Iressa. The most
active compound 14 (IC50 values of 0.05, 0.25, 0.16, 0.68µM), bearing 4-fluorostyryl at C-2 position and
3-(dimethylamino)-1-propylamino at C-4 position, showed great promise as a lead for the development of
more effective quinoline analogues.
Key words 2-arylvinyl-4-aminoquinoline; design; synthesis; cytotoxicity
Antitumor agents based on 4-aminoquinazoline and 4-ami- 5–19 with halogen atom at C-6 or C-7 position on quinoline
noquinoline skeletons have aroused increasing attentions in ring were designed and synthesized based on the structure of
the last few years, such as Iressa, EKB-569 and 2,4-disub- CQ derivative 21. Further modifications were performed by
stituted quinolines (Fig. 1).1,2) 4-Aminoquinoline derivative introducing various aliphatic amines into C-4 position and
chloroquine (CQ) has been widely applied for decades (Fig. arylvinyl into C-2 position of quinoline ring. Meanwhile, their
1) owing to its remarkable clinical effect on malaria, chronic pharmacological activity against four typical cancer cell lines
infectious arthritisother and other immunological diseases, including non-small-cell lung cancer cell line (H-460), human
which was further identified anti-tumor potency when com- colorectal cancer cell line (HT-29), human liver cancer cell
bined with radiation in 1970s.3) It was not until recently that line (HepG2) and stomach cancer cell line (SGC-7901) was
CQ was disclosed to possess direct cytotoxic activity against screened to evaluate their cytotoxicity.
different cancer cell lines, such as human lung cancer, breast
cancer and colon cancer cells.4–7) Moreover, Strekowski et al.
Results and Discussion
developed a short series of 2-alkyl-4-aminoquinoline deriva-
Chemistry The general methods employed for the prepa-
tives (e.g., 20, 21) as immunostimulatory agents.8,9) Thereinto, ration of 2-arylvinyl-4-aminoquinoline derivatives 5–19 are
compound 20 with aryl at C-2 position was reported unex- outlined in Chart 1. The compounds 1a–c were synthesized
pectedly for its significant anti-angiogenesis activity in chick from appropriate aniline and commercially available ethyl
embryo chorioallantoic membrane (CAM) assay superior to acetoacetate in the presence of ammonium ceric nitrate at
CQ.10) In view of the noteworthy cytotoxic activity of CQ and 40 C for 20–24h.
The crude products were purified by
11,12)
°
compound 20, analogue 21 with 2-styryl group is supposed to recrystallization from ethanol, which were treated with di-
°
phenyl ether at 250 C to afford the cyclization intermediates
possess similar effect as well.
With an aim to develop promising anti-tumor agents, a 2-methylquinolin-4-ones 2a–c.13,14) Furthermore, chlorina-
novel series of 2-arylvinyl-4-aminoquinoline derivatives tion of compounds 2a–c with phosphoryl chloride provided
Fig. 1. Structures of 4-Aminoquinazoline and 4-Aminoquinoline Derivatives
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: gongpinggp@126.com
© 2012 The Pharmaceutical Society of Japan

660
Vol. 60, No. 5
°
°
°
Reagents and conditions: (a) Ce(NH4)2(NO3)6, 40 C, 20–24h; (b) Ph2O, 250 C, 20min; (c) POCl3, 80 C, 1.5h; (d) NH2(CH2)nNR3R4, reflux, 6–10h; (e) ArCHO,
ZnCl2, DMF, reflux, 0.5–1h.
Chart 1. Synthesis of Compounds 5–19
4-chloro-2-methylquinolines 3a–c in good yields (95–98%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
Reaction of 3a–c with an excess of corresponding aliphatic (MTT) assay in vitro. The data for CQ derivative 20 and Ir-
amines at reflux without any solvent gave rise to the key inter- essa were included for comparison, and the results expressed
mediates 4a–g.15)
as IC50 values were summarized in Table 1. The IC50 values
The main challenge in this work was the development of a are the average of at least two independent experiments.
