Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones

Article abstract of DOI:10.1016/j.bmc.2010.03.054

A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC₅₀ values of 4.4 and 5.2 μM, respectively, compared to 5-fluorouracil (IC₅₀ = 15.2 μM) against MCF-7 cells.

Full text of DOI:10.1016/j.bmc.2010.03.054

Bioorganic & Medicinal Chemistry 18 (2010) 3570–3574
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Bioorganic & Medicinal Chemistry
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Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted
(Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones
Y. Thirupathi Reddy a, P. Narsimha Reddy a, Srinivas Koduru b, Chendil Damodaran b, Peter A. Crooks a,
*
a Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
b Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, KY 40536, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structur-
ally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl
moieties have been synthesized under microwave irradiation and conventional heating methods These
analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell
Received 11 January 2010
Revised 19 March 2010
Accepted 23 March 2010
Available online 27 March 2010
lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC50 values of 4.4 and 5.2
respectively, compared to 5-fluorouracil (IC50 = 15.2 M) against MCF-7 cells.
Ó 2010 Elsevier Ltd. All rights reserved.
lM,
l
Keywords:
Aplysinopsin analogs
Microwave irradiation
Anti-proliferative activity
Indole derivatives
1. Introduction
din-3-ol (Fig. 1, C) was identified as a potent thermal sensitizer,
capable of lowering the threshold for Hsf1 activation and increas-
ing the thermal sensitivity of cancer cells to ionizing radiation.8
Very recently, we have reported the synthesis and radio-sensitiza-
tion activity of a small library of (Z)-5-((N-benzyl-1H-indol-3-
yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-in-
Aplysinopsins (Fig. 1A) are indole-derived marine natural prod-
ucts. The parent aplysinopsin was isolated for the first time by
Kazlauskas et al.1 as the major metabolite of eight Indo-Pacific
sponge species, which are representatives of the genera Thorecta.
The N-1-unsubstituted aplysinopsins have generated considerable
interest due to their potentially useful medicinal properties.2
Aplysinopsin has been reported as a potent cytotoxic agent against
the Kb-cell line by Hollenbeak et al.,3 and Kondo et al. have
reported the anti-cancer activity of aplysinopsin and methyl-aplys-
inopsins against L-1210- and Kb-cell lines.4 Wen-Tai et al. reported
the synthesis and biological evaluation of N-heterocyclic indolyl-
glyoxylamides as orally active anticancer agents.5 Recently,
dol-3-yl)methylene)pyrimidine-2,4,6-(1H,3H,5H)trione
deriva-
tives.9 In this series, 4-[(3-((2,4,6-trioxotetrahydropyrimidin-5-
(6H)-ylidene)methyl)-1H-indol-1-yl)methyl]benzonitrile (Fig. 1,
D), methyl-4-[(3-((2,4,6-trioxotetrahydropyrimidin-5(6H)-ylidene)
methyl)-1H-indol-1-yl)methyl]benzoate (Fig. 2, E), and 5-((N-4-
nitrobenzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6-(1H, 3H,5H)-
trione (Fig. 1, F) were identified as potent radio-sensitizing agents
with additional synergistic anti-angiogenic properties, whereas the
(Z)-5-((N-benzyl-1H-indol-3-yl)methylene)-imidazolidine-2,4-dione
analogs exhibited very poor radio-sensitization activity.9
These observations prompted us to synthesize a series of substi-
tuted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones
that were expected to function as potent cytotoxic agents against
lung and breast cancer cells.
