Synthesis, structural investigations, and anti-cancer activity of new methyl indole-3-carboxylate derivatives

Article abstract of DOI:10.1016/j.molstruc.2012.05.031

Two new methyl indole-3-carboxylate derivatives: methyl 1-(3′-indolylmethane)-indole-3-carboxylate (1), and methyl 1-(1′-benzenosulfonyl-3′-indolylmethane)-indole-3-carboxylate (2) were synthesized. They are interesting as the analogs of 3,3′- diindolylmethane, which is intensively tested as a potent antitumor agent. Their solid-state structure was characterized using ¹³C CP/MAS NMR or X-ray diffraction measurements. Molecular modeling was used as a help in the structure elucidation. The solid-state NMR spectroscopy showed only one stable conformer of 1, but the X-ray diffraction results indicate that compound 2 crystallizes in the triclinic space group P-1 with two molecules, A and B, in the asymmetric unit. Both compounds inhibited the growth of melanoma, renal and breast cancers cell lines.

Full text of DOI:10.1016/j.molstruc.2012.05.031

Journal of Molecular Structure 1026 (2012) 30–35
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, structural investigations, and anti-cancer activity of new methyl
indole-3-carboxylate derivatives
b
a
Maria Niemyjska a, Dorota Maciejewska a, , Irena Wolska , Paweł Truszkowski
⇑
a Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Str., 02 097 Warsaw, Poland
b Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, 6 Grunwaldzka Str., 60 780 Poznan´, Poland
h i g h l i g h t s
"
"
"
"
Syntheses of two new bis-indoles were reported.
Solid-state structures were solved by X-ray or 13C CP/MAS NMR.
DFT computations were used to propose stable conformation in solid-state.
Both compounds inhibited human cancer cell lines.
a r t i c l e i n f o
a b s t r a c t
Two new methyl indole-3-carboxylate derivatives: methyl 1-(30-indolylmethane)-indole-3-carboxylate
(1), and methyl 1-(10-benzenosulfonyl-30-indolylmethane)-indole-3-carboxylate (2) were synthesized.
They are interesting as the analogs of 3,30-diindolylmethane, which is intensively tested as a potent anti-
tumor agent. Their solid-state structure was characterized using 13C CP/MAS NMR or X-ray diffraction
measurements. Molecular modeling was used as a help in the structure elucidation. The solid-state
NMR spectroscopy showed only one stable conformer of 1, but the X-ray diffraction results indicate that
compound 2 crystallizes in the triclinic space group Pꢀ1 with two molecules, A and B, in the asymmetric
unit. Both compounds inhibited the growth of melanoma, renal and breast cancers cell lines.
Ó 2012 Elsevier B.V. All rights reserved.
Article history:
Received 28 February 2012
Received in revised form 8 May 2012
Accepted 9 May 2012
Available online 26 May 2012
Keywords:
Bis-indoles
X-ray diffraction data
13C CP/MAS NMR
DFT calculations
Cytotoxicity
1. Introduction
observations suggest that synthetic analogs of DIM substituted at
indole nitrogen could also be more potent than DIM which is a very
The dietary plants such as cabbage, broccoli, cauliflower and
Brussels sprouts produce compounds that can be used as protective
agents against tumorigenesis in a variety of human cancers, includ-
ing breast cancer and prostate cancer [1–3]. Indole-3-carbinol and
its acid condensation product 3,30-diindolylmethane (DIM) are
among such compounds. Both compounds are intensively tested
in many bioassays [4–9] to elucidate their impact on signal
transduction, which leads to cell cycle arrest, apoptosis, down
regulation of cancer cell migration, modulation of expression of
the CDK inhibitor, p21Cip1/Waf1, and stimulation of mitochondrial
reactive oxygen species production. Although their activity is well
documented, several factors may limit their as chemotherapeutics
(due to low bioavailability and promoting of some cancer cells
proliferation) [10]. The substitution of indole nitrogen by alkoxy,
benzyl and toluenesulfonyl groups enhanced the potency of anti-
proliferative properties of indole-3-carbinol [11–13]. These
promising compound and can be used as the lead compound to de-
velop new chemotherapeutics with anti-cancer properties. All the
facts considered, two new bis-indoles were synthesized which have
a methylene linker between the N1 and C30 atoms (Scheme 1). In this
paper, as a part of systematic studies on the structural characteriza-
tion of bis-indoles [14–16], the synthesis and the spectroscopic
characterization of methyl 1-(30-indolylmethane)-indole-3-carbox-
ylate (1) and methyl 1-(10-benzenosulfonyl-30-indolylmethane)-in-
dole-3-carboxylate (2) were reported. The crystal structure of 2, and
the solid-state analysis of a powder sample of 1 using the 13C CP/
MAS NMR method and molecular modeling was also shown.