simple and efficient method to prepare 2-arylvinyl-4-amino- As shown, most of the target compounds were more potent
quinolines 5–19, which served as the target compounds. than the positive controls 20 and Iressa, and nine of them ex-
According to the literatures, 2-arylvinylquinolines can be hibited excellent cytotoxicity against all tested cell lines supe-
obtained by condensation of 2-methylquinolines and aryl al- rior to controls, with IC50 values of 0.05 to 2.52µM. The most
dehydes under Knoevenagel conditions, that is acetic acid as promising compound 14, bearing 4-fluorostyryl at C-2 position
16)
°
a solvent at 100 C for 24h, or catalyzed by melting zinc and 3-(dimethylamino)-1-propylamino at C-4 position, showed
chloride for 2h.17,18) However, both methods were failed for the best cytotoxicity (IC50 values of 0.05, 0.25, 0.16, 0.68µM),
the reasons of a number of side reactions or the black viscous which was 13- to 112-fold better than Iressa. In addition, all
state of reaction systems. After repeated experiments, we were compounds exhibited more potency on H-460 cell line than on
delighted to find that solvent had a great impact on the stabili- the other three cell lines, which reflected an excellent selectiv-
ty and rates of reactions, which encouraged us to optimize the ity for lung cancer.
reaction conditions to prepare pure products in high yields. Fi-
The differences in pharmacological activity are supposed
nally, the target compounds 5–19 were successfully achieved to be attributable to multiple factors such as the nature of
via the reaction of aryl aldehydes and the intermediates 4a–g substituents at the C-6 and C-7 positions, the side chains at
in the presence of zinc chloride anhydrous in refluxing N,N- C-2 and C-4 positions, and the genetic and biochemical back-
dimethylformamide for 0.5–1h. The products obtained were ground of the tested cell lines. Firstly, the arylvinyl side-chain
purified by recrystallization from methanol/N,N-dimethyl- at C-2 position had a major influence on cytotoxicity. Gener-
formamide, and their chemical structures were confirmed by ally, compounds bearing 4-fluorophenyl were more potent
1H-NMR and MS spectra.
than that bearing 4-methoxyphenyl and 5-piperonyl groups (16
This method for the preparation of 2-arylvinyl-4-amino- vs. 17, 19), as can be illustrated from the comparing between
quinolines is attractive since it predominantly generates the compounds 6 and 7 as well. The replacement of phenyl rings
(E)-isomer from simple building blocks. Coupling constants with five-membered heterocyclic groups resulted in a decrease
(J=14–17Hz) from the proton nuclear magnetic resonance in cytotoxicity (5 vs. 6, 18 vs. 17). It was noticeable that strong
(1H-NMR) spectra of the target compounds clearly indicated electrophilic groups at C-2 position weakened the activity dra-
that derivatives 5–19 were both geometrically pure and were matically, such as compounds 10–12 substituted with 4-meth-
exclusively trans (E) isomers.
ylsulphonylphenyl and 4-pyridyl groups were 1.5- to 4.9-fold
Biological Evaluation The cytotoxicity of all the tar- less potent relative to the positive control 20. The results are
get compounds was measured against four human cancer thought to be beneficial for further research on structure–ac-
cell lines (H-460, HT-29, HepG2 and SGC-7901) by the tivity relationships (SARs) of quinoline analogues.

May 2012
661
Table 1. The Substituents and Cytotoxicity of Compounds 5–19
IC50 (μmol/L)
Compd.
R1
F
R2
H
n
NR3R4
Ar
H-460
1.15
HT-29
HepG2
1.61
SGC-7901
5
2
2.13
2.43
6
7
F
F
H
H
H
H
H
2
2
3
3
2
0.74
0.42
0.12
1.83
2.56
1.25
1.22
0.72
0.36
2.07
4.54
2.09
0.75
0.59
2.31
4.35
1.23
0.74
3.72
6.31
8
F
9
F
10
Cl
11
12
13
14
15
16
17
Cl
Cl
Cl
Cl
Cl
F
H
H
2
3
2
3
3
3
3
5.28
3.69
0.28
0.05
1.09
0.15
0.32
6.34
6.58
0.63
0.25
1.27
0.40
0.76
8.60
5.30
0.33
0.16
1.62
0.29
0.62
13.93
10.34
0.95
0.68
2.52
0.85
1.25
H
H
H
Cl
Cl
F
18
19
F
F
Cl
Cl
3
3
1.80
1.24
4.52
1.56
1.76
1.84
3.43
2.38
20
3.52
5.59
1.35
3.36
2.06
6.42
4.92
Iressa
10.26

662
Vol. 60, No. 5
Further investigations were carried out on the effect of ali-
General Procedure for the Preparation of 6,7-Substitut-
phatic amines on the side chains at C-4 position. Remarkably, ed-2-methylquinolin-4-ol (2a–c) Compounds 1a–c (0.2mol)
compounds substituted with a morpholinyl group were less were added portion-wise to a stirred solution of diphenyl ether
°
active in comparison to that with a dimethylamino group (9 (200mL) at 250 C within 10min. The resulting solution was
°
vs. 8 and 15 vs. 14). Therefore, we can deduce that the bulk of stirred for 20min and cooled to 40 C, then the solid formed.
