Selenium-containing naphthalimides as anticancer agents: Design, synthesis and bioactivity

Article abstract of DOI:10.1016/j.bmc.2012.02.049

Selenium analogues (4b-4h, and 4j) of two known sulfur compounds were synthesized and tested their anticancer activities. The selenium compound 4b had comparable activity with its sulfur analogue 4a, while DNA-binding study showed these two compounds had similar interaction with ct-DNA, the K_b was 8.23 and 2.36, respectively. The primary results showed that most compounds had moderate anticancer activities with IC₅₀ values between 10 ^-6 and 10^-5 M. Another selenium analogue 4j showed the highest activity with the IC₅₀ values around 5.3 μM against K562 and MCF-7 cell lines. More importantly, the organochalcogen compounds exhibited stronger anticancer activities against K562 cell line than the other cell lines tested.

Full text of DOI:10.1016/j.bmc.2012.02.049

Bioorganic & Medicinal Chemistry 20 (2012) 2558–2563
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Selenium-containing naphthalimides as anticancer agents: Design, synthesis
and bioactivity
Liwei Zhao a,b, Jianfeng Li a, Yiquan Li a, Jianwen Liu a, Thomas Wirth b, Zhong Li a,
⇑
a Shanghai Key Lab of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
b School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Selenium analogues (4b–4h, and 4j) of two known sulfur compounds were synthesized and tested their
anticancer activities. The selenium compound 4b had comparable activity with its sulfur analogue 4a,
while DNA-binding study showed these two compounds had similar interaction with ct-DNA, the Kb
was 8.23 and 2.36, respectively. The primary results showed that most compounds had moderate anti-
cancer activities with IC50 values between 10ꢀ6 and 10ꢀ5 M. Another selenium analogue 4j showed the
Received 29 December 2011
Revised 21 February 2012
Accepted 22 February 2012
Available online 1 March 2012
highest activity with the IC50 values around 5.3 lM against K562 and MCF-7 cell lines. More importantly,
the organochalcogen compounds exhibited stronger anticancer activities against K562 cell line than the
other cell lines tested.
Keywords:
Anticancer
Naphthalimides
Selenium
K562
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
DNA
1. Introduction
N
N
In the last decade, naphthalimide analogs have been considered
as a promising group of anticancer agents by intercalating DNA.
Amonafide and mitonafide (see Fig. 1) were two of the most active
naphthalimide-based topo II inhibitors and had been tested in clin-
ical trials.1 However, on account of the central neurotoxicity and
limited efficacy in solid tumors, the clinical development was
regrettably terminated, while amonafide was found easily metabo-
lized to N-acetyl-amonafide which caused unpredictable toxicity.2
To improve the efficacy and toxicological profiles, considerable
efforts have been made on the design of more active naphthali-
mides focusing on the analogues with higher DNA-binding affi
nity3–9 and contacting two naphthalimide moiety together such
as bisnafide and elinafide.10–13
Recently, Qian co-workers have prepared several novel
naphthalimides as potent anticancer reagents.14–18 Sulfur-contain-
ing amine substituted in the position 6 attracted our attention as
the secondary amine in this position was difficult to acetylate and
the sulfur moiety was part of novel apoptotic inducer.19 And also,
previous study showed that sulfur-containing compound had high-
er activities than the corresponding oxygen analogue in some
cases.20 This research prompted us to explore the effect of exchang-
ing the sulfur to selenium on anticancer activities.
O
N
O
O
N
O
NH2
Amonafide
NO2
Mitonafide
Figure 1. Structural formulas of amonafide and mitonafide.
The application of organoselenium compounds in cancer pre-
vention and treatment is a fascinating field for selenium research.
Selenium compounds have been proven as potent anticarcinogenic
agents in different models, such as spontaneous, chemically
induced, transplanted tumors or in culture.21,22 Although the bio-
isosteric replacement of the oxygen or sulfur atom in known bioac-
tive compounds with selenium is usually an easy strategy, it is still
efficient and encouraged in medicinal chemistry. Firstly, the struc-
tural features were retained. Secondly, selenium is a softer atom
which can be served as hydrogen-bond acceptor or electron donor.