Peng-Fei et al. reported the synthesis of a series of 4a-O- and 4b-
N-indol-3-yl-glyoxyl-substituted derivatives of podophyllotoxin
as potent cytotoxic agents against Hela, SKOV3, K562, and
K562ADR cells.6 James et al.7 have also reported synthesis and
SAR studies on a series of N-benzylindole and indolizine-glyoxyla-
mides (Fig. 1, B) that exhibit significant in vitro anti-proliferative
activities against a variety of cancer cell lines, including hemato-
logic and solid tumor cell lines (e.g., leukemia, breast, colon, and
uterine). Recently, we have reported the synthesis and thermal
sensitization activity of a series of novel substituted (Z)-2-(N-ben-
zylindol-3-ylmethylidene)quinuclidin-3-ol analogs. In this series,
(Z)-( )-2-[N-(4-chlorobenzyl)-indole-3-ylmethylidene]quinucli-
2. Results and discussion
2.1. Chemistry
The appropriate substituted (Z)-5-(N-benzylindol-3-yl-methy-
lene)imidazolidine-2,4-dione (3a–m) was synthesized via the
general synthetic route shown in Scheme 1.
* Corresponding author. Tel.: +1 859 257 1718; fax: +1 859 257 7585.
E-mail address: pcrooks@email.uky.edu (P.A. Crooks).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.03.054

Y. Thirupathi Reddy et al. / Bioorg. Med. Chem. 18 (2010) 3570–3574
3571
Figure 1. Potent aplysinopsin analogs that are anticancer and radio-sensitizing agents.
The substituted N-benzylindole-3-carboxaldehyde derivatives
2a–m were prepared in 85–90% yield utilizing literature proce-
dures8 by treating the appropriate commercially available indole-
3-carboxaldehyde (1a–e) with various substituted benzyl halides
under phase-transfer catalytic (PTC) conditions utilizing triethylb-
enzylammonium chloride and 50% (w/v) NaOH aqueous solution/
dichloromethane (1:1 v/v). Aldol condensation of the resulting
product (2a–m) with hydantoin in the presence of ammonium
acetate in acetic acid under microwave irradiation or under reflux
conditions, afforded the corresponding substituted (Z)-5-(N-benzy-
lindol-3-ylmethylene)imidazolidine-2,4-dione derivatives 3a–m.
The desired products were formed in very good yields (80–85%)
within 40–60 s utilizing the previously reported microwave irradi-
ation method (Method-A).9 The products were also obtained in
good yields (74–80%) utilizing a conventional heating procedure
(Method-B, 115–116 °C) within 8–12 h. A comparison between
these two methods with respective to reaction time and yield of
product is shown in Table 1. All the synthesized compounds were
characterized by 1H NMR and 13C NMR spectrometry. The geome-
try of the double bond in the representative compounds 3b and 3e
was established from X-ray crystallographic data.10,11
120
A
Untreated
1 µM
5 µM
10 µM
20 µM
100
*
40 µM
*
80
60
40
20
0
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
A549
H460
MCF-7
MDA231
Untreated
1 µM
120
100
80
60
40
20
0
2.2. Evaluation of biological activity
B
5 µM
10 µM
20 µM
40 µM
MCF-7, MDA-231, A549, and H460 cancer cells lines were pur-
chased from the American Type Culture Collection (ATCC) (Manas-
sas, VA) and were utilized to test the antitumor activity of the
above indole-derived analogs. Breast cancer cell lines, MCF-7 and
MDA-231 were grown in DMEM medium supplemented with
*
*
*
*
*
*
*
10% fetal bovine serum (FBS) and 1%
cancer cell lines A549 and H460 were maintained and propagated
in RPMI 1640 medium containing 2 -glutamine, 4.5 g/L glu-
cose, 10 M HEPES, 1.0 M sodium pyruvate and 10% FBS. All cell
L-glutamine, whereas lung
*
*
*
*
*
l
M L
*
*
l
l
*
*
cultures were maintained at 37 °C in a 5% CO2/95% air-humidified
atmosphere. Anti-proliferative activity of the indole-derived ana-
logs 3a–m were assessed in cell viability assays (trypan blue dye
exclusion)12 on both breast (MCF-7 and MDA-231) and lung
(A549 and H460) cancer cells at 24 h post-treatment at 5 concen-
A549
H460
MCF-7
MDA231
Figure 2. Breast (MDA-231 and MCF-7) and lung (A548 and H460) cancer cell lines
were treated with varying concentrations of 3f (A) and 3j (B) for 24 h and Trypan
Blue Exclusion assays were performed to determine cell viability. Each data point
represents the mean SD for four wells.