morpholinyl group blocked the conjunction between molecule Ether (150mL) was added, the mixture was stirred for a while
and receptor, which exerts an important effect on the pharma- and cooled to room temperature. The gray powder formed
cological activity. Furthermore, a chlorine atom was favorable was filtered and washed with ether to afford compounds 2a–c
in this region, and compounds with a chlorine atom at the (89–95%).
C-6- or C-7 position on quinoline ring (13–17) were slightly
more active than that (7–9) with a fluorine atom, respectively.
General Procedure for the Preparation of 6,7-Substi-
tuted-4-chloro-2-methylquinoline (3a–c) mixture of
compounds 2a–c (0.1mol) in phosphorus oxychloride (70mL)
A
°
were heated to 80 C for 1.5h. Excess phosphorus oxychloride
Conclusion
Taken as a whole, an efficient optimized method was em- was then removed under reduced pressure. The residues were
ployed to generate 2-arylvinylquinolines, using zinc chloride poured into ice water (500mL), stirred intensively for 1h and
anhydrous in refluxing N,N-dimethylformamide. A novel filtered in order to remove insoluble solid. The filtrate was
series of 2-arylvinyl-4-aminoquinoline derivatives were de- neutralized with aqueous ammonia to a pH of 8–9, filtered and
signed and synthesized. Meanwhile, their cytotoxicity against dried to give compounds 3a–c (95–98%) as pale or light pink
four human cancer cell lines (H-460, HT-29, HepG2 and solids.
SGC-7901) was evaluated. The most potent compound 14 was
112-fold more active than Iressa on H-460 cell. In comparison tuted-2-methyl-4-aminoquinoline (4a–g)
General Procedure for the Preparation of 6,7-Substi-
mixture of
A
with Iressa, the potent compounds exhibited better cytotoxic- compounds 3a–c (50mmol) and aliphatic amines (0.2mol)
ity owning to the structural modification by introduction of was stirred at reflux for 6–10h and then cooled to room tem-
2-arylvinyl and 4-alkylamino group instead of the 4-phenyl- perature. Water (200mL) was added to the solution, and the
amino group. The preliminary SARs showed that 4-fluoro- products were precipitated and collected, washed several times
phenylvinyl at C-2 positon and steric hindrance of substituents with water, and dried to afford compounds 4a–g (95–99%) as
on the side chains at C-4 positon were essential for antitumor pale solids.
activity. Moreover, introduction of chlorine atom into the C-6
Compound 4a was prepared from 3a and N,N-dimethyl-
or C-7 position of quinoline ring is beneficial for cytotoxicity. ethylenediamine. Compound 4b was prepared from 3a and
These encouraging results could offer an excellent framework N,N-dimethyl-1,3-propane diamine. Compound 4c was pre-
for further development.
pared from 3a and N-(3-aminopropyl)morpholine. Compound
4d was prepared from 3b and N,N-dimethylethylenediamine.
Compound 4e was prepared from 3b and N,N-dimethyl-1,3-
Experimental
Reagents and General Procedures Melting points were propane diamine. Compound 4f was prepared from 3b and
obtained on a Büchi Melting Point B-540apparatus (Büchi N-(3-aminopropyl)morpholine. Compound 4g was prepared
Labortechnik, Flawil, Switzerland) and were uncorrected. from 3c and N,N-dimethyl-1,3-propane diamine.