Several reports and our reaearch23 indicated that selenium-con-
taining compounds had higher activity than their sulfur analogues
or additional properties in some aspects. Se,Se0-1,4-phenylene-
bis(1,2-ethanediyl) bisisoselenourea(PBISe), which were designed
by Desai et al. demonstrated that substitution of sulfur with sele-
nium in known iNOS inhibitor increased the compound’s antican-
cer potency by several folds.24 The novel Se-analogue as a potent
⇑
Corresponding author. Tel.: +86 21 64253540; fax: +86 21 64252603.
E-mail address: lizhong@ecust.edu.cn (Z. Li).
0968-0896/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2012.02.049

L. Zhao et al. / Bioorg. Med. Chem. 20 (2012) 2558–2563
2559
R1
N
R1
N
N
N
O
O
O
O
N
R1
N
O
N
O
NH2
R2
Se
O
N
O
O
O
O
O
O
O
N
O
amine
selenium
3
selenium
exchange
exchange
HN
Se
HN
and
Ar, EtOH,
reflux 2h
Ar, DMF, rt, 24 h
HN
Se
N
NO2
NO2
N
S
S
Se
1
2
4j
R2
4 b-h
R2
4b-h
4i
N
4a
N
O
N
O
Figure 2. Selenium bioisosteric exchange of sulfur.
H
N
O
N
O
HOCH2CH2OCH3
reflux 3h
+
Se
N
peroxisome proliferator-activated receptors(PPARs) b/d ligand
developed by Sharma et al. also might possess additional antican-
cer properties.25 A series of 40-selenonucleosides were prepared by
Jeong et al. as the 3rd generation nucleosides, some of which were
found exhibit high potent anticancer activity.26,27 The improved
photosensitizers were used as antimicrobial drugs in photody-
namic therapy of localized infections, while the replacement of
oxygen with selenium slightly enhanced corresponding effective-
ness.28 In DNA crystal structure studies, Huang et al replaced oxy-
gen on the nucleobases in DNA with selenium and observed new
Se-mediated hydrogen bond formation in base-paring selectivity.29
Therefore we prepared the selenium analogues of the former
reported compounds 4a and 4i (see Fig. 2). After the successful bio-
isosteric exchange of phenylthio to phenylseleno, more attention
was focused on additional modification of the phenyl ring and
naphthalimide to improve anticancer activity or selectivity.
6
Br
Se
4j
5
Scheme 1. The synthesis of 4b–h and 4j.
Table 1
Structures and yields of target compounds
Compound
R1
R2
Yield (%)
4b
4c
4d
4e
4f
4g
4h
4j
CH2CH2N(CH3)2
CH2CH2N(CH3)2
CH2CH2N(CH3)2
CH2CH2N(CH3)2
CH2CH2N(CH2CH3)2
C4H9
H
56
51
65
38
48
60
57
35
CH3
OCH3
OCF3
H
H
H
C8H17
—
—
2. Results and discussion
2.1. Synthesis
Table 2
Absorption and emission dataa,b of selenium-containing naphthalimide derivatives
The intermediates 2-aryl-selanyl-ethylamine 3 were prepared
from 2-chloroethylamine with organylselenolate anions which gen-
erated in situ by treatment of the corresponding diselenides with
NaBH4 in ethnaol.30 Selenomorpholine was prepared according to
published procedure.31 The target compounds 4b–4h were synthe-
sized similar to the sulfur analogues, starting from 6-nitro-naph-
thalimides 2. The nitro group was easily substituted by amine 3 in
DMF at room temperature after 24 h. Compound 4j was prepared
by the substitution of bromine with selenomorpholine (see Scheme
1). After completion, the reaction mixture was concentrated under
vacuum to give crude oil, which was further purified by silica gel
column chromatography using CH2Cl2/CH3OH 50:1 (v/v) as eluent.