trations of drug (1, 5, 10, 20, and 40
lM) and with vehicle (DMSO)
alone. All assays were performed in triplicate. Results were ex-

3572
Y. Thirupathi Reddy et al. / Bioorg. Med. Chem. 18 (2010) 3570–3574
Scheme 1. Reagents and conditions: (a) appropriate benzylhalide, aqueous NaOH solution, triethylbenzylammonium chloride, DCM, rt; (b) Method-A: hydantoin,
ammonium acetate in acetic acid, microwave irradiation, 40–60 s, 80–85% yield; (c) Method-B: hydantoin, ammonium acetate in acetic acid, 115–116 °C, 8–12 h, 74–85%
yield.
Table 1
Table 2
Synthesis of (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones 3a–m
IC50 values for (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione deriva-
tives 3a–m
Entry
Method-A9
Method-B
Entry
Lung cancer cell lines
Breast cancer cell lines
MCF-7 (IC50 MDA-231 (IC50)
Yield (%)
Time (s)
Yield (%)
Time (h)
A-549 (IC50
)
H-460 (IC50
)
)
3a
3b
3c
3d
3e
3f
3g
3h
3i
84
82
85
83
81
80
81
80
85
84
83
80
82
40
60
40
40
50
60
60
60
40
60
50
60
50
80
75
76
74
75
80
74
76
79
76
75
78
79
8
10
10
10
12
9
12
12
10
12
12
10
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
>40
>40
>40
25.4
>40
39.5
27.8
29.7
25.2
27.7
>40
>40
34.8
5.4
14.2
19.1
>40
27.3
14.1
10.9
21.4
15.4
4.4
22.3
9.2
16.4
5.2
15.7
17.6
23.3
25.3
18.4
21.8
32.8
18.0
23.2
20.1
12.4
7.0
25.4
30.8
16.9
16.3
26.9
22.3
14.6
>40
3j
3k
3l
3j
3k
3l
7.6
7.2
3m
28.4
26.1
2.7
3m
20.2
15.2
22.1
3.5
5-FU14,15
pressed as percentage growth inhibition compared to control val-
ues.13 IC50 values for growth inhibition were derived from a non-
linear regression model based on sigmoidal dose–response
curves and computed using GraphPad Prism 5 (Graphpad).
We initially evaluated the abilities of compounds 3a–m to inhi-
bit the growth of the two distinct human lung cancer cell lines
A549 and H460 (Table 2). All thirteen compounds exhibited IC50
against MCF-7 cell lines comparable to 5-FU. Analogs 3a–m gener-
ally exhibited lower anti-proliferative potency against MDA-231
cells. Only one compound, the 5-methoxy analog (3l, IC50 = 7.0
lM)
exhibited moderate anti-proliferative activity against MDA-231
cells, which was similar to that obtained for 5-FU (IC50 = 3.5
l
M).15
values >14 lM in both cancer cell lines, and generally showed
poorer growth inhibition against A549 lung cancer cells and
3. Conclusions
H460 lung cancer cells when compared to the positive control
drug, 5-fluorouracil (5-FU, IC50 = 5.4 and 2.7 lM, respectively).
In conclusion, a small library of (Z)-2-(N-benzylindol-3-ylmeth-
ylene)imidazolidine-2,4-dione analogs that incorporate a variety of
aromatic substituents in both the indole and N-benzyl moieties
have been synthesized under both microwave irradiation and con-
ventional heating procedures, and evaluated for their anti-prolifer-
ative activity against breast cancer and lung cancer cells in culture.