Mass spectra (MS) were taken in electrospray ionization
General Procedure for the Preparation of Compounds
(ESI) mode on Agilent 1100 LC-MS (Agilent, Palo Alto, CA, 5–19 Zinc chloride anhydrous (0.5mmol) was added rapidly
U.S.A.). High-resolution mass spectra (HR-ESI-MS) were ob- to a mixture of compounds 4a–4g (1mmol), aryl aldehyde
tained on Bruker microTOF-Q 125 mass spectrometer (Bruker (1.1mmol) and N,N-dimethylformamide (1mL). The reaction
Daltonics, Bremen, Germany). Proton (1H) nuclear magnetic mixture was refluxed for 20–60min and cooled to 70 C, meth-
°
resonance spectroscopy were performed using Bruker ARX- anol (8mL) was added and refluxed for 1h. The yellow solids
300, 300MHz spectrometers (Bruker Bioscience, Billerica, were precipitated, filtered while the mixture was brought to
MA, U.S.A.) with TMS as an internal standard. Unless oth- room temperature and washed with methanol. The crude prod-
erwise noted, all common reagents and solvents were used as ucts were purified by recrystallization from methanol/N,N-
obtained from commercial suppliers without further purifica- dimethylformamide to afford the title compounds 5–19.
tion.
General Procedure for the Preparation of Ethyl-3-(3,4- N2,N2-dimethylethane-1,2-diamine (5) Compound
substituted-phenylamino)but-2-enoate (1a–c) 3,4-Substi- a dark yellow powder was prepared from 4a and furan-
(E)-N1-(6-Fluoro-2-(2-(furan-2-yl)vinyl)quinolin-4-yl)-
as
5
°
tuted aniline (0.5mol) were dissolved in ethyl acetoacetate 2-carbaldehyde. Yield: 80%; mp 106–110 C; MS (ESI) m/z:
(0.6mol) at room temperature. Then, ammonium ceric nitrate 326.2, 327.1 (M+); HR-MS (ESI) m/z: 326.1986 (M+) (Calcd
1
°
(5mmol) was added and the mixture was stirred at 40 C for for C19H20FN3O: 326.1989); H-NMR (DMSO-d6) δ: 8.03 (1H,
20–24h. After the reaction was completed, ethanol (50mL) d, J=9.9Hz), 7.85–7.73 (2H, m), 7.58 (1H, d, J=16.7Hz), 7.49
was added and the mixture was stirred for another 0.5h. The (1H, t), 7.05 (1H, d, J=16.7Hz), 6.97 (1H, s), 6.74 (2H, s), 6.60
°
mixture was cooled to 0 C, separated by filtration, washed (1H, s), 3.50 (2H, q), 2.60 (2H, t), 2.24 (6H, s).
with cool ethanol. The crude products were purified by recrys-
(E)-N1-(6-Fluoro-2-(4-methoxystyryl)quinolin-4-yl)-
tallization from ethanol to give compounds 1a–c (65–72%) as N2,N2-dimethylethane-1,2-diamine (6) Compound
6 as
white crystals.
a bright yellow powder was prepared from 4a and p-anisal-
°
Compound 1a was prepared from 4-fluoroaniline, com- dehyde. Yield: 85%; mp 151–155 C; MS (ESI) m/z: 366.2,
pound 1b was prepared from 4-chloroaniline, and compound 367.2 (M+); HR-MS (ESI) m/z: 366.1979 (M+) (Calcd for
1c was prepared from 3-chloro-4-fluoroaniline.
C22H25FN3O: 366.1980); 1H-NMR (DMSO-d6) δ: 8.02 (1H,

May 2012
663
dd, J=11.1Hz), 7.81 (1H, dd, J=8.7, 6.3Hz), 7.71–7.63 (3H, 7.69 (3H, t, J=17.4, 6.3Hz), 7.65–7.55 (2H, m, J=16.5, 5.4Hz),
t, J=15.3, 8.1Hz), 7.49 (1H, td, J=8.1, 9.0Hz), 7.16 (1H, d, 7.43 (1H, t), 6.83 (1H, s), 3.38 (2H, q), 2.39 (2H, t), 2.20 (6H,
J=16.2Hz), 6.98 (2H, d, J=8.4Hz), 6.94 (1H, t), 6.77 (1H, s), s), 1.92–1.80 (2H, p).