2. Experimental
2.1. Chemistry
⇑
The transformation of methyl 3-indolecarboxylate to bis-in-
doles 1 and 2 was made using 3-hydroxymethylindole (for 1) or
Corresponding author. Tel./fax: +48 22 5720643.
E-mail address: dorota.maciejewska@wum.edu.pl (D. Maciejewska).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.05.031

M. Niemyjska et al. / Journal of Molecular Structure 1026 (2012) 30–35
31
O
14
11
C
OCH3
4
7
9
8
3
5
6
2
N
1
10
4'
N H
HOH2C
5'
6'
9'
3'
KOH
toluene 110oC
2'
N
H
8'
7'
1'
H3CO
(1)
+
N H
C
O
O
O
N S
O
14
11
C
BrH
4
7
OCH3
2C
9
8
3
5
6
2
N
1
10
9'
4'
KOH
DMSO r.t.
5'
6'
3'
2'
N
8'
7'
1'
SO2
18
(2)
19
20
23
22
21
Scheme 1. Syntheses of methyl indole-3-carboxylate derivatives 1 and 2, their chemical formulas together with the atoms numbering.
1-benzenesulfonyl-3-bromomethylindole (for 2) as the substrates.
1-Benzenesulfonyl-3-bromomethylindole was synthesized from 1-
benzenesulfonyl-3-methylindole as was described earlier [17].
Alkylation of the indole ring at the N atom was reported with re-
agents such as alcohols in the Pd/Fe2O3 catalyzed system [18] or
with aldehydes in a benzoic acid catalyzed redox isomerization
[19]. The formation of N-alkylindoles was also shown for simple
alkylhalides [20]. N-alkylation of the indole moiety in our experi-
ments was performed by treating equimolar amounts of reagents
with sodium in toluene (for 1) or with potassium hydroxide in
dimethylsulfoxide (for 2) leading to the desired products with good
yields. To the best of our knowledge, this is the first report on the
1-(30-indolylmethane)-indoles. Indispensable chemicals were ob-
tained from major chemicals suppliers as high or highest purity
and were used without further purification. Melting points were
determined with an Electrothermal 9001 Digital Melting Point
Apparatus and are uncorrected. Elemental analyses were per-
formed on a C, H, N, S Elementar GmbH Vario EL III analyzer. IR
spectra were recorded on Schimazu FTIR-8300 in KBr tablets.
1535, 1482, 1461, 1446, 1338 (CAN) cmꢀ1 1H NMR (299.87 MHz,
.