The product was then recrystallized from dichloromethane and
petroleum ether, affording the product as bright yellow solid. The
structures and yields of these compounds were shown in Table 1.
All newly synthesized compounds were well identified by 1H
NMR, 13C NMR, HRMS and IR spectra.
Compound
UV kmax (log
e
)
FL kmax (U)
4b
4c
4d
4e
4f
4g
4h
4j
437 (4.20)
438 (4.26)
441 (4.25)
437 (4.29)
439 (4.31)
438 (4.23)
437 (4.17)
393 (4.18)
528 (0.2548)
528 (0.2936)
527 (0.2499)
527 (0.2635)
523 (0.2805)
529 (0.2418)
527 (0.2726)
519 (0.0491)
a
In absolute ethanol.
With quinine sulfate in 0.1 mol/L sulfuric acid as quantum yield standard
(U = 0.58).
b
2.2. Cytotoxic evaluation in vitro
The in vitro antitumor activities of the target compounds were
evaluated by examining their cytotoxic effects using MTT tetrazo-
lium dye assay against Hela (human cervical carcinoma cell line),
HCT116 (human colon cancer cell line), K562 (chronic myeloge-
nous leukemia cell line), A549 (human lung cancer cell line) and
MCF-7 (Human Caucasian breast adenocarcinoma cell line),
respectively. The IC50 values representing the drug concentration
M) required to inhibit cell growth by 50% were summarized in
Table 3.
In Table 3, it can be seen that most compounds showed moder-
Naphthalimides were known chromophoric group,32 and the
UV–vis and fluorescent data of the target compounds was shown
in Table 2. The different substituents of 4b–4h had a slight effect
on absorption and emission, which convinced us to believe that
the electronic property of aryl–selanyl moiety was not the domi-
nant factor. The absorption and emission maxima of these
compounds were around 438 and 528 nm, respectively. But com-
pound 4j with a quite different substitution had blue shift of both
absorption and emission maxima, the values were 393 and
519 nm respectively, while its fluorescence quantum yield was
dramatically deceased.
(
l
ate cytotoxicities against all tested cancer cell lines except 4g. The
selenium analogue 4b and the sulfur compound 4a nearly exhibited
the same cytotoxicities. Our preliminary modification showed that

2560
L. Zhao et al. / Bioorg. Med. Chem. 20 (2012) 2558–2563
mitochondrial pathway according to a former report.16 Compound
4j, selenium analogue of 4i, showed the best bioactivity against
all cell lines, although no better selectivity was observed.
Table 3
Cytotoxicity of the target compounds against Hela, HCT116, K562, A549 and MCF-7
cell lines
Compound
Cytotoxicity (IC50
l
M)
The K562 cell lines attracted our attention as a previous report
revealed that amonafide was less cytotoxic against K562 cells with
Hela
HCT116
K562
A549
MCF-7
IC50 >50 l
M.33 However, in our study these compounds showed
4a18
4b
4c
4d
4e
15.11
16.8
>25
17.9
>25
15.5
>25
16.7
6.06
5.6
16.4
19.5
20
17.6
9.9
14.6
>25
18.1
ND
11.2
11.7
21.3
16.6
9.4
18.0
17.4
21
22.3
14.4
10.7
>25
20.6
1.27
8.7
19.11
18.2
19.3
18.3
16.4
11.9
>25
11.6
16.04
5.3
stronger cytotoxic activity against K562 than other cell lines.
Though several phenylaminoethyl selenides were served protective
effects against oxidant-induced DNA damage,34 selenium com-
pounds could play multi-roles such as cancer prevention or DNA
damage.35 Some chalcogen-based agents could turn the oxidizing
environment in certain cells over a critical redox threshold and at
last induce apoptosis with high selectivity.36,37 Selenium com-
pound Na5SeV5O18ꢁ3H2O could significantly inhibit the prolifera-
tion of K562 cells in vitro in a time and concentration-dependent
manner, and its mechanism of apoptosis was partially due to eleva-
tion of intracellular reactive oxygen species (ROS) concentration.38
This selective anticancer activity may related to the chalcogen atom
sulfur or selenium, which can act as a redox catalyst center, modu-
lating the intracellular redox balance.