3.80 (3H, s), 3.47 (2H, q), 2.64 (2H, t), 2.29 (6H, s).
(E)-N1-(6-Chloro-2-(4-fluorostyryl)quinolin-4-yl)-N2,N2-
(E)-N1-(6-Fluoro-2-(4-fluorostyryl)quinolin-4-yl)-N2,N2- dimethylethane-1,2-diamine (13) Compound 13 as a saf-
dimethylethane-1,2-diamine (7) Compound 7 as a saf- fron yellow powder was prepared from 4d and 4-fluorine
°
fron yellow powder was prepared from 4a and 4-fluorine benzaldehyde. Yield: 90%; mp 174–176 C,; MS (ESI) m/z:
benzaldehyde. Yield: 90%; mp 118–122 C; MS (ESI) m/z: 370.1, 371.1 (M+); HR-MS (ESI) m/z: 370.0895 (M+) (Calcd for
°
1
354.3, 355.3 (M+); HR-MS (ESI) m/z: 354.3097 (M+) (Calcd C21H21ClFN3: 370.0898); H-NMR (DMSO-d6) δ: 8.34 (1H, d,
1
for C21H21F2N3: 354.3099); H-NMR (DMSO-d6) δ: 8.05 (1H, J=1.8Hz), 7.82–7.72 (4H, m, J=15.3, 9.0, 6.6Hz), 7.59 (1H, dd,
dd, J=9.0Hz), 7.83 (1H, dd, J=9.1, 6.0Hz), 7.79–7.70 (3H, m, J=9.0Hz), 7.32–7.20 (3H, m, J=15.9, 9.0, 8.7Hz), 7.16 (1H, t),
J=16.2, 8.1, 5.4Hz), 7.51 (1H, td, J=9.1, 8.4Hz), 7.26 (3H, m, 6.79 (1H, s), 3.46 (2H, q), 2.63 (2H, t), 2.27 (6H, s).
J=16.2, 8.1, 9.0Hz), 7.02 (1H, t), 6.80 (1H, s), 3.47 (2H, q),
(E)-N1-(6-Chloro-2-(4-fluorostyryl)quinolin-4-yl)-N3,N3-
dimethylpropane-1,3-diamine (14) Compound 14 as a
2.66 (2H, t), 2.30 (6H, s).
(E)-N1-(6-Fluoro-2-(4-fluorostyryl)quinolin-4-yl)-N3,N3- saffron yellow powder was prepared from 4e and 4-fluorine
°
dimethylpropane-1,3-diamine (8) Compound 8 as a saffron benzaldehyde. Yield: 85%; mp 137–140 C; MS (ESI) m/z:
yellow powder was prepared from 4b and 4-fluorine benz- 384.1, 386.1 (M+); HR-MS (ESI) m/z: 384.1636 (M+) (Calcd
1
°
aldehyde. Yield: 87%; mp 171–173 C; MS (ESI) m/z: 368.2, for C22H24ClFN3: 384.1640); H-NMR (DMSO-d6) δ: 8.32 (1H,
369.2 (M+); HR-MS (ESI) m/z: 368.1968 (M+) (Calcd for d, J=2.4Hz), 7.79–7.74 (3H, m, J=9.0, 6.6Hz), 7.72 (1H, d,
C22H23F2N3: 368.1970); H-NMR (DMSO-d6) δ: 7.98 (1H, dd, J=16.2Hz), 7.59 (1H, dd, J=9.0, 2.4Hz), 7.37 (1H, t), 7.30–7.23
1
J=11.1Hz), 7.82 (1H, dd, J=9.3, 6.0Hz), 7.78–7.66 (3H, m, J (3H, m, J=15.6, 8.4, 9.0Hz), 6.76 (1H, s), 2.38 (2H, t),2.19 (6H,
=5.7, 8.7, 17.1Hz), 7.54–7.46 (1H, td, J=8.4, 8.7Hz), 7.30–7.21 s), 1.85 (2H, p).