DMSO) d = 3.772 (s, 3H, 10-H), 5.607 (s, 2H, 8-H), 6.988 (td,
J = 0.9 Hz, 1H, 50-H), 7.073 (td, J = 1.2 Hz, 1H, 60-H), 7.190 (td,
J1 = 7.0 Hz, J2 = 1.0 Hz, 1H, 5-H), 7.241 (td, J1 = 7.0 Hz, J2 = 2.0 Hz,
1H, 6-H), 7.367 (bd, J = 8.0 Hz, 1H, 70-H), 7.516 (bd, J = 8.0 Hz, 1H,
40-H), 7.594 (d, J = 2.4 Hz, 1H, 20-H), 7.796 (d, J = 2.0 Hz, 1H, 7-H),
7.969 (d, J = 8.1 Hz, 1H, 4-H), 8.203 (s, 1H, 2-H). 13C NMR
(75.41 MHz, DMSO): d = 41.78 (10-C), 50.62 (14-C), 105.17 (3-C),
109.51 (30-C), 111.39 (7-C), 111.71 (70-C), 118.27 (40-C), 119.03
(50-C), 120.63 (4-C), 121.42 (60-C), 121.51 (5-C), 122.30 (6-C),
125.56 (20-C), 126.19 (90-C), 126.30 (9-C), 134.93 (2-C), 136.25
(8-C), 136.31 (80-C), 164.43 (11-C) ppm. C19H16N2O2 (304.33): calcd.
C 74.98, H 5.30, N 9.21; found C 74.98, H 5.38, N 9.21.
2.1.2. Methyl 1-(10-benzenosulfonyl-30-indolylmethane)-indole-3-
carboxylate (2)
Methyl indole-3-carboxylate (0.50 g, 0.009 mol) was added to a
suspension of potassium hydroxide (0.50 g, 0.009 mol) in 15 ml
DMSO. The mixture was stirred at room temperature for 45 min
and then 1-benzenesulfonyl-3-bromomethylindole (1.05 g, 0.009
mol) dissolved in 8 ml DMSO was added dropwise. The stirring
was continued for 2 h. Then 100 ml of water was added. The ob-
tained beige solid was separated (0.96 g, 72.18%) and crystallized
from methanol; 0.58 g bright yellow product (43.61%) yield. M.p.
2.1.1. Methyl 1-(30-indolylmethane)-indole-3-carboxylate (1)
Methyl indole-3-carboxylate (1.75 g, 0.01 mol) was dissolved in
anhydrous toluene (80 ml) and 3-indolylmethanol (1.77 g, 0.12
mol) in 30 ml anhydrous toluene was added. Before addition of
(0.1 g, 0.0043 mol) sodium, 10 ml of the toluene/water azeotrope
was removed by distillation. The mixture was stirred at the solvent’s
boiling temperature for 10 h. To the obtained mixture 3 ml of meth-
anol was added, then 50 ml of water. The organic phase was
separated, washed in water and dried with MgSO4. The toluene
was evaporated in vacuo. The oily residue of the crude product
crystallized after several hours at 4 °C (1.58 g, 51.97%). The crude
precipitate was crystallized from ethanol/water (2:1); 0.52 g
175.7–176.2 °C. IR (KBr):
1533, 1490, 1465, 1446, 1362 (CAN) 1245, 1117 CAOAC, 1218,
1184 (SO2) cmꢀ1 1H NMR (299.87 MHz, DMSO) d = 3.791 (s,
m = 3150–3000, 3000–2800, 1692 (C@O),
.