4f
8.9
4g
4h
4i18
4j
>25
18.7
ND
5.4
5.3
ND: not determined.
the substitution of benzene ring with 4-CH3-phenyl (4c), 4-OCH3-
phenyl (4d), 4-OCF3-phenyl (4e) group was less successful com-
pared with 4b. Meanwhile 4e had a good result against K562 cell
line. The modification position and functional group selection need
to be further optimized. N,N-dimethylamine was a classic basic
chain for DNA-binding, while compound 4f with N,N-diethylamine
had a slightly better activity than 4b. For compounds 4g and 4h, the
length of the alkyl chain significantly affected the cytotoxic activity,
and this may due to the long chain can induce apoptosis via a
2.3. DNA binding properties
The interactions of the target compounds between ct-DNA were
determined by spectroscopic techniques. The UV–vis spectra and
A
400
A
0.12
0
0
ct DNA
ct DNA
200
160
160
0.06
0.00
0
300
400
500
600
500
600
700
800
Wavelength (nm)
Wavelength(nm)
400
200
0
B
B
0.12
0.06
0.00
0
ct DNA
0
ctDNA
160
160
300
400
500
600
500
600
700
800
Wavelength (nm)
Wavelength (nm)
Figure 3. UV–vis absorption spectra of compound 4a (10
20 mM Tris–HCl buffer (pH 7.5, 25 °C) containing different concentrations of ct-
DNA from 0 to 160 M. (A) 4a, (B) 4b.
l
M) and 4b (10
l
M) in
Figure 4. Fluorescence emission spectra of compound 4a (10
in 20 mM Tris–HCl buffer (pH 7.5, 25 °C) containing different concentrations of ct-
DNA from 0 to 160 M. (A) 4a, (B) 4b.
lM) and 4b (10 lM)
l
l

L. Zhao et al. / Bioorg. Med. Chem. 20 (2012) 2558–2563
2561
fluorescence spectra for compounds 4a and 4b were illustrated in
Figures 3 and 4, respectively.
It was obvious that UV–vis absorption spectra of compounds 4a
and 4b exhibited dramatic hypochromic effects with increasing
(pH 7.5) gave a ratio of UV absorbance at 260 and 280 nm of
1.8–1.9:1, indicating that the ct-DNA was sufficiently free of
protein. The concentration of ct-DNA determined by the molar
absorption was 6600 Mꢀ1 cmꢀ1 (260 nm).40 The solution was
stored at 4 °C and used within 4 days.
ct-DNA concentration from 0 to 160 lM, while no significant
wavelength shift was observed (Fig. 3). These spectral characteris-
tics suggested that there were similar interactions between com-
pounds 4a and 4b with ct-DNA. To further investigate the
interactions of 4a and 4b with DNA, the fluorescence quenching
technique was employed to measure the Scatchard binding
constants (Kb). The typical binding constant between organic com-
4.3.2. DNA titration experiments
The concentrations of compounds (4a and 4b) were 10
ct-DNA were increased from 0 to 10, 20, 40, 60, 80, 100, 120, 140,
160 M respectively, in 20 mM Tris–HCl (pH 7.5). The final solu-
lM and
l
tion volume was 10 mL for fluorescence titration experiments. All
the solutions were stored at 25 °C in dark after 1 day for equilib-
rium. The scatchard binding constants (Kb) were calculated accord-
ing to the equation I = I0 + {(I1ꢀI0)/2[Q]0} ꢂ {([DNA]0 + [Q]0 + 1/
Kb)ꢀ{([DNA]0 + [Q]0 + 1/Kb)2ꢀ4[DNA]0[Q]0}1/2}, wherein I0, I, and
pound and DNA usually range from 104 to 106 Mꢀ1 14
As shown in
.