(3H, m, J=16.9, 9.0, 9.0Hz), 7.13 (1H, t), 6.75 (1H, s), 2.39 (2H,
t), 2.19 (6H, s), 1.89–1.80 (2H, p).
(E)-6-Chloro-2-(4-fluorostyryl)-N-(3-morpholinopropyl)-
quinolin-4-amine (15) Compound 15 as a saffron yellow
(E)-6-Fluoro-2-(4-fluorostyryl)-N-(3-morpholinopropyl)- powder was prepared from 4f and 4-fluorine benzaldehyde.
+
°
quinolin-4-amine (9) Compound 9 as a saffron yellow pow- Yield: 87%; mp 177–179 C; MS (ESI) m/z: 426.1, 428.1 (M );
der was prepared from 4c and 4-fluorine benzaldehyde. Yield: HR-MS (ESI) m/z: 426.1359 (M+) (Calcd for C24H25ClFN3O:
+
1
°
92%; mp 142–144 C; MS (ESI) m/z: 410.4, 411.4 (M ); HR-MS 426.1362); H-NMR (DMSO-d6) δ: 8.32 (1H, s), 7.82–7.69 (4H,
(ESI) m/z: 410.4194 (M+) (Calcd for C24H25F2N3O: 410.4195); m, J=17.1, 9.0, 7.5Hz), 7.60 (1H, d, J=9.0Hz), 7.34–7.20 (4H,
1H-NMR (DMSO-d6) δ: 8.05 (1H, d, J=10.5Hz), 7.83 (1H, m, J=15.8, 9.0, 8.4Hz), 6.76 (1H, s), 3.66–3.57 (4H, m), 3.39
dd, J=9.0, 6.0Hz), 7.75 (3H, m, J=16.2, 8.7, 5.7Hz), 7.51 (1H, (2H, q), 2.47–2.34 (6H, m), 1.94–1.82 (2H, p).
td, J=8.4, 8.7Hz), 7.30–7.22 (3H, m, J=16.2, 9.0, 8.4Hz), 7.14
(E)-N1-(7-Chloro-6-fluoro-2-(4-fluorostyryl)quinolin-
(1H, t), 6.75 (1H, s), 3.60 (4H, s), 3.39 (2H, q), 2.50–2.33 (6H, 4-yl)-N3,N3-dimethylpropane-1,3-diamine (16) Compound
m), 1.96–1.81 (2H, m).
16 as a saffron yellow powder was prepared from 4g and
(E)-N1-(6-Chloro-2-(4-(methylsulfonyl)styryl)quinolin- 4-fluorine benzaldehyde. Yield: 83%; mp 170–174 C; MS
4-yl)-N2,N2-dimethylethane-1,2-diamine (10) Compound (ESI) m/z: 402.3, 404.2 (M+); HR-MS (ESI) m/z: 402.2964
°
10 as a dark yellow powder was prepared from 4d and p- (M+) (Calcd for C22H22ClF2N3: 402.2967); H-NMR (DMSO-
1
°
methylsulphonyl benzaldehyde. Yield: 92%; mp 198–199 C; d6) δ: 7.86–7.80 (1H, m), 7.79–7.66 (5H, m, J=16.5, 9.3,
MS (ESI) m/z: 430.3, 432.3 (M+); HR-MS (ESI) m/z: 430.2139 8.7Hz), 7.31–7.23 (3H, m, J=16.5, 8.7Hz), 6.83 (1H, s), 3.39
1
(M+) (Calcd for C22H24ClN3O2S: 430.2142); H-NMR (DMSO- (2H, q), 2.42 (2H, t), 2.19 (6H, s), 1.92–1.81 (2H, p).
d6) δ: 8.33 (1H, s), 7.96 (4H, s), 7.84 (2H, t, J=14.4, 8.4Hz),
(E)-N1-(7-Chloro-6-fluoro-2-(4-methoxystyryl)quinolin-
7.64 (1H, d, J=8.7Hz), 7.53 (1H, d, J=15.9Hz), 7.21 (1H, s), 4-yl)-N3,N3-dimethylpropane-1,3-diamine (17) Compound
6.89 (1H, s), 3.52 (2H, q), 3.26 (3H, s), 2.81 (2H, s), 2.41 (6H, 17 as a yellow powder was prepared from 4g and p-anisal-
°
s).