3H,14-H), 5.638 (s, 2H, 10-H), 7.163–7.259 (m, 3H, 5-H, 50-H, 6-H),
7.308 (t, J = 8.0 Hz, 1H,60-H), 7.471 (d, J = 8.0 Hz, 1H, 40-H), 7.539
(t, J = 7.6 Hz, 2H, 20-H, 22-H), 7.660 (t, J = 7.6 Hz, 1H, 21-H), 7.715
(d, J = 8.0 Hz, 1H, 7-H), 7.907 (d, J = 8.0 Hz, 1H, 70-H), 7.933 (d,
J = 7.6 Hz, 2H, 19-H, 23-H), 7.967 (d, J = 8.0 Hz, 1H, 4-H), 8.133
(s, 1H, 2-H), 8.356 (s, 1H, 2-H). 13C NMR (75.40 MHz, DMSO):
d = 41.31 (10-C), 50.73 (14-C), 105.76 (3-C), 111.37 (7-C), 113.39
(17.10%) yield. M.p. 154.5–154.8 °C.-IR (KBr):
m = 3450–3150
(NAH associated), 3120–3000, 3000–2800, 1662 (C@O), 1610,

32
M. Niemyjska et al. / Journal of Molecular Structure 1026 (2012) 30–35
(70-C), 118.21(30-C), 119.88 (40-C), 120.71 (4-C), 121.70 (5-C), 122.55
(6-C), 123.70 (50-C), 125.22 (60-C), 126.22 (9-C), 126.48 (20-C),
126.58 (19-C, 23-C), 129.03 (90-C), 129.78 (20-C, 22-C), 134.61 (80-
C), 134.67 (21-C), 135.42 (2-C), 136.12 (8-C), 136.65 (18-C),
164.32 (11-C) ppm. C25H20N2O4S (444.43): calcd. C 67.56, H 4.54,
N 6.30, S 7.20; found C 67.54, H 4.52, N 6.30, S 7.05.
NMRS-300 spectrometer and standard Varian software was em-
ployed. Chemical shifts d (ppm) for 13C were referenced to TMS.
The optimized atom coordinates of 1 were used for computa-
tion of shielding constants
r
(ppm) of 13C atoms as a help in assign-
ment of resonances in the solid-state NMR spectrum, and
structural analysis. We employed the DFT method with B3LYP/6-
311(d,p) hybrid functional for structure optimization, and the
CPHF–GIAO approach for the NMR shielding constants computa-
tions using Gaussian 09 program [23].
2.2. Crystallography
Crystals of 2 suitable for X-ray analysis were grown by slow evap-
oration from methanol solution. Diffraction data were collected on a
KUMA-KM4CCD diffractometer with graphite-monochromated Mo
2.4. Cytotoxicity against human cancer cell lines
The in vitro cell line screening was carried out in The National
Institute of Health, Bethesda, USA as a part of the DTP anti-cancer
drug discovery program. The evaluation against 60 human tumor
cell lines including leukemia, melanoma, and non-small cell lung,
colon, CNC, ovarian, renal, prostate, breast cancers was made at a
Ka radiation at room temperature. The data were corrected for Lor-
entz-polarization effects as well as for absorption [21]. The unit cell
parameters were determined by least-squares treatment of setting
angles of highest-intensity reflections selected from the whole
experiment. The structure was solved by direct methods using
SHELXS-97 program and refined on F2 by the full-matrix least-
single dose of 10 lM. Detailed information about the methodology
and the screening services are available at the website http://
dtp.nci.nih.gov.
squares method with the SHELXL97 program [22]. The function
P
w(|Fo|2 ꢀ |Fc|2)2 was minimized with wꢀ1 = [
r
2(Fo)2 + (0.0475P)2
+ 0.4876P], where P ¼ ðF2o þ 2Fc2Þ=3. All non-hydrogen atoms were
refined anisotropically. The coordinates of the hydrogen atoms were
generated geometrically and refined ‘riding’ on their parent atoms
with Uiso set at 1.2 (1.5 for methyl group) times Ueq of the appropri-
ate carrier atom. All details concerning data collection, crystal data
and structure refinement are given in Table 1. The Supplementary
information in the CIF form is available from Cambridge Crystallo-
graphic Database Centre, No. CCDC 878579.
3. Results and discussion
3.1. X-ray analysis of 2
The molecular and crystal structure of methyl 1-(10-benze-
nosulfonyl-30-indolylmethane)-indole-3-carboxylate (2) in solid
2.3. 13C CP/MAS NMR and molecular modeling
The 13C CP/MAS NMR spectrum of 1 in solid state was recorded
with a Bruker Avance DMX 400. The acquisition conditions for 13
C
CP/MAS NMR at 100.62 MHz were: pulse duration, 4.5 ls; contact
time, 4 ms; repetition time, 20 s; spectral width, 24 kHz; number
of transients, 1000; spinning speed, 8 kHz. 1H and 13C NMR, HSQC
and HMBC spectra in solution were recorded at 25 °C with a Varian
Table 1
Crystal data, data collection and structure refinement for compound 2.