Fig. 4, the Scatchard binding constant (Kb) to ct-DNA for 4a and 4b
was 8.26 ꢂ 104, and 2.43 ꢂ 104 Mꢀ1, respectively. As the two com-
pounds had same scaffold, we assume this difference can be attrib-
uted to the bigger size of selenium atom compared to sulfur atom,
which lead to more steric demand when binding DNA. The emis-
sion intensities of 4a and 4b decreased with increasing the amount
of ct-DNA as most of the intercalators did, and the wavelength
showed slight blue shift.39
I
1
represented the fluorescence intensities of compounds alone,
the sample, and DNA totally bound, respectively. [DNA]0 and [Q]0
were the initial analytical concentrations of ct-DNA and the agents,
respectively.17,41
4.4. Synthesis
3. Conclusion
4.4.1. 2-(2-(Dimethylamino)ethyl)-6(2(phenylseleno)
ethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione (4b)
Yield 56%, orange solid, mp 142.3–143.4 °C; 1H NMR (400 MHz,
CDCl3): d 8.57 (d, 1H, J = 7.3 Hz), 8.41 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H,
J = 8.3 Hz), 7.62–7.54 (m, 3H), 7.36–7.28 (m, 3H), 6.59 (d, 1H,
J = 8.4 Hz), 5.72 (s, br, 1H), 4.39 (t, 2H, J = 6.8 Hz), 3.68 (dd, 2H,
J1 = 6.1 Hz, J2 = 11.8 Hz), 3.30 (t, 2H, J = 6.4 Hz), 2.85 (s, br, 2H),
2.52 (s, 6H) ppm; 13C NMR (100 Hz, CDCl3): d 164.70, 164.07,
134.40, 133.71, 131.22, 129.81, 129.53, 128.21, 127.88, 126.19,
124.79, 122.91, 120.39, 110.58, 104.37, 56.77, 45.29, 43.16, 37.28,
29.69 ppm; IR (KBr, cmꢀ1): 3451.46, 2988.32, 2902.17, 1639.55,
1586.99, 1394.71, 1344.24, 1251.02, 1066.63, 824.31; HRMS (EI)
m/z (M)+ calcd for C24H25N3O280Se 467.1112, found 467.1111.
In this paper, the selenium analogues of former reported sulfur
compounds were designed and evaluated their antitumor activi-
ties. The cytotoxictives of the two classic compounds 4a and 4b
were nearly the same and spectroscopic technique confirmed that
4a and 4b had similar interactions with ct-DNA. Compound 4f with
a basic side chain N,N-diethylamine showed a slight higher activity
than 4b. The para-substituted derivatives were also prepared,
while only the compound with trifluromethoxyl group (OCF3) in
this position showed good activity. Importantly, most of the target
compounds exhibited selective cytotoxicty against K562 cell than
other cell lines tested. Further structural optimization and struc-
ture–antitumor activity relationships are currently in progress.
4.4.2. 2-(2-(Dimethylamino)ethyl)-6-(2-(4-methyl-phenylse
leno)ethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione (4c)
Yield 51%, yellow solid, mp 127.9–129.0 °C; 1H NMR (400 MHz,
CDCl3): d 8.55 (d, 1H, J = 7.0 Hz), 8.38 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H,
J = 8.3 Hz), 7.54 (t, 1H, J = 7.8 Hz), 7.49 (d, 2H, J = 8.0 Hz), 7.10 (d,
2H, J = 7.8 Hz), 6.57 (d, 1H, J = 8.4 Hz), 5.74 (s, br, 1H), 4.35 (t, 2H,
J = 7.1 Hz), 3.66 (dd, 2H, J1 = 6.0 Hz, J2=11.8 Hz), 3.25 (t, 2H,
J = 6.4 Hz), 2.74 (t, 1H, J = 7.0 Hz), 2.44 (s, 6H), 2.35 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3): d 164.67, 164.07, 148.93, 138.15,
134.35, 134.09, 131.15, 130.32, 129.81, 126.15, 124.69, 124.30,
122.96, 120.37, 110.58, 104.36, 56.93, 45.50, 43.19, 37.56, 26.88,
21.13 ppm; IR (KBr, cmꢀ1): 3382.02, 3264.04, 2933.20, 2758.43,
1679.44, 1637.26, 1586.64, 1344.82, 1386.99, 1243.59, 852.18,
693.25; HRMS (ESI) m/z (M+H)+ calcd for C25H28N3O280Se
482.1347, found 482.1346.