dehyde. Yield: 85%; mp 166–169 C; MS (ESI) m/z: 414.4,
(E)-N1-(6-Chloro-2-(2-(pyridin-4-yl)vinyl)quinolin-4-yl)- 416.4 (M+); HR-MS (ESI) m/z: 414.4273 (M+) (Calcd for
N2,N2-dimethylethane-1,2-diamine (11) Compound 11 as C23H25ClFN3O: 414.4275); H-NMR (DMSO-d6) δ: 8.28 (1H,
1
a bright yellow powder was prepared from 4d and isonicoti- d, J=11.4Hz), 7.92 (1H, d, J=7.6Hz), 7.66 (3H, t, J=14.1,
°
naldehyde. Yield: 82%; mp 139–142 C; MS (ESI) m/z: 353.1, 7.8Hz), 7.29 (1H, t), 7.16 (1H, d, J=16.2Hz), 6.99 (2H, d,
355.1 (M+); HR-MS (ESI) m/z: 353.1477 (M+) (Calcd for J=8.4Hz), 6.74 (1H, s), 3.80 (3H, s), 2.36 (2H, t), 2.18 (6H, s),
1
C20H21ClN4: 353.1480); H-NMR (DMSO-d6) δ: 8.59 (2H, d, 1.90–1.78 (2H, p).
J=5.4Hz), 8.34 (1H, s), 7.81 (1H, d, J=9.0Hz), 7.72 (1H, d,
J=16.2Hz), 7.66 (2H, d, J=5.4Hz), 7.62 (1H, d, J=9.0Hz), quinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
7.59 (1H, d, J=16.2Hz), 7.18 (1H, s), 6.86 (1H, s), 3.46 (2H, q), Compound 18 as a dark yellow powder was prepared from
(E)-N1-(7-Chloro-6-fluoro-2-(2-(thiophen-2-yl)vinyl)-
(18)
°
4g and thiophene-2-carbaldehyde. Yield: 79%; mp 132–136 C;
2.65 (2H, s), 2.29 (6H, s).
(E)-N1-(6-Chloro-2-(2-(pyridin-4-yl)vinyl)quinolin-4-yl)- MS (ESI) m/z: 390.1, 392.1 (M+); HR-MS (ESI) m/z: 390.1743
1
N3,N3-dimethylpropane-1,3-diamine (12) Compound 12 (M+) (Calcd for C20H21ClFN3S: 390.1744); H-NMR (DMSO-
as a bright yellow powder was prepared from 4e and iso- d6) δ: 8.31 (1H, d, J=11.4Hz), 7.92 (2H, m, J=12.0, 4.2Hz),
°
nicotinaldehyde. Yield: 87%; mp 149–154 C; MS (ESI) m/z: 7.57 (1H, d, J=4.8Hz), 7.38 (1H, d, J=3.0Hz), 7.36 (1H, t),
367.1, 369.1 (M+); HR-MS (ESI) m/z: 367.1259 (M+) (Calcd 7.12 (1H, t, J=4.8, 4.2Hz), 7.00 (1H, d, J=15.9Hz), 6.78 (1H,
1
for C21H23ClN3: 367.1261); H-NMR (DMSO-d6) δ: 8.59 (2H, s), 3.37 (2H, q), 2.26 (8H, d), 1.90–1.85 (2H, p).
d, J=5.4Hz), 8.35 (1H, d, J=1.2Hz), 7.80 (1H, d, J=9.0Hz),
(E)-N1-(2-(2-(Benzo[d][1,3]dioxol-5-yl)vinyl)-7-chloro-

664
Vol. 60, No. 5
6-fluoroquinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
(19) Compound 19 as a light yellow powder was prepared
References
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from 4g and heliotropin. Yield: 92%; mp 172–175 C; MS
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Approximately 4×103 cells, suspended in MEM medium,
were plated onto each well of a 96-well plate and incubated
°
in 5% CO2 at 37 C for 24h. The test compounds were added
to the culture medium at the indicated final concentrations
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°
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Acknowledgments This work was supported by a Grant
from National S&T Major Project (No. 2009ZX09301-
012) and the S and T Project of Liaoning Province (No.
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