The compounds all contain an N-benzylindole nucleus linked to a
hydantoin moiety via a double bond with Z-geometry. Several ana-
The analogs were also tested for their anti-proliferative activity
against ER positive MCF-7 and ER negative MDA-231 breast cancer
cell lines. All the compounds showed growth inhibition against
MCF-7 cell lines with IC50 values ranging from 4.4
27.3 M), 5-methyl (3j,
M. The 20-bromo (3f, IC50 = 4.4
M), and 5-bromo (3k,
M) analogs were identified as the most potent cytotoxic
lM to
l
l
IC50 = 5.2
IC50 = 7.6
l
l
M), 5-methoxy (3l, IC50 = 7.2 l
agents against MCF-7 cells, and were significantly more cytotoxic
logs exhibited IC50 values <8
against the MCF-7 cell line, and those analogs were more active
than 5-FU (IC50 = 15.2 M). We consider analogs 3f, 3j, 3k, and 3l
to be lead compounds worthy of consideration for further
lM as anti-proliferative agents
that 5-FU (IC50 = 15.2
l
M).14 The 40-cyano (3b, IC50 = 14.1
M), 5-chloro (3h, IC50 = 9.2 M), and 5-
M) analogs also exhibited cytotoxicity
l
M), 40-
nitro (3c, IC50 = 10.9
l
l
l
COOCH3 (3e, IC50 = 15.4
l

Y. Thirupathi Reddy et al. / Bioorg. Med. Chem. 18 (2010) 3570–3574
3573
structural optimization and development as potential anticancer
agents for the treatment of breast cancer.
5.2. 5-Bromo-1-(4-methoxybenzyl)-1H-indole-3-
carboxaldehyde (2i)
Mp 101–103 °C; 1H NMR (CDCl3): d 3.79 (s, 3H, OCH3), 5.25 (s,
2H, CH2), 6.86–6.89 (d, 2H, Ar-H), 7.10–7.13 (d, 2H, Ar-H), 7.18–
7.21 (d, 2H, Ar-H), 7.35–7.39 (dd, 1H, Ar-H), 8.46 (s, 1H, C2H),
9.92 (s, 1H, CHO); 13C NMR (CDCl3): d 50.94, 55.59, 111.98,
114.70 (2C), 116.84, 117.80, 124.94, 126.70, 127.14, 127.21,
128.95 (2C), 136.13, 138.88, 159.82, 184.34. HRMS (+EI; mean va-
lue): m/z found, 343.0205, calcd. C17H14BrNO2 (+EI; mean value):
343.0208.
4. Experimental procedure
The purity of the compounds synthesized was assessed by thin
layer chromatography (TLC) performed on microscopic slides,
2 ꢀ 7.5 cm, coated with Silica Gel G as stationary phase and the
spots were visualized by exposure to iodine vapors or to UV light.
Melting points were measured with a Fischer Scientific apparatus
and are reported uncorrected. All the synthesized final compounds
(3a–m) had melting points above 300 °C. 1H NMR and 13C NMR
spectra of the final compounds (3a–m) were recorded in
DMSO-d6 and those of intermediate compounds (2a–m) were
recorded in CDCl3 on a Varian 300 MHz spectrometer utilizing
TMS as internal standard. Chemical shift values are reported in
ppm downfield on the d scale. High resolution electron impact
(EI) ionization mass spectra were recorded at 25 eV on a JEOL
JMS-700T MStation (magnetic sector instrument) at a resolution
of greater than 10,000. Perflouorokerosene (pfk) was used to pro-
duce reference masses.