4. Experimental
4.1. Material and methods
All chemical reagents and solvents were purchased from com-
mercial sources and used without further purification. Thin-layer
chromatography (TLC) was performed on silica gel plate. Column
chromatography was performed using silica gel 200–300 mesh.
1H and 13C NMR were obtained with a Bruker AV-400 spectrometer
with chemical shifts reported as ppm (in CDCl3, TMS as internal
standard). IR spectra were obtained using a Perkin–Elmer 2000
FTIR instrument. High-resolution mass spectra (HRMS) were ob-
tained on a HPLC-Q-Tof MS (Micro) spectrometer. Melting points
were determined using a Büchi melting point B-540 apparatus
and were uncorrected.
4.4.3. 2-(2-(Dimethylamino)ethyl)-6-(2-(4-methoxyl-phenylse
leno)ethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione (4d)
Yield 65%, yellow solid, mp 134.9-135.6 °C; 1H NMR (400 MHz,
CDCl3): d 8.57 (d, 1H, J = 6.6 Hz), 8.40 (d, 1H, J = 8.4 Hz), 7.86 (d, 1H,
J = 7.8 Hz), 7.59–7.51(m,3H), 6.83 (d, 2H, J = 8.8 Hz), 6.57 (d, 1H,
J = 8.4 Hz), 5.72 (t, 1H, J = 4.8 Hz), 4.34 (t, 2H, J = 7.2 Hz), 3.81 (s,
3H), 3.64 (dd, 2H, J1=6.0 Hz, J2 = 11.8 Hz), 3.21 (t, 2H, J = 6.3 Hz),
2.71 (t, 2H, J = 7.1 Hz), 2.42 (s, 6H) ppm; 13C NMR (100 MHz,
CDCl3): d 164.67, 164.08, 159.96, 148.87, 136.35, 134.36, 131.18,
129.78, 126.04, 124.74, 123.03, 120.36, 117.76, 115.20, 110.66,
104.39, 57.00, 55.32, 45.61, 43.03, 37.68, 27.42 ppm; IR (KBr, cmꢀ1):
3387.64, 3280.90, 2843.82, 2814.61, 2758.43, 1682.25, 1645.15,
1583.33, 1541.65, 1545.41, 1384.19, 1240.77, 1117.05, 1024.25,
765.55; HRMS (ESI) m/z (M+H)+ calcd for C25H28N3O380Se
498.1296, found 498.1297.
4.2. Evaluation of in vitro cell proliferation by means of the MTT
colorimetric assay
The target compounds were submitted to School of Pharmacy in
East China University of Science and Technology for in vitro antitu-
mor activity assays. Growth inhibitory effects on the cell lines
(Hela, HCT116, K562, A549 and MCF-7) were measured by using
MTT assay.