Fig. 1. The displacement ellipsoid representation of the molecule B of 2.
Compound
2
Empirical formula
Formula weight
T (K)
C
25H20N2O4S
444.49
293(2)
Table 2
Wavelength (Å)
Crystal system, space group
Unit cell dimensions
a (Å)
b (Å)
c (Å)
0.71073
Triclinic, Pꢀ1
Selected bond lengths (Å) and angles (°) and torsional angles (°) for 2.
2A
2B
11.2632(7)
12.4373(8)
16.5899(7)
80.409(4)
83.086(4)
69.724(6)
2144.6(2)
4, 1.377
0.187
928
4.10–25.35
ꢀ13 ꢁ h ꢁ 9
ꢀ14 ꢁ k ꢁ 14
ꢀ19 ꢁ l ꢁ 19
N1AC2
N10AC20
N1AC8
N10AC80
C2AC3
1.349(3)
1.398(3)
1.387(2)
1.417(3)
1.365(3)
1.338(3)
1.405(3)
1.394(3)
1.461(3)
1.655(2)
1.358(3)
1.400(3)
1.387(3)
1.405(3)
1.368(3)
1.339(3)
1.411(3)
1.403(3)
1.462(3)
1.672(2)
a
(°)
b (°)
c
(°)
C20AC30
C8AC9
Volume (Å3)
Z, Dx (Mg/m3)
C80AC90
N1AC10
N10AS15
l
(mmꢀ1
)
F(000)
h range for data collection (°)
hkl range
C8AN1AC10
N1AC8AC7
N1AC10AC30
C80AN10AS15
N10AS15AC18
126.0(2)
126.0(2)
130.0(2)
113.1(2)
126.2(2)
106.7(1)
130.0(2)
113.0(2)
124.7(1)
103.9(1)
Reflections
Collected
13,645
C20AN10AS15AC18
N10AS15AC18AC19
N1AC10AC30AC20
C70AC80AN10AS15
C2AC3AC11AO12
C2AC3AC11AO13
C3AC11AO13AC14
ꢀ75.7(2)
ꢀ97.5(2)
111.3(2)
26.3(3)
92.2(2)
99.2(2)
115.5(2)
ꢀ21.8(3)
3.7(4)
Unique (Rint
Observed (I > 2
)
7806 (0.020)
5600
7806/0/577
1.032
0.0462
0.1176
r
(I))
Data/restraints/parameters
Goodness-of-fit on F2
R(F) (I > 2(I))
ꢀ3.3(4)
wR(F2) (all data)
177.1(2)
ꢀ179.5(2)
ꢀ174.8(2)
Max./min.
D
q
(e/Å3)
0.238/ꢀ0.351
178.8(2)

M. Niemyjska et al. / Journal of Molecular Structure 1026 (2012) 30–35
33
Fig. 2. The arrangement of particular fragments of the molecules A and B together with the numbering of atoms essential for the conformational analysis.