5.3. (Z)-5-((1-Benzyl-1H-indol-3-yl)methylene)imidazolidine-
2,4-dione (3a)
1H NMR (DMSO-d6): d 5.56 (s, 2H, CH2), 6.73 (s, 1H, CH), 7.13–
7.23 (m, 5H, Ar-H), 7.29–7.31 (d, 2H, Ar-H), 7.51–7.54 (d, 1H, Ar-H),
7.75–7.77 (d, 1H, Ar-H), 8.32 (s, 1H, C2H), 10.15 (br s, 1H, NH),
11.07 (br s, 1H, NH); 13C NMR (DMSO-d6): d 49.76, 100.92,
108.09, 110.58, 118.28, 120.38, 122.43, 123.81, 127.15, 127.35,
127.46, 128.46, 129.95, 135.48, 137.28, 155.08, 165.08. HRMS
(+EI; mean value): m/z found, 317.1162, calcd. C19H15N3O2 (+EI;
mean value) 317.1164.
4.1. Representative synthetic procedure: Microwave irradiation
method (Method-A)
5.4. (Z)-4-((3-((2,5-Dioxoimidazolidin-4-ylidene)methyl)-1H-
indol-1-yl)methyl)benzonitrile (3b)
A mixture of the appropriate substituted N-benzylindole-3-car-
boxaldehyde (1 mmol), hydantoin (1.1 mmol) and ammonium ace-
tate (1.1 mmol) in acetic acid (1 ml) was irradiated in a domestic
microwave oven (1100 W; Kenmore) for 40–60 s. During this time
period, intermittent removal of reaction vessel from the oven was
carried out every 10 s, in order to cool the reaction mass to room
temperature. The reaction mixture was allowed to cool to room
temperature, water (10 ml), was added, and the mixture was basi-
fied with saturated NaHCO3 solution and stirred for 10 min. The
precipitate thus obtained was collected by filtration, washed with
cold water, and finally washed with methanol and dried to afford
the crude product. Crystallization from methanol and ethyl acetate
(1:1) afforded a yellow crystalline product.
1H NMR (DMSO-d6): d 5.56 (s, 2H, CH2), 6.74 (s, 1H, CH), 7.13–
7.23 (m, 2H, Ar-H), 7.44–7.53 (m, 3H, Ar-H), 7.79–7.83 (m, 3H, Ar-
H), 8.30 (s, 1H, C2H), 10.15 (br s, 1H, NH), 11.07 (br s, 1H, NH); 13C
NMR (DMSO-d6): d 50.07, 101.46, 109.25, 111.06, 111.22, 119.21,
119.29, 121.34, 123.42, 124.95, 128.10, 128.70, 130.63, 133.26,
136.25, 143.71, 155.94, 165.87. HRMS (+EI; mean value): m/z
found, 342.1116, calcd. C20H14N4O2 (+EI; mean value): 342.1117.
5.5. (Z)-5-((1-(4-Nitrobenzyl)-1H-indol-3-yl)methylene)-imidaz
olidine-2,4-dione (3c)
1H NMR (DMSO-d6): d 5.61 (s, 2H, CH2), 6.74 (s, 1H, CH), 7.13–
7.53 (m, 4H, Ar-H), 7.79–7.82 (d, 2H, Ar-H), 8.18–8.21 (d, 2H, Ar-H),
8.31(s, 1H, C2H), 10.16 (br s, 1H, NH), 11.08 (br s, 1H, NH); 13C NMR
4.2. Conventional heating method (Method-B)
(DMSO-d6):
d 49.80, 101.48, 109.35, 111.19, 119.22, 121.36,
A mixture of the appropriate substituted N-benzylindole-3-car-
boxaldehyde (1 mmol), hydantoin (1.1 mmol), and ammonium
acetate (1.1 mmol) was stirred in acetic acid (5 ml) at 115–116 °C
for 8–12 h. The reaction mixture was cooled to room temperature,
water (10 ml) added, and the mixture was basified with saturated
NaHCO3 solution and stirred for 10 min. The precipitate thus ob-
tained was collected by filtration, washed with cold water, and fi-
nally washed with methanol and dried to afford the crude product.