4.3. DNA-binding studies
4.3.1. Preparation of ct-DNA solution
Ct-DNA (highly polymerized) was purchased from Sigma–Al-
drich. Solutions of ct-DNA in 20 mM Tris–HCl, 1 mM EDTA buffer

2562
L. Zhao et al. / Bioorg. Med. Chem. 20 (2012) 2558–2563
4.4.4. 2-(2-(Dimethylamino)ethyl)-6-(2-(4-trifluoromethoxyl-
phenylseleno)ethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-
dione (4e)
2H), 2.50 (s, br, 6H) ppm; 13C NMR (100 MHz, CDCl3): d 164.50,
164.00, 157.40, 132.60, 132.55, 131.33, 130.12, 130.08, 129.98,
126.78, 125.97, 116.24, 77.10, 56.29, 18.53 ppm; IR (KBr, cmꢀ1):
2952.25, 2917.32, 2765.35, 1724.55, 1654.46, 1583.71, 1415.29,
1326.15, 1290.49, 1152.11, 1127.47, 959.62, 785.38; HRMS (ESI)
m/z (M+H)+ calcd for C20H24N3O280Se 418.1034, found 418.1035.
Yield 38%, orange solid, mp 112.5–114.1 °C; 1H NMR (400 MHz,
CDCl3): d 8.58 (d, 1H, J = 7.2 Hz), 8.42 (d, 1H, J = 8.3 Hz), 7.97 (d, 1H,
J = 8.4 Hz), 7.62–7.58(m, 3H), 7.14 (d, 2H, J = 8.2 Hz), 6.63 (d, 1H,
J = 8.4 Hz), 5.73 (s, br, 1H), 4.39 (t, 2H, J = 6.8 Hz), 3.70 (dd, 2H,
J1 = 5.6 Hz, J2 = 11.3 Hz), 3.31 (t, 2H, J = 6.6 Hz), 2.50 (s, br, 3H),
1.66 (s, br, 6H) ppm; 13C NMR (100 MHz, CDCl3): d 177.25,
156.17, 147.79, 139.18, 134.13, 133.09, 131.54, 130.20, 128.97,
127.60, 122.17, 116.55, 114.88, 112.15, 108.60, 44.43, 25.88 ppm;
IR (KBr, cmꢀ1): 3396.46, 3310.95, 2936.87, 2849.67, 2800.13,
1697.29, 1625.95, 1597.34, 1384.19, 1120.68, 872.73; HRMS (ESI)
m/z (M+H)+ calcd for C25H25 F3N3O380Se 552.1013, found 552.1015.
Acknowledgments
This work was financially supported by the National Basic Re-
search Program of China (973 Program, 2010CB126100), National
High Technology Research, the Development Program of China
(863 Program, 2011AA10A207), and the National Key Technology
R&D Program of China (2011BAE06B01). This work was also partly
supported by the Fundamental Research Funds for the Central Uni-
versities. The authors would like to thank Professors Jianwen Liu
and Yiquan Li from School of Pharmacy, East China University
and Science and Technology, for anticancer evaluation and valu-
able suggestions.
4.4.5. 2-(2-(Diethylamino)ethyl)-6-(2-(phenylseleno)-
ethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione (4f)
Yield 48%, yellow solid, mp 136.5–137.9 °C; 1H NMR (400 MHz,
CDCl3): d 8.57 (d, 1H, J = 7.2 Hz), 8.41 (d, 1H, J = 8.4 Hz), 7.83 (d,
1H, J = 8.3 Hz), 7.61–7.55 (m, 3H), 7.35–7.28 (m, 3H), 6.60 (d, 1H,
J = 8.4 Hz), 5.67 (t, 1H, J = 4.9 Hz), 4.31–4.27 (m, 2H), 3.69 (dd, 2H,
J1 = 6.0 Hz, J2=11.8 Hz), 3.31 (t, 2H, J = 6.4 Hz), 2.83–2.79 (m, 2H),
2.71 (q, 4H, J = 7.1 Hz), 1.14 (t, 6H, J = 7.1 Hz) ppm; 13C NMR
164.59, 164.02, 148.74, 134.23, 133.71, 131.10, 129.73, 129.54,