state were analyzed by single crystal X-ray diffraction. The results
indicate that the compound crystallizes in the triclinic Pꢀ1 space
group with two independent molecules, A and B, in the asymmetric
unit cell. The atomic numbering scheme, for a clarity only for mol-
ecule B, is shown in Fig. 1 (the drawings were performed with The
Mercury Program [24]). The structure consists of two indole rings
with the methylene group joined N1 and C30 atoms, benzenosulfo-
nyl substituent at N10 and methylester at C3. Selected bond lengths,
bond angles and torsion angles are listed in Table 2. As we can see
only the N10AAS15A and N10BAS15B bond lengths vary slightly,
but some torsion angles reveal important dissimilarities. In conse-
quence, in the molecules A and B the principal differences lie in
the steric arrangement of the indole system N10ꢂ ꢂ ꢂC90 and the ben-
zenosulfonyl group (Fig. 2). Different arrangement of these frag-
ments can be described by the torsion angle C20AN10AS15AC18 as
well as N10AS15AC18AC19 (Table 2). The indole frameworks are
essentially planar and their planes make an angle of 74.78(4)° and
82.17(4)° in A and B, respectively. The orientation the ester group
at C3 with respect to the indole (N1ꢂ ꢂ ꢂC9) part can be described
by the appropriate torsion angles (Table 2). In the crystals, intermo-
lecular CAHꢂ ꢂ ꢂO and CAHꢂ ꢂ ꢂN hydrogen bonds were found to be
the main force which determines the crystal packing of molecules.
The geometric parameters of all these bonds are given in Table 3.
The packing arrangement is shown in Fig. 3. The crystal structure
is built of layers of the molecules A (red) and B (blue1), alternately,
parallel to (010) plane. Within the layers the molecules are con-
nected via C5ꢂ ꢂ ꢂO17, C6ꢂ ꢂ ꢂO16, C60ꢂ ꢂ ꢂO12 hydrogen bonds for A
and C2ꢂ ꢂ ꢂ O12, C20ꢂ ꢂ ꢂN1 for B. Then the layers interact via C20
Bꢂ ꢂ ꢂO12A, C2Aꢂ ꢂ ꢂO16B contacts and van der Waals interactions.
Table 3
Hydrogen bonding geometry (Å and °) for 2.
DAHꢂ ꢂ ꢂA
d(DAH)
d(Hꢂ ꢂ ꢂA)
2.72
2.61
2.48
d(Dꢂ ꢂ ꢂA)
3.634(3)
3.426(3)
3.398(3)
<(DHA)
C5AAH5Aꢂ ꢂ ꢂO17Ai
C6AAH6Aꢂ ꢂ ꢂO16Aii
C60AAH60Aꢂ ꢂ ꢂO12Aiii
0.93
0.93
0.93
169
146
170
C20BAH20Bꢂ ꢂ ꢂN1Bi
0.93
0.93
2.69
2.53
3.576(3)
3.310(3)
160
142
C2BAH2Bꢂ ꢂ ꢂO12Biv
C2AAH2Aꢂ ꢂ ꢂ16Biii
0.93
0.93
2.37
2.30
3.269(3)
3.170(3)
163
155
C20BAH20Bꢂ ꢂ ꢂO12Aiii
Symmetry codes: (i) ꢀx + 2, ꢀy, ꢀz; (ii) x, y + 1, z; (iii) x, y ꢀ 1, z; (iv) x ꢀ 1, y, z; (v)
ꢀx, ꢀy, ꢀz + 1.