Crystallization from methanol and ethyl acetate (1:1) afforded a
yellow crystalline product.
123.44, 124.47, 124.99, 128.12, 128.95, 130.66, 136.26, 145.7,
147.56, 155.88, 165.81. HRMS (+EI; mean value): m/z found,
362.1013, calcd. C19H14N4O4 (+EI; mean value): 362.1015.
5.6. (Z)-5-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3d)
1H NMR (DMSO-d6): d 5.44 (s, 2H, CH2), 6.73 (s, 1H, CH), 7.12–
39 (m, 4H, Ar-H), 7.52–7.55 (d, 2H, Ar-H), 7.77–7.80 (d, 2H, Ar-H),
8.30 (s, 1H, C2H), 10.15 (br s, 1H, NH), 11.06 (br s, 1H, NH); 13C
NMR (DMSO-d6): d 48.97, 100.78, 108.21, 110.49, 118.31, 120.42,
122.49, 123.93, 127.32, 128.42, 129.02, 129.81, 132.07, 135.40,
136.26, 155.05, 165.01. HRMS (+EI; mean value): m/z found,
351.0776, calcd. C19H14ClN3O2 (+EI; mean value): 351.0775.
5. Analytical data for the synthesized compounds
5.1. 1-(2-Bromobenzyl)-1H-indole-3-carbaldehyde (2f)
5.7. (Z)-Methyl-4-((3-((2,5-dioxoimidazolidin-4-ylidene)-
methyl)-1H-indol-1-yl)methyl)benzoate (3e)
Mp 127–129 °C; 1H NMR (CDCl3): d 5.45 (s, 2H, CH2), 6.77–
6.80 (t, 1H, Ar-H), 7.21–7.24 (m, 3H, Ar-H), 7.33–7.37 (m, 2H,
Ar-H), 7.64–7.67 (d, 1H, Ar-H) 7.72 (s, 1H, C2H), 8.34–8.37 (d,
1H NMR (DMSO-d6): d 3.81 (s, 3H, OCH3), 5.54 (s, 2H, CH2), 6.74
(s, 1H, CH), 7.15–7.23 (m, 2H, Ar-H), 7.40–7.42 (d, 2H, Ar-H,), 7.50–
7.52 (d, 1H, Ar-H), 7.79–7.81 (d, 1H, Ar-H), 7.91–7.93 (d, 2H, Ar-H),
8.32 (s, 1H, C2H), 10.15 (br s, 1H, NH), 11.06 (br s, 1H, NH); 13C
NMR (DMSO-d6): d 49.52, 52.2, 101.44, 109.26, 111.26, 119.22,
121.35, 123.44, 124.01, 127.29, 128.95, 129.35, 131.23, 136.28,
1H, Ar-H), 10.03 (s, 1H, CHO); 13C NMR (CDCl3):
d 51.12,
110.42, 118.82, 122.33, 122.98, 123.28, 124.42, 125.45, 128.19,
128.72, 130.01, 138.29, 134.67, 137.45, 138.62, 184.63. HRMS
(+EI; mean value): m/z found, 313.0098, calcd. C16H12BrNO (+EI;
mean value): 313.0102.

3574
Y. Thirupathi Reddy et al. / Bioorg. Med. Chem. 18 (2010) 3570–3574
142.64, 155.93, 165.85, 167.12. HRMS (+EI; mean value): m/z
5.13. (Z)-5-((1-Benzyl-5-bromo-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3k)
found, 375.1213, calcd. C21H17N3O4 (+EI; mean value): 375.1218.