128.17, 127.90, 125.93, 124.84, 123.09, 120.41, 110.85, 104.42,
49.87, 47.70, 43.15, 37.60, 26.80, 12.2 ppm; IR (KBr, cmꢀ1):
3337.64, 2960.67, 2921.35, 1727.24, 1679.44, 1626.01, 1575.40,
1538.84, 1392.62, 1361.69, 1243.59, 768.37; HRMS (ESI) m/z
(M+H)+ calcd for C26H30N3O280Se 496.1503, found 496.1505.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2012.02.049. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
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4.4.6. 2-n-Butyl-6-(2-(phenylseleno)ethylamino)-1H-benzo[de]
isoquinoline-1,3(2H)-dione (4g)
Yield 60%, orange solid, mp 121.1–121.8 °C; 1H NMR (400 MHz,
CDCl3): d 8.58 (d, 1H, J = 6.7 Hz), 8.42 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H,
J = 8.3 Hz), 7.61–7.56 (m, 3H), 7.33–7.28 (m, 3H), 6.62 (d, 1H,
J = 8.4 Hz), 5.52 (br, s, 1H), 4.17–4.11 (m, 2H), 3.70 (t, 2H,
J = 6.3 Hz), 3.31 (t, 2H, J = 6.3 Hz), 1.74–1.68 (m, 2H), 1.48–1.43
(m, 2H), 1.00–0.97 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3): d
164.61, 164.08, 148.71, 134.20, 133.66, 131.06, 128.62, 127.86,
124.79, 123.13, 120.38, 110.90, 104.36, 43.16, 39.99, 30.32, 26.76,
20.44, 13.90 ppm; IR (KBr, cmꢀ1): 3426.83, 3168.89, 2953.30,
1686.04, 1648.09, 1587.79, 1399.42, 1277.25, 785.87; HRMS (ESI)
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4.4.7. 2-Octyl-6-(2-(phenylseleno)ethylamino)-1H-benzo[de]
isoquinoline-1,3(2H)-dione (4h)
Yield 57%, yellow solid, mp 116.7–117.5 °C; 1H NMR (400 MHz,
CDCl3): d 8.58 (d, 1H, J = 7.3 Hz), 8.42 (d, 1H, J = 8.4 Hz), 7.83 (d,
1H, J = 8.3 Hz), 7.61–7.55 (m, 3H), 7.33–7.28 (m, 3H), 6.61 (d, 1H,
J = 8.4 Hz), 5.57 (s, br, 1H), 4.16 (t, 2H, J = 6.0 Hz), 3.69 (t, 2H,
J = 6.4 Hz), 3.31 (t, 2H, J = 6.4 Hz), 1.73 (td, 2H, J1 = 7.5 Hz,
J2 = 15.3 Hz), 1.45–1.39 (m, 2H), 1.35–1.25 (m, 7H), 0.98–0.87 (m.
4H) ppm; 13C NMR (100 Hz, CDCl3): d 164.59, 164.07, 148.64,
134.20, 133.70, 131.08, 129.70, 129.54, 128.18, 127.89, 125.82,
124.82, 123.21, 120.39, 111.03, 104.41, 43.13, 40.26, 31.83, 29.39,
29.24, 28.22, 27.21, 26.82, 22.64, 14.09 ppm; IR (KBr, cmꢀ1):
3426.97, 2960.67, 2915.73, 2853.93, 1679.44, 1645.60, 1536.03,
1578.21, 1384.50, 1237.96, 1100.18, 779.61; HRMS (ESI) m/z
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4.4.8. 2-(2-(Dimethylamino)ethyl)-6selenomorpholino-1H-
benzo[de]isoquinoline-1,3(2H)-dione (4j)
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CDCl3): d 8.61 (d, 1H, J = 7.2 Hz), 8.54 (d, 1H, J = 8.2 Hz), 8.41 (d, 1H,
J = 8.4 Hz), 7.74 (t, 1H, J = 7.9 Hz), 7.27 (d, 1H, J = 10.1 Hz), 4.40 (t,
2H, J = 6.2 Hz), 3.67–3.64 (m, 4H), 3.04–3.01 (m, 4H), 2.83 (s, br,
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