solid state. It is unlike the single-crystal structure of 2 in which two
independent molecules, A and B, in the asymmetric unit cell are
detected (see Section 3.1). To propose the solid-state structure of
1 we have analyzed two conformations of 1, named 1a and 1b
(see Fig. 5,Tables 1S and 2S in Supplement) which differ in the tor-
sion angle C1AC10AC30AC90 (ꢀ61.4° and 71.5° for 1a and 1b,
respectively). Geometry calculations were made at DFT level with
B3LYP/6-311(d,p) hybrid functional. We found that both conforma-
tions are almost energetically equivalent. The conformation 1b is
slightly preferred by 2.5 kJ/mol but this difference could not be
decisive for the preferred structure in the solid state where the
intermolecular interactions play a significant role. Thus, we com-
puted the NMR shielding constants
nates corresponding to both conformations, and compared them
r (ppm) for the atomic coordi-
with the experimental chemical shifts d (ppm). Next, we analyzed
the correlation coefficients R2 for the linear function d = f(
r) calcu-
lated for both conformers (see Fig. 1S in Supplement). On the basis
of the higher correlation coefficient (R2 = 0.996) and by comparison
with the conformation of 2, we propose the structure of 1a as
favored in the solid state. The packing mode of molecules is stabi-
lized by quite strong intermolecular hydrogen bonds, which shifts
(as compared with the solution spectrum) downfield the resonance
3.2. Solid-state structure of 1 based on 13C CP/MAS NMR spectrum
So far, it was impossible to obtain single crystals of 1 suitable
for X-ray diffraction measurements. To analyze the solid-state
structure of 1, we decided to employ the 13C CP/MAS NMR method
for the analysis of a powder sample of 1. Solid-state NMR spectros-
copy is broadly used to characterize pharmaceutical solids and
compounds which are produced during the drug development pro-
cess. The correlation between the 13C experimental resonances and
the theoretical values of the shielding constants obtained for the
corresponding structure pointed to the stable conformation
present in the solid state [25]. The solid-state 13C CP/MAS NMR
spectrum of 1 is shown in Fig. 4. We have observed the peak mul-
tiplicity of resonances in agreement with the solution-like spec-
trum which means that only a single structure is detected in the
of C11 carbonyl atom (
upfield the resonances of C5 and C2 atoms (
ꢀ0.9 ppm, respectively). The ester group is located in the plane
of the indole ring which is characterized by the C9AC3AC11AO12
torsion angle equal to 179.9°, and downfield shift of C4 atom reso-
nance by 2.2 ppm.
D
d = 2.6 ppm), and simultaneously shifts
d = ꢀ0.6 and
D
3.3. Cytotoxicity in preliminary anti-cancer assay
Compounds 1 and 2 were accepted for evaluation in the DTP
anti-cancer drug discovery program (National Cancer Institute,
Bethesda, USA) in a 60-cell line panel. Detailed information is
1
For interpretation of color in Figs. 1–3 and 5, the reader is referred to the web
version of this article.

34
M. Niemyjska et al. / Journal of Molecular Structure 1026 (2012) 30–35
Fig. 3. Projection of the crystal structure of 2 along the a axis with layers of the molecules A (red) and B (blue), alternately.
Fig. 4. 13C CP/MAS NMR spectrum of 1 in solid state. Sidebands are marked with an asterisk.
available at the website http://dtp.nci.nih.gov. Full results are
shown in Figs. 2S and 3S in the Supplement.
Both compounds inhibited the growth of the treated cells as
compared with the untreated control cells of melanoma, renal

M. Niemyjska et al. / Journal of Molecular Structure 1026 (2012) 30–35
35
Single resonances in the 13C CP/MAS NMR spectrum of 1 indi-
cate that only one conformer is present in the solid state. The pack-
ing mode of molecules is stabilized by quite strong intermolecular
hydrogen bonds between C11AO and C5AH or C2AH groups.
Acknowledgments
The theoretical results presented in this work were obtained
using the resources of Interdisciplinary Center for Mathematical
and Computational Modeling (ICM) Warsaw University.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2012.
05.031.
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Two new bis-indoles methyl 1-(30-indolylmethane)-indole-3-
carboxylate (1) and methyl 1-(10-benzenosulfonyl-30-indolylme-
thane)-indole-3-carboxylate (2) were synthesized in sufficient
yields. Both compounds inhibited the growth of melanoma, renal
and breast cancers cell lines at a dose of 10 lM. Substitution of N
atom by the benzenesulfonyl group gave a compound that was
more potent relative to the unsubstituted analog.
Their solid-state conformations were successfully established.
The X-ray diffraction studies showed that compound 2 crystallizes
in the triclinic space group Pꢀ1 with two independent molecules, A
and B, in the asymmetric unit cell. The principal differences in the
molecules A and B were found to lie in the steric arrangement of
the indole system N10ꢂ ꢂ ꢂC90 and the benzenosulfonyl group. The
three-dimensional supramolecular structure results from the com-
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