5.8. (Z)-5-((1-(2-Bromobenzyl)-1H-indol-3-yl)methylene)-imi-
dazolidine-2,4-dione (3f)
1H NMR (DMSO-d6): d 5.44 (s, 2H, CH2), 6.72 (s, 1H, CH), 7.24–
7.31 (m, 4H, Ar-H), 7.50–7.54 (d, 2H, Ar-H), 8.03–8.04 (d, 2H, Ar-H),
8.35 (s, 1H, C2H), 10.46 (br s, 2H, 2NH); 13C NMR (DMSO-d6): d
50.66, 101.42, 108.56, 113.40, 114.01, 121.68, 124.99, 125.81,
127.81, 128.39, 129.30, 129.79, 131.75, 134.95, 137.62, 155.89,
165.93. HRMS (+EI; mean value): m/z found, 395.0268, calcd.
C19H14BrN3O2 (+EI; mean value) 395.0269.
1H NMR (DMSO-d6): d 5.51 (s, 2H, CH2), 6.69–6.70 (d, 1H Ar-H),
6.74 (s, 1H, CH), 7.16–7.30 (m, 4H, Ar-H), 7.44–7.47 (d, 1H, Ar-H),
7.69–7.72 (d, 1H, Ar-H), 7.846–7.85 (d, 1H, Ar-H), 8.24 (s, 1H,
C2H), 10.13 (br s, 1H, NH), 11.06 (br s, 1 H, NH); 13C NMR
(DMSO-d6):
d 49.85, 100.75, 108.48, 10.39, 118.45, 120.58,
121.73, 122.70, 124.16, 127.23, 128.02, 128.26, 129.49, 130.17,
132.59, 135.76, 136.05, 155.08, 165.05. HRMS (+EI; mean value):
m/z found, 395.0267, calcd. C19H14BrN3O2 (+EI; mean value)
395.0269.
5.14. (Z)-5-((1-(4-Methoxybenzyl)-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3l)
1H NMR (DMSO-d6): d 3.80 (s, 3H, OCH3), 5.38 (s, 2H, CH2), 6.74
(s, 1H, CH), 6.80–6.83 (d, 1H, Ar-H), 7.22–7.32 (m, 6H, Ar-H), 7.41–
7.44 (d, 1H, Ar-H), 8.29 (s, 1H, C2H), 10.10 (br s, 1H, NH), 11.02 (br
s, 1H, NH); 13C NMR (DMSO-d6): d 49.56, 55.59, 100.76, 104.19,
108.58, 111.08, 111.52, 126.74, 127.24, 128.38, 128.88, 130.54,
132.13, 137.66, 154.11, 155.15, 165.06. HRMS (+EI; mean value):
m/z found, 347.1267, calcd. C20H17N3O3 (+EI; mean value)
347.1270.
5.9. (Z)-5-((1-(4-Fluorobenzyl)-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3g)
1H NMR (DMSO-d6): d 5.43 (s, 2H, CH2), 6.73 (s, 1H, CH), 7.12–
40 (m, 4H, Ar-H), 7.55–7.58 (d, 2H, Ar-H), 7.77–7.80 (d, 2H, Ar-H),
8.32 (s, 1H, C2H), 10.16 (br s, 1H, NH), 11.06 (br s, 1H, NH); 13C
NMR (DMSO-d6): d 49.02, 101.07, 108.61, 110.67, 118.42, 120.63,
122.72, 124.05, 127.61, 128.92, 129.33, 129.98, 132.27, 135.56,
136.79, 155.27, 165.12. HRMS (+EI; mean value): m/z found,
335.1065, calcd. C19H14FN3O2 (+EI; mean value) 335.1070.
5.15. (Z)-5-((1-(4-Methylbenzyl)-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3m)
1H NMR (DMSO-d6): d 2.37 (s, 3H, CH3), 5.36 (s, 2H, CH2), 6.74 (s,
1H, CH), 7.00–7.05 (d, 2H, Ar-H), 7.23–7.29 (m, 3H Ar-H), 7.39–7.69
(d, 2H, Ar-H), 7.54 (s, 1H, Ar-H), 8.26 (s, 1H, C2H), 10.48 (br s, 2H,
NH), 13C NMR (DMSO-d6): d 20.97, 49.93, 101.71, 108.27, 110.96,
118.56, 120.83, 122.86, 123.91, 127.51, 127.69, 129.34, 134.48,
135.72, 137.15, 155.45, 165.59. HRMS (+EI; mean value): m/z
found, 331.1318, calcd. C20H17N3O2 (+EI; mean value): 331.1321.
5.10. (Z)-5-((1-Benzyl-5-chloro-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3h)
1H NMR (DMSO-d6): d 5.44 (s, 2H, CH2), 6.73 (s, 1H, CH), 7.22–
7.29 (m, 4H, Ar-H), 7.51–7.55 (d, 2H, Ar-H), 8.10–8.14 (d, 2H, Ar-H),
8.37 (s, 1H, C2H), 10.44 (br s, 2H, 2NH); 13C NMR (DMSO-d6): d
49.95, 100.47, 108.02, 112.23, 118.06, 122.43, 124.34, 125.25,
127.14, 127.56, 128.52, 131.27, 134.02, 137.04, 155.14, 165.01.
HRMS (+EI; mean value): m/z found, 351.0773, calcd. C19H14ClN3O2
(+EI; mean value): 351.0775.
Acknowledgment
This research was supported by NIH/National Cancer Institute
Grant PO1 CA104457.
5.11. (Z)-5-((5-Bromo-1-(4-methoxybenzyl)-1H-indol-3-yl)
methylene)imidazolidine-2,4-dione (3i)
References and notes
1. Kazlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J. Tetrahedron Lett. 1977, 18,
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1H NMR (DMSO-d6): d 3.70 (s, 3H, OCH3), 5.35 (s, 2H, CH2), 6.72
(s, 1H, CH), 6.87–6.90 (d, 2H, Ar-H), 7.27–7.29 (d, 2H, Ar-H), 7.52–
7.56 (d, 2H, Ar-H), 8.02 (s, 1H, Ar-H), 8.33 (s, 1H, C2H), 10.48 (br s,
2H, 2NH); 13C NMR (DMSO-d6): d 50.34, 55.96, 100.63, 104.06,
108.38, 111.02, 111.12, 126.54, 127.13, 128.17, 128.78, 130.43,
132.07, 137.58, 154.08, 155.15, 165.03. HRMS (+EI; mean value):
m/z found, 425.0372, calcd. C20H16BrN3O3 (+EI; mean value):
425.0375.
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5.12. (Z)-5-((1-Benzyl-5-methyl-1H-indol-3-yl)methylene)
imidazolidine-2,4-dione (3j)
10. Penthala, N. R.; Reddy, T. R. Y.; Parkin, S.; Crooks, P. A. Acta Crystallogr., Sect. E
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1H NMR (DMSO-d6): d 2.39 (s, 3H, CH3), 5.39 (s, 2H, CH2), 6.73 (s,
1H, CH), 7.00–7.03 (d, 1H, Ar-H), 7.28–7.30 (m, 4H, Ar-H), 7.41–
7.43 (d, 2H, Ar-H), 7.57 (s, 1H, Ar-H), 8.28 (s, 1H, C2H), 10.5 (br s,
2H, NH), 13C NMR (DMSO-d6): d 21.10, 49.77, 101.04, 107.59,
110.29, 117.85, 123.47, 123.93, 127.04, 127.38, 127.59, 128.39,
129.24, 129.91, 133.89, 137.34, 155.02, 165.03. HRMS (+EI; mean
value): m/z found, 331.1319, calcd. C20H17N3O2 (+EI; mean value)
331.1321.
14. Zrinka, R.; Branka, Z.; Silvana, R. M.; Katja, E.; Marijeta, K.; Kresimir, P.; Jan, B.;
Erik, D. C.; Mladen, M. Molecules 2006, 11, 837.
15. Ling, P.; Yun, Z.; De, Y. K.; Wei, D. Z., Phytother. Res. 2009, (published online).